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Chronic Renal Insufficiency in Heart Transplant Recipients: Risk Factors and Management Options

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Abstract

Renal dysfunction after heart transplantation is a frequently observed complication, in some cases resulting in significant limitation of quality of life and reduced survival. Since the pathophysiology of renal failure (RF) is multifactorial, the current etiologic paradigm for chronic kidney disease after heart transplantation relies on the concept of calcineurin inhibitor (CNI)-related nephrotoxicity acting on a predisposed recipient. Until recently, the management of RF has been restricted to the minimization of CNI dosage and general avoidance of classic nephrotoxic risk factors, with somewhat limited success. The recent introduction of proliferation signal inhibitors (PSIs) (sirolimus and everolimus), a new class of immunosuppressive drugs lacking intrinsic nephrotoxicity, has provided a completely new alternative in this clinical setting. As clinical experience with these new drugs increases, new renal-sparing strategies are becoming available. PSIs can be used in combination with reduced doses of CNIs and even in complete CNI-free protocols. Different strategies have been devised, including de novo use to avoid acute renal toxicity in high-risk patients immediately after transplantation, or more delayed introduction in those patients developing chronic RF after prolonged CNI exposure. In this review, the main information on the clinical relevance and pathophysiology of RF after heart transplantation, as well as the currently available experience with renal-sparing immunosuppressive regimens, particularly focused on the use of PSIs, is reviewed and summarized, including the key practical points for their appropriate clinical usage.

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References

  1. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349(10):931–40.

    CAS  PubMed  Google Scholar 

  2. Stehlik J, Edwards LB, Kucheryavaya AY, et al. International Society of Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report—2012. J Heart Lung Transplant. 2012;31(10):1052–64.

    PubMed  Google Scholar 

  3. Crespo-Leiro MG, Delgado JF, Paniagua MJ, et al. Prevalence and severity of renal dysfunction among 1062 heart transplant patients according to criteria based on serum creatinine and estimated glomerular filtration rate: results from the CAPRI study. Clin Transplant. 2010;24(4):E88–93.

    PubMed  Google Scholar 

  4. Delgado JF, Crespo-Leiro MG, Gómez-Sánchez MA, et al. Risk factors associated with moderate-to-severe renal dysfunction among heart transplant patients: results from the CAPRI study. Clin Transplant. 2010;24(5):E194–200.

    PubMed  Google Scholar 

  5. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: thirtieth official adult heart transplant report—2013; focus theme: age. J Heart Lung Transplant. 2013;32(10):951–64.

    PubMed  Google Scholar 

  6. Alam A, Badovinac K, Ivis F, et al. The outcome of heart transplant recipients following the development of end-stage renal disease: analysis of the Canadian Organ Replacement Register (CORR). Am J Transplant. 2007;7(2):461–5.

    CAS  PubMed  Google Scholar 

  7. Villar E, Boissonnat P, Sebbag L, et al. Poor prognosis of heart transplant patients with end-stage renal failure. Nephrol Dial Transplant. 2007;22(5):1383–9.

    PubMed  Google Scholar 

  8. Lonze BE, Warren DS, Stewart ZA, et al. Kidney transplantation in previous heart or lung recipients. Am J Transplant. 2009;9(3):578–85.

    CAS  PubMed  Google Scholar 

  9. Greenberg A, Thompson ME, Griffith BJ, Hardesty RL, Kormos RL, el-Shahawy MA, Janosky JE, Puschett JB. Cyclosporine nephrotoxicity in cardiac allograft patients—a seven-year follow-up. Transplantation. 1990;50(4):589–93.

    CAS  PubMed  Google Scholar 

  10. Arora S, Andreassen A, Simonsen S, et al. Prognostic importance of renal function 1 year after heart transplantation for all-cause and cardiac mortality and development of allograft vasculopathy. Transplantation. 2007;84(2):149–54.

    PubMed  Google Scholar 

  11. Kobashigawa JA, Starling RC, Mehra MR, et al. Multicenter retrospective analysis of cardiovascular risk factors affecting long-term outcome of de novo cardiac transplant recipients. J Heart Lung Transplant. 2006;25(9):1063–9.

    PubMed  Google Scholar 

  12. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for the development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108(17):2154–69.

    PubMed  Google Scholar 

  13. Myers BD, Newton L. Cyclosporine-induced chronic nephropathy: an obliterative microvascular renal injury. J Am Soc Nephrol. 1991;2(2 Suppl 1):S45–52.

