This report was reviewed for medical and scientific accuracy by David A. Laskow, MD, Chief, Kidney/Pancreas Transplant Service, Associate Professor of Surgery, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

The incidence of atherosclerotic cardiovascular disease is higher in patients with chronic kidney disease compared to the general population and results in significant morbidity and mortality.¹ Between 1997 and 1999, it was estimated that 41% of deaths among patients with chronic kidney disease (treated with hemodialysis, peritoneal dialysis or kidney transplantation) were due to coronary heart disease with another 6% to cerebrovascular disease.² Similarly, the prevalence of cardiovascular disease in renal transplant recipients is significantly higher than the general population and also results in significant morbidity and mortality.¹ Indeed, cardiovascular disease is the leading cause of death among renal transplant recipients with a functioning graft.³ More specifically, among renal transplant recipients with functioning grafts, 13% of deaths are attributable to myocardial infarction, 7.4% to cerebrovascular disease, and 25.3% to other cardiovascular causes. Recently, literature examining the relationship between renal function and cardiovascular disease demonstrated the importance of even minor alterations in renal function as it related to cardiovascular death.⁴ Therefore, reducing the risk of atherosclerotic cardiovascular disease among patients with chronic kidney disease and renal transplant recipients is an important clinical goal.

Epidemiology of Cardiovascular Disease in the Renal Patient

It is likely that, as in the general population, dyslipidemias play a major role in the development of atherosclerotic cardiovascular disease in patients with chronic kidney disease, including those who have undergone renal transplant surgery.⁵ Whereas no well-designed, prospective clinical trials have evaluated the relationship between dyslipidemias and atherosclerotic cardiovascular disease in these populations, results of several observational studies suggest that such a relationship exists. In one such study, the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) in patients with Stage 5 chronic kidney disease was independently associated with lower total mortality (relative risk 0.68, 95% Confidence Interval (CI), 0.54-0.87) and cardiovascular mortality (relative risk 0.64, 95% CI, 0.45-0.91).⁶ In the renal transplant population, associations between elevated total cholesterol,^7-9 low levels of high-density lipoprotein (HDL)-cholesterol,^10,11 and high levels of triglycerides^8,12 and atherosclerotic cardiovascular disease have been reported. Moreover, renal transplant recipients may also have non-traditional lipoprotein abnormalities that could theoretically contribute to atherosclerotic cardiovascular disease.^13-15 However, the role of these lipoprotein abnormalities in the pathogenesis of atherosclerotic cardiovascular disease in chronic kidney disease is unclear.

Additional cardiovascular risks have been described in the chronic kidney disease and renal transplant populations; however, less is known about these risks and their relative contribution to overall cardiovascular morbidity and mortality.¹⁶ Among renal transplant recipients, associations between diabetes, age at transplant, obesity, smoking, hyperuricemia, pre-transplantation vascular disease, number of previous acute rejection episodes, elevated hematocrit, with hypertension and atherosclerotic cardiovascular disease have been reported.

Dyslipidemias Among Renal Transplant Recipients

Dyslipidemias are common in the renal transplant population particularly in transplant recipients with underlying diabetes, the single leading cause of end-stage renal disease.¹⁷ In the face of hyperlipidemia, the impact of an episode of acute rejection is more severe than in transplant recipients with normal lipid profiles.¹⁸ In clinical studies of at least one-year duration, frequently reported abnormalities include elevated total cholesterol (estimates range from 23%¹⁹ to 90%²⁰ of patients), low-density lipoprotein (LDL)-cholesterol (present in 81%²¹ to 97%²⁰), and triglycerides (prevalence not known). HDL-cholesterol usually remains within normal limits. These changes in lipid levels likely result from a combination of patient, disease, and treatment-related factors, including the transplant procedure, graft function, acute rejection, and immunosuppressant therapy. For this reason, the American Society of Transplantation currently recommends lipid measurement during the first six months post-transplant, one year post-transplant, and annually thereafter.²² These measurements should detect any changes in the lipid profile that result from the procedure, changes in graft function, and/or immunosuppressive therapies.

Management of Cardiovascular Risk Factors in Renal Disease

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF K/DOQI) Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease⁵ closely resemble the cholesterol management guidelines recommended for the general population [National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treat-ment Panel III)²³]. Therapeutic lifestyle changes (diet, weight reduction, increased physical activity, abstinence from alcohol, and treatment of hyperglycemia [if present]) are generally recommended as initial treatment options either alone (in patients with LDL-cholesterol 100-129 mg/dL, target <100 mg/dL) or in combination with lipid-lowering therapies (in patients with LDL-cholesterol≥130 mg/dL or triglycerides≥500 mg/dL, targets <100 mg/dL and <500 mg/dL, respectively).⁵

For kidney transplant recipients with LDL-cholesterol≥100 mg/dL, despite maximal medical management, consideration should be given to changing the immunosuppressive protocol to one that is less likely to exacerbate high LDL-cholesterol levels without causing undue risk to the allograft. Management strategies include: (1) tapering and discontinuing prednisone,^24-27 with or without adding or increasing the dose of azathioprine or mycophenolate mofetil; (2) replacing cyclosporine with tacrolimus^28-30; (3) tapering and discontinuing cyclosporine,³⁰ with or without adding or increasing the dose of azathioprine or mycophenolate mofetil; or (4) discontinuing or replacing sirolimus with an alternative immunosuppressive agent.^31,32 Evidence suggests that these management strategies may reduce the prevalence and severity of dyslipidemias and other atherosclerotic risk factors such as hypertension and glucose intolerance.

