Cardiovascular Disease after Renal Transplantation
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
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 triglycerides8,12 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 tacrolimus28-30; (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.
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.
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 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.
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.
1. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis. 1998;32:853-906.
2. United States Renal Data System. USRDS 2000 Annual Data Report: Atlas of End-stage Renal Disease in the United States (ed 12th Annual Report), Division of Kidney, Urologic, and Hematological Diseases, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD, 2000.
3. United States Renal Data System. USRDS 1999 Annual Data Report: Atlas of End-Stage Renal Disease in the United States (ed 11th Annual Report), Division of Kidney, Urologic, and Hematological Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 1999.
4. Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation. 2003;75:1291-1295.
5. K/DOQI clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J Kid Dis. 2003;41(suppl 3):S1-S77.
6. Seliger SL, Weiss NS, Gillen DL, et al. HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int. 2002;61:297-304.
7. Aker S, Ivens K, Grabensee B, Heering P. Cardiovascular risk factors and diseases after renal transplantation. Int Urol Nephrol. 1998;30:777-788.
8. Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol. 2000;11:1735-1743.
9. Ong CS, Pollock CA, Caterson RJ, Mahony JF, Waugh DA, Ibels LS. Hyperlipidemia in renal transplant recipients: natural history and response to treatment. Medicine. 1994;73:215-223.
10. Barbagallo CM, Pinto A, Gallo S, et al. Carotid atherosclerosis in renal transplant recipients: relationships with cardiovascular risk factors and plasma lipoproteins. Transplantation. 1999;67:366-371.
11. Massy ZA, Mamzer-Bruneel MF, Chevalier A, et al. Carotid atherosclerosis in renal transplant recipients. Nephrol Dial Transplant. 1998;13:1792-1798.
12. Kasiske BL, Guijarro C, Massey ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal transplantation. J Am Soc Nephrol. 1996;7:158-165.
13. Ghanem H, van den Dorpel MA, Weimar W, Man in't Veld AJ, El-kannishy MH, Jansen H. Increased low density lipoprotein oxidation in stable kidney transplant recipients. Kidney Int. 1996;49:488-493.
14. van den Dorpel MA, Ghanem H, Rischen-Vos J, Man in't Veld AJ, Jansen H, Weimar W. Conversion from cyclosporine A to azathioprine treatment improves LDL oxidation in kidney transplant recipients. Kidney Int. 1997;51:1608-1612.
15. Quaschning T, Mainka T, Nauck M, Rump LC, Wanner C, Kramer-Guth A. Immunosuppression enhances atherogenicity of lipid profile after transplantation. Kidney Int. 1999;71(suppl):S235-S237.
16. Kasiske BL, Ballantyne CM. Cardiovascular risk factors associated with immunosuppression in renal transplantation. Transplant Reviews. 2002;16:1-21.
17. Standards of medical care for patients with diabetes mellitus. American Diabetes Association. Diabetes Care. 2003;26(Suppl 1):S33-S50.
18. Wissing KM, Abramowicz D, Broders N, Vereerstraeten P. Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection. Transplantation. 2000;70:464-472.
19. Shoji T, Nishizawa Y, Kawagishi T, et al. Intermediate-density lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol. 1998;9:1277-1284.
20. Moore R, Thomas D, Morgan E, et al. Abnormal lipid and lipoprotein profiles following renal transplantation. Transplant Proc. 1993;25:1060-1061.
21. Hernandez E, Praga M, Alamo C, et al. Lipoprotein(a) and vascular access survival in patients on chronic hemodialysis. Nephron. 1996;72:145-149.
22. Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol. 2000;11(suppl 15):S1-S86.
23. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
24. Vanrenterghem Y, Lebranchu Y, Hene R, Oppenheimer F, Ekberg H. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation. 2000;70:1352-1359.
25. Hollander AA, Hene RJ, Hermans J, van Es LA, van der Woude FJ. Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol. 1997;8:294-301.
26. Kupin W, Venkat KK, Oh HK, Dienst S. Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients. Transplantation. 1988;45:53-55.
27. Ingulli E, Tejani A, Markell M. The beneficial effects of steroid withdrawal on blood pressure and lipid profile in children posttransplantation in the cyclosporine era. Transplantation. 1993;55:1029-1033.
28. Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation. 2000;69:834-841.
29. McCune TR, Thacker LR II, Peters TG, et al. Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study. Transplantation. 1998;65:87-92.
30. Hilbrands LB, Demacker PN, Hoitsma AJ, Stalenhoef AF, Koene RA. The effects of cyclosporine and prednisone on serum lipid and (apo)lipoprotein levels in renal transplant recipients. J Am Soc Nephrol. 1995;5:2073-2081.
31. Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation. 1999;67:1036-1042.
32. Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of sirolimus on the metabolism of apoB100-containing lipoproteins in renal transplant patients. Transplantation. 2001;72:1244-1250.
33. Ligtenberg G, Henй RJ, Blankestijn PJ, Koomans HA. Cardiovascular risk factors in renal transplant patients: cyclosporin A versus tacrolimus. J Am Soc Nephrol. 2001;12:368-373.
34. Mange KC, Cizman B, Joffe M, Feldman HI. Arterial hypertension and renal allograft survival. JAMA. 2000;283:633-638.
35. Mange KC, Feldman HI, Joffe MM, Fa K, Bloom RD. Curvilinear relationship of blood pressure and survival of renal allografts from living donors. Am J Transplant. 2003;3(suppl 5):238. Abstract 336.
36. Kasiske B, Ballantyne CM. Cardiovascular risk factors associated with immunosuppression in renal transplantation. Transplant Reviews. 2002;16:1-21.
37. Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant. 2003;3:178-185.
38. Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC. Posttransplantation diabetes. Diabetes Care. 2002;25:583-592.
39. Trompeter R, Filler G, Webb NJ, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol. 2002;17:141-149.
40. Margreiter R for the European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Lancet. 2002;359:741-746.
41. Asberg A, Hartmann A, Fjeldsa E, Bergan S, Holdaas H. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Am J Transplant. 2001;1:382-386.
42. Mьck W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther. 1999;65:251-261.
43. Arnadottir M, Eriksson LO, Thysell H, Karkas JD. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron. 1993;65:410-413.
44. Ichimaru M, Takahara S, Kokado Y, et al. Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis. 2001;158:417-423.
45. Velosa JA, LaBelle P, Ronca PD, et al. Pharmacokinetics of lovastatin in renal transplant recipients on azathioprine or cyclosporine. J Am Soc Nephrol. 1990;1:325. Abstract.
46. Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther. 1997;62:311-321.
47. Goldberg R, Roth D. Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. Transplantation. 1996;62:1559-1564.
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