    CAS  PubMed  Google Scholar 

  14. Lewis RM, Van Buren CT, Radovancevic B, et al. Impact of long-term cyclosporine immunosuppressive therapy on native kidneys versus renal allografts: serial renal function in heart and kidney transplant recipients. J Heart Lung Transplant. 1991;10(1 Pt 1):63–70.

    CAS  PubMed  Google Scholar 

  15. Gonwa TA, Mai ML, Pilcher J, et al. Stability of long-term renal function in heart transplant patients treated with induction therapy and low-dose cyclosporine. J Heart Lung Transplant. 1992;11(5):926–8.

    CAS  PubMed  Google Scholar 

  16. Zietse R, Balk AH, vd Dorpel MA, et al. Time course of the decline in renal function in cyclosporine-treated heart transplant recipients. Am J Nephrol. 1994;14(1):1–5.

    CAS  PubMed  Google Scholar 

  17. Tinawi M, Miller L, Bastani B. Renal function in cardiac transplant recipients: retrospective analysis of 133 consecutive patients in a single center. Clin Transplant. 1997;11(1):1–8.

    CAS  PubMed  Google Scholar 

  18. Goral S, Ynares C, Shyr Y, et al. Long-term renal function in heart transplant recipients receiving cyclosporine therapy. J Heart Lung Transplant. 1997;16(11):1106–12.

    CAS  PubMed  Google Scholar 

  19. Lindelöw B, Bergh C-H, Herlitz H, et al. Predictors and evolution of renal function during 9 years following heart transplantation. J Am Soc Nephrol. 2000;11(5):951–7.

    PubMed  Google Scholar 

  20. Al Aly Z, Abbas S, Moore E, et al. The natural history of renal function following orthotopic heart transplant. Clin Transplant. 2005;19(5):683–9.

    PubMed  Google Scholar 

  21. González-Vílchez F, Arizón JM, Segovia J, et al. ICEBERG Study Group. Chronic renal dysfunction in maintenance heart transplant patients: the ICEBERG study. Transplant Proc. 2014;46(1):14–20.

    PubMed  Google Scholar 

  22. Hamour IM, Omar F, Lyster HS, et al. Chronic kidney disease after heart transplantation. Nephrol Dial Transplant. 2009;24(5):1655–62.

    PubMed  Google Scholar 

  23. Navarro-Manchón J, Martínez-Dolz L, Almenar L, et al. Prognostic value of glomerular filtration rate 1 year after heart transplantation. Rev Esp Cardiol. 2010;63(5):564–70.

    Google Scholar 

  24. Bertani T, Ferrazzi P, Schieppati A. Nature and extent of glomerular injury induced by cyclosporin in heart transplant patients. Kidney Int. 1991;40(2):243–50.

    CAS  PubMed  Google Scholar 

  25. Kubal C, Cockwell P, Gunson B, et al. Chronic kidney disease after nonrenal solid organ transplantation: a histological assessment and utility of chronic allograft damage index scoring. Transplantation. 2012;93(4):406–11.

    PubMed  Google Scholar 

  26. Coopersmith CM, Brennan DC, Miller B, et al. Renal transplantation following previous heart, liver, and lung transplantation: an 8-year single-center experience. Surgery. 2001;130(3):457–62.

    CAS  PubMed  Google Scholar 

  27. Pinney SP, Balakrishnan R, Dikman S, et al. Histopathology of renal failure after heart transplantation: a diverse spectrum. J Heart Lung Transplant. 2012;31(3):233–7.

    PubMed  Google Scholar 

  28. Myers BD, Ross J, Newton L, et al. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984;311(11):699–705.

    CAS  PubMed  Google Scholar 

  29. Lanese DM, Conger JD. Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles. J Clin Invest. 1993;91(5):2144–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Ojo OA. Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol. 2007;27(4):498–507.

    PubMed  Google Scholar 

  31. Pichler RH, Franceschini N, Young BA, et al. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J Am Soc Nephrol. 1995;6(4):1186–96.

    CAS  PubMed  Google Scholar 

  32. Langham RG, Egan MK, Dowling JP, et al. Transforming growth factor-beta1 and tumor growth factor-beta-inducible gene-H3 in nonrenal transplant cyclosporine nephropathy. Transplantation. 2001;72(11):1826–9.

    CAS  PubMed  Google Scholar 

  33. Rubel JR, Milford EL, McKay DB, et al. Renal insufficiency and end-stage renal disease in the heart transplant population. J Heart Lung Transplant. 2004;23(3):289–300.

    PubMed  Google Scholar 

  34. Wilkinson AH, Cohen DJ. Renal failure in the recipients of nonrenal solid organ transplants. J Am Soc Nephrol. 1999;10(5):1136–44.