Additional recommendations include the treatment of proteinuria (using angiotensin II converting enzyme inhibitors, angiotensin II receptor antagonists, and/or low-protein diets) and optimization of immunosuppressive therapies (elimination of dyslipidemia-inducing immunosuppressive agents) to reduce cardiovascular risk.⁵

Minimizing Cardiovascular Risks Associated with Immunosuppression

Available immunosuppressive therapies have varied effects on cardiovascular disease risk factors, including dyslipidemias, hypertension, and diabetes (Table 1). Optimal regimens should minimize these drug-related cardiovascular risks.

Dyslipidemia

Renal transplant patients who fail to respond to traditional medical management of abnormal lipid levels should be evaluated for potential modification of immunosuppressive therapy. In such patients, clinicians should consider eliminating immunosuppressive agents known to adversely affect lipoprotein levels and replacing them with agents that are less likely to cause unfavorable lipid effects. Agents known to adversely affect lipoprotein levels include prednisone, cyclosporine, and sirolimus. In most cases, drugs that do not or minimally influence lipid levels (eg, azathioprine, mycophenolate mofetil, and tacrolimus) can be used instead. For example, the results of one short-term (12-week) study suggest that switching therapies can quickly improve lipid levels in stabilized renal transplant recipients.³³ In this study, switching from cyclosporine to tacrolimus therapy (titrated to trough concentrations of 5 to 15 ng/mL) for 4 weeks resulted in significant reductions in total cholesterol (from 236 mg/dL to 197 mg/dL; P<.001) and LDL-cholesterol (from 148 mg/dL to 115 mg/dL; P<.001) to within the ranges recommended by the NKF K/DOQI guidelines (Figure 1). When switched back to cyclosporine therapy for 4 additional weeks, lipoprotein levels returned to pre-tacrolimus levels.

Hypertension

Effects on blood pressure should also be considered. In the 12-week study described above, switching from cyclosporine to tacrolimus therapy for 4 weeks resulted in significant reductions in mean daytime (from 149/95 mm Hg to 138/87 mm Hg; P<.001) and nighttime (from 140/86 mm Hg to 132/79 mm Hg; P<.05) blood pressures.³³ These beneficial blood pressure changes were reversed upon return to cyclosporine therapy. It was postulated that the beneficial effect of tacrolimus on blood pressure was the result of reduced peripheral vascular resistance. Mange et al identified hypertension as an independent risk factor for graft failure,³⁴ and more recently indicated a curvilinear association between systolic blood pressure and renal allograft survival.³⁵ Long-term studies are needed to evaluate the impact of blood pressure reduction and cardiovascular morbidity and mortality in this population.

Diabetes

Diabetes is reportedly an independent risk factor for atherosclerotic cardiovascular disease.³⁶ Many patients with chronic kidney disease have pre-existing diabetes. Commonly utilized drug therapies can worsen diabetes in some of these patients and cause glucose abnormalities in patients with no pre-existing disease. In a large observational study (N = 11,659 first kidney transplant recipients), tacrolimus therapy was associated with an increased risk of post-transplant diabetes mellitus (relative risk vs no tacrolimus therapy, 1.53; 95% CI, 1.29-1.81; P<.0001).³⁷ However, in the same study, tacrolimus was associated with reduced risk of graft failure (relative risk, 0.70; 95% CI, 0.59-0.83; P<.0001) and death (relative risk, 0.65; 95% CI, 0.50-0.84; P<.001). Multiple recent prospective, multicenter trials and a systematic review³⁸ have demonstrated the current incidence of post-transplant diabetes mellitus is not significantly different when either tacrolimus or cyclosporine is used in renal transplant recipients.^28,39,40 Therefore, immunosuppression-related post-transplant diabetes mellitus risks must be evaluated in light of overall patient and graft outcomes.

Concomitant Statin and Immunosuppressive Therapies

While statins are recommended for the treatment of certain dyslipidemias in patients with chronic kidney disease and renal transplant recipients, safe administration requires cognizance of the effects of renal function and concomitant medications on statin blood levels and risk of myopathy. Few data are available to guide statin therapy in these populations. It is recommended that doses of lovastatin, fluvastatin, and simvastatin be reduced 50% in patients with Stage 4 or 5 chronic kidney disease (glomerular filtration rate <30 mL/min/1.73m²), as drug levels may be increased by poor renal function.⁵ Statin dose reductions are also recommended for patients receiving cyclosporine or tacrolimus. Cyclosporine increases blood levels of all statins (Table 2). Few studies have evaluated the effects of tacrolimus on statin drug levels. For this reason, dose reductions are generally recommended when statins are used with either of these immunosuppressive agents.

Conclusion

Atherosclerotic cardiovascular disease is associated with significant morbidity and mortality among patients with chronic kidney disease and renal transplant recipients. Dyslipidemias likely contribute to the development of atherosclerotic cardiovascular disease in these populations. For this reason, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative recently published guidelines for managing dyslipidemias in chronic kidney disease, including patients who have undergone renal transplantation. Therapeutic lifestyle changes and lipid-lowering therapies form the basis of these recommendations. Additional strategies to minimize factors that may exacerbate dyslipidemias are also suggested, including the correction of proteinuria and optimization of immunosuppressive therapies.

References

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Disclosure
David A. Laskow, MD
Grant/Research Support-Fujisawa Healthcare, Inc., Novartis; Speakers Bureau-Fujisawa Healthcare, Inc., Roche

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Fujisawa Healthcare, Inc.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with the recommendation of other authorities. This Transplantation Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Transplantation Express Report™ was made possible through an educational grant from Fujisawa Healthcare, Inc.

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