    CAS  PubMed  Google Scholar 

  35. Falkenhain ME, Cosio FG, Sedmak DD. Progressive histologic injury in kidneys from heart and liver transplant recipients receiving cyclosporine. Transplantation. 1996;62(3):364–70.

    CAS  PubMed  Google Scholar 

  36. Greenberg A, Egel JW, Thompson ME, et al. Early and late forms of cyclosporine nephrotoxicity: studies in cardiac transplant recipients. Am J Kidney Dis. 1987;9(1):12–22.

    CAS  PubMed  Google Scholar 

  37. Myers BD, Sibley R, Newton L, et al. The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int. 1988;33(2):590–600.

    CAS  PubMed  Google Scholar 

  38. Miller LW, Pennington DG, McBride LR. Long-term effects of cyclosporine in cardiac transplantation. Transplant Proc. 1990;22(3 Suppl 1):15–20.

    CAS  PubMed  Google Scholar 

  39. Hunt SA, Gamberg P, Stinson EB, et al. The Stanford experience: survival and renal function in the pre-sandimmune era compared to the sandimmune era. Transplant Proc. 1990;22(3 Suppl 1):1–5.

    CAS  PubMed  Google Scholar 

  40. Garrido IP, Crespo-Leiro MG, Paniagua MJ, et al. Independent predictors of renal dysfunction after heart transplantation in patients with normal pretransplant renal function. J Heart Lung Transplant. 2005;24(9):1226–30.

    CAS  PubMed  Google Scholar 

  41. McKenzie N, Keown P, Stiller C, et al. Effects of cyclosporine on renal function following orthotopic heart transplantation. J Heart Lung Transplant. 1985;4(4):400–3.

    CAS  Google Scholar 

  42. van Gelder T, Balk AH, Zietse R, et al. Renal insufficiency after heart transplantation: a case-control study. Nephrol Dial Transplant. 1998;13(9):2322–6.

    PubMed  Google Scholar 

  43. Meiser BM, Uberfuhr P, Fuchs A, et al. Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection. J Heart Lung Transplant. 1998;17(8):782–8.

    CAS  PubMed  Google Scholar 

  44. Taylor DO, Barr ML, Radovancevic B, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant. 1999;18(4):336–45.

    CAS  PubMed  Google Scholar 

  45. Kobashigawa JA, Miller LW, Russell SD, et al. Study investigators. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant. 2006;6(6):1377–86.

    CAS  PubMed  Google Scholar 

  46. Israni A, Brozena S, Pankewycz O, et al. Conversion to tacrolimus for the treatment of cyclosporine-associated nephrotoxicity in heart transplant recipients. Am J Kidney Dis. 2002;39(3):E16.

    PubMed  Google Scholar 

  47. Garlicki M, Czub P, Labuś K, et al. Conversion from cyclosporine to tacrolimus improves renal function and lipid profile after cardiac transplantation. Ann Transplant. 2006;11(1):24–7.

    PubMed  Google Scholar 

  48. Kobashigawa JA, Patel J, Furukawa H, et al. Five-year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine in heart transplant patients. J Heart Lung Transplant. 2006;25(4):434–9.

    PubMed  Google Scholar 

  49. Sehgal V, Radhakrishnan J, Appel GB, et al. Progressive renal insufficiency following cardiac transplantation: cyclosporine, lipids, and hypertension. Am J Kidney Dis. 1995;26(1):193–201.

    CAS  PubMed  Google Scholar 

  50. Esposito C, Semeraro L, Bellotti N, et al. Risk factors for chronic renal dysfunction in cardiac allograft recipients. Nephron. 2000;84(1):21–8.

    CAS  PubMed  Google Scholar 

  51. Lubitz SA, Pinney S, Wisnivesky JP, Gass A, Baran DA. Statin therapy associated with a reduced risk of chronic renal failure after cardiac transplantation. J Heart Lung Transplant. 2007;26(3):264–72.

    PubMed  Google Scholar 

  52. Goldstein DJ, Zuech N, Sehgal V, et al. Cyclosporine-associated end-stage nephropathy after cardiac transplantation: incidence and progression. Transplantation. 1997;63(5):664–8.

    CAS  PubMed  Google Scholar 

  53. Lewis RM, Verani RR, Vo C, et al. Evaluation of chronic renal disease in heart transplant recipients: importance of pretransplantation native kidney histologic evaluation. J Heart Lung Transplant. 1994;13(3):376–80.

    CAS  PubMed  Google Scholar 

  54. Rocha PN, Rocha AT, Palmer SM, et al. Acute renal failure after lung transplantation: incidence, predictors and impact on perioperative morbidity and mortality. Am J Transplant. 2005;5(6):1469–76.

    PubMed  Google Scholar 

  55. Schmid H, Burg M, Kretzler M, et al. BK virus associated nephropathy in native kidneys of a heart allograft recipient. Am J Transplant. 2005;5(6):1562–8.

    PubMed  Google Scholar 

  56. Boyle JM, Moualla S, Arrigain S, et al. Risks and outcomes of acute kidney injury requiring dialysis after cardiac transplantation. Am J Kidney Dis. 2006;48(5):787–96.

    PubMed  Google Scholar 

  57. Brozena SC, Johnson MR, Ventura H, et al. Effectiveness and safety of diltiazem or lisinopril in treatment of hypertension after heart transplantation: results of a prospective, randomized multicenter trial. J Am Coll Cardiol. 1996;27(7):1707–12.

    CAS  PubMed  Google Scholar 

  58. Fassi A, Sangalli F, Colombi F, et al. Beneficial effects of calcium channel blockade on acute glomerular hemodynamic changes induced by cyclosporine. Am J Kidney Dis. 1999;33(2):267–75.

    CAS  PubMed  Google Scholar 

  59. Bunke M, Ganzel B. Effect of calcium channel antagonists on renal function in hypertensive heart transplant recipients. J Heart Lung Transplant. 1992;11(6):1194–9.

    CAS  PubMed  Google Scholar 

  60. Chan C, Maurer J, Cardella C, et al. A randomized controlled trial of verapamil on cyclosporine nephrotoxicity in heart and lung transplant recipients. Transplantation. 1997;63(10):1435–40.

    CAS  PubMed  Google Scholar 

  61. Elliott WJ, Murphy MB, Karp R. Long-term preservation of renal function in hypertensive heart transplant recipients treated with enalapril and a diuretic. J Heart Lung Transplant. 1991;10(3):373–9.

    CAS  PubMed  Google Scholar 

  62. Karabsheh S, Verma DR, Jain M, et al. Clinical and hemodynamic effects of renin–angiotensin system blockade in cardiac transplant recipients. Am J Cardiol. 2011;108(12):1836–9.

    CAS  PubMed  Google Scholar 

  63. González-Vilchez F, de Prada JA, Castrillo C, et al. Predictors of long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients. J Heart Lung Transplant. 2011;30(5):552–7.

    PubMed  Google Scholar 

  64. Aliabadi AZ, Pohanka E, Dunkler D, et al. Impact of ACE-inhibitor and angiotensin receptor blocker therapy on development of proteinuria after switch to sirolimus in cardiac transplant recipients. J Heart Lung Transplant. 2008;27(Suppl 1):S67.

    Google Scholar 

  65. Hausen B, Demertzis S, Rohde R, et al. Low-dose cyclosporine therapy in triple-drug immunosuppression for heart transplant recipients. Ann Thorac Surg. 1994;58(4):999–1004.

    CAS  PubMed  Google Scholar 

  66. Bunke M, Sloan R, Brier M, et al. An improved glomerular filtration rate in cardiac transplant recipients with once-a-day cyclosporine dosing. Transplantation. 1995;59(4):537–40.

    CAS  PubMed  Google Scholar 

  67. Cantarovich M, Giannetti N, Barkun J, et al. Antithymocyte globulin induction allows a prolonged delay in the initiation of cyclosporine in heart transplant patients with postoperative renal dysfunction. Transplantation. 2004;78(5):779–81.

    CAS  PubMed  Google Scholar 

  68. Rosenberg PB, Vriesendorp AE, Drazner MH, et al. Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation. J Heart Lung Transplant. 2005;24(9):1327–31.

    PubMed  Google Scholar 

  69. Delgado DH, Miriuka SG, Cusimano RJ, et al. Use of basiliximab and cyclosporine in heart transplant patients with pre-operative renal dysfunction. J Heart Lung Transplant. 2005;24(2):166–9.

    PubMed  Google Scholar 

  70. Cantarovich M, Metrakos P, Giannetti N, et al. Anti-CD25 monoclonal antibody coverage allows for calcineurin inhibitor “holiday” in solid organ transplant patients with acute renal dysfunction. Transplantation. 2002;73(7):1169–72.

    CAS  PubMed  Google Scholar 

  71. Hamour IM, Lyster HS, Burke MM, et al. Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients. Transplantation. 2007;83(5):570–6.

    CAS  PubMed  Google Scholar 

  72. Boissonnat P, Gaillard S, Mercier C, et al. Impact of the early reduction of cyclosporine on renal function in heart transplant patients: a French randomised controlled trial. Trials. 2012;13:231.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Aleksic I, Baryalei M, Busch T, et al. Improvement of impaired renal function in heart transplant recipients treated with mycophenolate mofetil and low-dose cyclosporine. Transplantation. 2000;69(8):1586–90.

    CAS  PubMed  Google Scholar 

  74. Zuckermann A, Ploner M, Keziban U, et al. Benefit of mycophenolate-mofetil (MMF) in patients with cyclosporine (CYA) induced nephropathy after cardiac transplantation. J Heart Lung Transplant. 2001;20(2 Suppl):163.

    PubMed  Google Scholar 

  75. Tedoriya T, Keogh AM, Kusano K, et al. Reversal of chronic cyclosporine nephrotoxicity after heart transplantation-potential role of mycophenolate mofetil. J Heart Lung Transplant. 2002;21(9):976–82.

    PubMed  Google Scholar 

  76. Arizón del Prado JM, Aumente MD, Lopez Granados A, et al. Use of mycophenolate mofetil in patients with transplanted heart and renal insufficiency: the relevance of the pharmacokinetic study. Transplant Proc. 2002;34(1):144–5.

    PubMed  Google Scholar 

  77. Sanchez V, Delgado JF, Morales JM, et al. Chronic cyclosporine-induced nephrotoxicity in heart transplant patients: long-term benefits of treatment with mycophenolate mofetil and low-dose cyclosporine. Transplant Proc. 2004;36(9):2823–5.

    CAS  PubMed  Google Scholar 

  78. Al-Aly Z, Sachdeva A, Philoctete Ashley JM, et al. Preliminary experience with mycophenolate mofetil for preservation of renal function in cardiac transplant patients with documented cyclosporine nephrotoxicity. Nephrology (Carlton). 2006;11(2):151–5.

    CAS  Google Scholar 

  79. Faulhaber M, Mäding I, Malehsa D, et al. Steroid withdrawal and reduction of cyclosporine A under mycophenolate mofetil after heart transplantation. Int Immunopharmacol. 2013;15(4):712–7.

    CAS  PubMed  Google Scholar 

  80. Manito N, Kaplinsky EJ, Roca J, et al. Heart transplant recipient clinical profile improvement following mycophenolate mofetil late incorporation into the treatment schedule. Clin Transplant. 2005;19(3):304–8.

    PubMed  Google Scholar 

  81. Angermann CE, Störk S, Costard-Jäckle A, et al. Reduction of cyclosporine after introduction of mycophenolate mofetil improves chronic renal dysfunction in heart transplant recipients—the IMPROVED multi-centre study. Eur Heart J. 2004;25(18):1626–34.

    CAS  PubMed  Google Scholar 

  82. Baryalei M, Zenker D, Pieske B, et al. Renal function and safety of heart transplant recipients switched to mycophenolate mofetil and low-dose cyclosporine. Transplant Proc. 2003;35(4):1539–42.

    CAS  PubMed  Google Scholar 

  83. Manito N, Rábago G, Palomo J, et al. Improvement in chronic renal failure after mycophenolate mofetil introduction and cyclosporine dose reduction: four-year results from a cohort of heart transplant recipients. Transplant Proc. 2011;43(7):2699–706.

    CAS  PubMed  Google Scholar 

  84. Dureau G, Obadia JF, Chuzel M, et al. Introduction of mycophenolate mofetil and cyclosporine withdrawal in heart transplant patients with progressive deteriorating renal function. Transplant Proc. 2000;32(2):461–2.

    CAS  PubMed  Google Scholar 

  85. Groetzner J, Kaczmarek I, Schirmer J, et al. Calcineurin inhibitor withdrawal and conversion to mycophenolate mofetil and steroids in cardiac transplant recipients with chronic renal failure: a word of caution. Clin Transplant. 2008;22(5):587–93.

    PubMed  Google Scholar 

  86. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349(9):847–58.

    CAS  PubMed  Google Scholar 

  87. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004;110(17):2694–700.

    CAS  PubMed  Google Scholar 

  88. Lehmkuhl HB, Arizon J, Viganò M, et al. 2411 Study Investigators. Everolimus with reduced cyclosporine versus MMF with standard cyclosporine in de novo heart transplant recipients. Transplantation. 2009;88(1):115–22.

    CAS  PubMed  Google Scholar 

  89. Zuckermann A, Wang SS, Ross H, et al. Efficacy and safety of low-dose cyclosporine with everolimus and steroids in de novo heart transplant patients: a multicentre, randomized trial. J Transplant. 2011;2011:535983. doi:10.1155/2011/535983.

    PubMed Central  PubMed  Google Scholar 

  90. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013;13(5):1203–16.

    CAS  PubMed  Google Scholar 

  91. Zucker MJ, Baran DA, Arroyo LH, et al. De novo immunosuppression with sirolimus and tacrolimus in heart transplant recipients compared with cyclosporine and mycophenolate mofetil: a one-year follow-up analysis. Transplant Proc. 2005;37(5):2231–9.

    CAS  PubMed  Google Scholar 

  92. Lehmkuhl H, Hetzer R. Clinical experience with Certican (everolimus) in de novo heart transplant patients at the Deutsches Herzzentrum Berlin. J Heart Lung Transplant. 2005;24(4 Suppl):S201–5.

    PubMed  Google Scholar 

  93. Meiser B, Kaczmarek I, Mueller M, et al. Low-dose tacrolimus/sirolimus and steroid withdrawal in heart recipients is highly efficacious. J Heart Lung Transplant. 2007;26(6):598–603.

    PubMed  Google Scholar 

  94. Lehmkuhl HB, Mai D, Dandel M, et al. Observational study with everolimus (Certican) in combination with low-dose cyclosporine in de novo heart transplant recipients. J Heart Lung Transplant. 2007;26(7):700–4.

    PubMed  Google Scholar 

  95. Kahan BD, Podbielski J, Napoli KL, et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation. 1998;66(8):1040–6.

    CAS  PubMed  Google Scholar 

  96. Kobashigawa J, Ross H, Bara C, et al. Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation. Transpl Infect Dis. 2013;15(2):150–62.

    CAS  PubMed  Google Scholar 

  97. Meiser B, Reichart B, Adamidis I, et al. First experience with de novo calcineurin-inhibitor-free immunosuppression following cardiac transplantation. Am J Transplant. 2005;5(4 Pt 1):827–31.

    PubMed  Google Scholar 

  98. Hunt J, Bedanova H, Starling RC, et al. Premature termination of a prospective, open-label, randomized, multicentre trial of Srl to replace CNIs in a standard care regimen of CNI, MMF and corticosteroids early after heart transplantation [abstract]. J Heart Lung Transplant. 2007;26(2):S203.

    Google Scholar 

  99. González-Vílchez F, de Prada JA, Exposito V, et al. Avoidance of calcineurin inhibitors with use of proliferation signal inhibitors in de novo heart transplantation with renal failure. J Heart Lung Transplant. 2008;27(10):1135–41.

    PubMed  Google Scholar 

  100. Leet AS, Bergin PJ, Richardson M, et al. Outcomes following de novo CNI-free immunosuppression after heart transplantation: a single-center experience. Am J Transplant. 2009;9(1):140–8.

    CAS  PubMed  Google Scholar 

  101. Meiser B, Buchholz S, Kaczmarek I. De-novo calcineurin-inhibitor-free immunosuppression with sirolimus and mycophenolate mofetil after heart transplantation: 5-year results. Curr Opin Organ Transplant. 2011;16(5):522–8.

    CAS  PubMed  Google Scholar 

  102. Snell GI, Levvey B, Chin W, et al. Sirolimus(rapamycin) allows renal recovery in lung and heart transplant recipients with chronic renal impairment. J Heart Lung Transplant. 2001;20(2):163–4.

    PubMed  Google Scholar 

  103. Zakliczynski M, Nozynski J, Zakliczynska H, et al. Deterioration of renal function after replacement of cyclosporine with sirolimus in five patients with severe renal impairment late after heart transplantation. Transplant Proc. 2003;35(6):2331–2.

    CAS  PubMed  Google Scholar 

  104. Groetzner J, Kaczmarek I, Landwehr P, et al. Renal recovery after conversion to a calcineurin inhibitor-free immunosuppression in late cardiac transplant recipients. Eur J Cardiothorac Surg. 2004;25(3):333–41.

    PubMed  Google Scholar 

  105. Lyster H, Panicker G, Leaver N, et al. Initial experience with sirolimus and mycophenolate mofetil for renal rescue from cyclosporine nephrotoxicity after heart transplantation. Transplant Proc. 2004;36(10):3167–70.

    CAS  PubMed  Google Scholar 

  106. Cabezón S, Lage E, Hinojosa R, et al. Sirolimus improves renal function in cardiac transplantation. Transplant Proc. 2005;37(3):1546–7.

    PubMed  Google Scholar 

  107. Kushwaha SS, Khalpey Z, Frantz RP, et al. Sirolimus in cardiac transplantation: use as a primary immunosuppressant in calcineurin inhibitor-induced nephrotoxicity. J Heart Lung Transplant. 2005;24(12):2129–36.

    PubMed  Google Scholar 

  108. Gleissner CA, Doesch A, Ehlermann P, et al. Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy. Am J Transplant. 2006;6(11):2750–8.

    CAS  PubMed  Google Scholar 

  109. Engelen MA, Amler S, Welp H, et al. Prospective study of everolimus with calcineurin inhibitor-free immunosuppression in maintenance heart transplant patients: results at 2 years. Transplantation. 2011;91(10):1159–65.

    CAS  PubMed  Google Scholar 

  110. Fernandez-Valls M, Gonzalez-Vilchez F, de Prada JA, et al. Sirolimus as an alternative to anticalcineurin therapy in heart transplantation: experience of a single center. Transplant Proc. 2005;37(9):4021–3.

    CAS  PubMed  Google Scholar 

  111. Hunt J, Lerman M, Magee M, et al. Improvement of renal dysfunction by conversion from calcineurin inhibitors to sirolimus after heart transplantation. J Heart Lung Transplant. 2005;24(11):1863–7.

    PubMed  Google Scholar 

  112. Bestetti R, Theodoropoulos TA, Burdmann EA, et al. Switch from calcineurin inhibitors to sirolimus-induced renal recovery in heart transplant recipients in the midterm follow-up. Transplantation. 2006;81(5):692–6.

    CAS  PubMed  Google Scholar 

  113. Aranda-Dios A, Lage E, Sobrino JM, et al. Sirolimus experience in heart transplantation. Transplant Proc. 2006;38(8):2547–9.

    CAS  PubMed  Google Scholar 

  114. Gustafsson F, Ross HJ, Delgado MS, et al. Sirolimus-based immunosuppression after cardiac transplantation: predictors of recovery from calcineurin inhibitor-induced renal dysfunction. J Heart Lung Transplant. 2007;26(10):998–1003.

    PubMed  Google Scholar 

  115. Raichlin E, Khalpey Z, Kremers W, et al. Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients. Transplantation. 2007;84(4):467–74.

    CAS  PubMed  Google Scholar 

  116. Moro J, Almenar L, Martínez-Dolz L, et al. mTOR inhibitors: do they help preserve renal function? Transplant Proc. 2007;39(7):2135–7.

    CAS  PubMed  Google Scholar 

  117. Rothenburger M, Teerling E, Bruch C, et al. Calcineurin inhibitor-free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients: 6 months’ follow-up. J Heart Lung Transplant. 2007;26(3):250–7.

    PubMed  Google Scholar 

  118. Moro Lopez JA, Almenar L, Martínez-Dolz L, et al. Progression of renal dysfunction in cardiac transplantation after the introduction of everolimus in the immunosuppressive regimen. Transplantation. 2009;87(4):538–41.

    CAS  PubMed  Google Scholar 

  119. Groetzner J, Kaczmarek I, Schulz U, et al. Mycophenolate and sirolimus as calcineurin inhibitor-free immunosuppression improves renal function better than calcineurin inhibitor-reduction in late cardiac transplant recipients with chronic renal failure. Transplantation. 2009;87(5):726–33.

    CAS  PubMed  Google Scholar 

  120. Aliabadi AZ, Pohanka E, Seebacher G, et al. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant. 2008;8(4):854–61.

    CAS  PubMed  Google Scholar 

  121. Delgado JF, Crespo MG, Manito N, et al. Usefulness of sirolimus as rescue therapy in heart transplant recipients with renal failure: analysis of the Spanish Multicenter Observational Study (RAPACOR). Transplant Proc. 2009;41(9):3835–7.

    CAS  PubMed  Google Scholar 

  122. Demirjian S, Stephany B, Abu Romeh IS, et al. Conversion to sirolimus with calcineurin inhibitor elimination vs. dose minimization and renal outcome in heart and lung transplant recipients. Clin Transplant. 2009;23(3):351–60.

    CAS  PubMed  Google Scholar 

  123. Bestetti RB, Theodoropoulos TA, Nakazone MA, et al. Usefulness of sirolimus-based immunosuppression in ameliorating pre-transplant renal dysfunction in patients with Chagas’ heart disease. J Heart Lung Transplant. 2010;29(11):1312–4.

    PubMed  Google Scholar 

  124. Ayub-Ferreira SM, Avila MS, Feitosa FS, et al. Recovery of renal function in heart transplantation patients after conversion from a calcineurin inhibitor-based therapy to sirolimus. Transplant Proc. 2010;42(2):542–4.

    CAS  PubMed  Google Scholar 

  125. Gude E, Gullestad L, Arora S, et al. Benefit of early conversion from CNI-based to everolimus-based immunosuppression in heart transplantation. J Heart Lung Transplant. 2010;29(6):641–7.

    PubMed  Google Scholar 

  126. Stypmann J, Engelen MA, Eckernkemper S, et al. Calcineurin inhibitor-free immunosuppression using everolimus (Certican) after heart transplantation: 2 years’ follow-up from the University Hospital Münster. Transplant Proc. 2011;43(5):1847–52.

    CAS  PubMed  Google Scholar 

  127. Kaplinsky E, González-Costello J, Manito N, et al. Renal function improvement after conversion to proliferation signal inhibitors during long-term follow-up in heart transplant recipients. Transplant Proc. 2012;44(9):2564–6.

    CAS  PubMed  Google Scholar 

  128. Zuckermann A, Keogh A, Crespo-Leiro MG, et al. Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency. Am J Transplant. 2012;12(9):2487–97.

    CAS  PubMed  Google Scholar 

  129. Topilsky Y, Hasin T, Raichlin E, et al. Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation. Circulation. 2012;125(5):708–20.

    CAS  PubMed  Google Scholar 

  130. Michel S, Bigdeli AK, Hagl C, et al. Renal recovery alter conversion to an everolimus-based immunosuppression in early and late heart transplant recipients: a 12-month analysis. Exp Clin Transplant. 2013;11(5):429–34.

    PubMed  Google Scholar 

  131. Engelen MA, Welp HA, Gunia S, et al. Prospective study of everolimus with calcineurin inhibitor-free immunosuppression after heart transplantation: results at four years. Ann Thorac Surg. 2014;97(3):888–93.

    PubMed  Google Scholar 

  132. Gonzalez-Vilchez F, Vazquez de Prada JA, Paniagua MJ, et al. Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: calcineurin-inhibitors conversion or minimization? Int J Cardiol. 2014;171(1):15–23.

    CAS  PubMed  Google Scholar 

  133. Gustafsson F, Andreassen A, Arora S, et al. A CNI-free, everolimus based regimen in de-novo heart transplant recipients increases albuminuria but improves glomerular filtration rate compared with conventional immunosuppression. J Heart Lung Transplant. 2014;33(4):S281.

    Google Scholar 

  134. Baur B, Oroszlan M, Hess O, et al. Efficacy and safety of sirolimus and everolimus in heart transplant patients: a retrospective analysis. Transplant Proc. 2011;43(5):1853–61.

    CAS  PubMed  Google Scholar 

  135. Schweiger M, Wasler A, Prenner G, et al. Everolimus and reduced cyclosporine trough levels in maintenance heart transplant recipients. Transpl Immunol. 2006;16(1):46–51.

    CAS  PubMed  Google Scholar 

  136. Potter BJ, Giannetti N, Edwardes MD, et al. Calcineurin inhibitor substitution with sirolimus vs. reduced-dose calcineurin inhibitor plus sirolimus is associated with improved renal dysfunction in heart transplant patients. Clin Transplant. 2007;21(3):305–8.

    PubMed  Google Scholar 

  137. Ross H, Pflugfelder P, Haddad H, et al. CADENCE Study Group (CAnadian Pilot Study to determine safe and effective dosing of neoral and CErtican in stable cardiac transplant recipients). Reduction of cyclosporine following the introduction of everolimus in maintenance heart transplant recipients: a pilot study. Transpl Int. 2010;23(1):31–7.

    PubMed  Google Scholar 

  138. Khandhar SJ, Shah HV, Shullo MA, et al. Long-term effects on renal function of dose-reduced calcineurin inhibitor and sirolimus in cardiac transplant patients. Clin Transplant. 2012;26(1):42–9.

    CAS  PubMed  Google Scholar 

  139. Fuchs U, Zittermann A, Hakim-Meibodi K, et al. Everolimus plus dosage reduction of cyclosporine in cardiac transplant recipients with chronic kidney disease: a two-year follow-up study. Transplant Proc. 2011;43(5):1839–46.

    CAS  PubMed  Google Scholar 

  140. Gullestad L, Iversen M, Mortensen SA, et al. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial. Transplantation. 2010;89(7):864–72.

    CAS  PubMed  Google Scholar 

  141. Gullestad L, Mortensen SA, Eiskjær H, et al. Two-year outcomes in thoracic transplant recipients after conversion to everolimus with reduced calcineurin inhibitor within a multicenter, open-label, randomized trial. Transplantation. 2010;90(12):1581–9.

    CAS  PubMed  Google Scholar 

  142. Potena L, Bianchi IG, Magnani G, et al. Cyclosporine lowering with everolimus or mycophenolate to preserve renal function in heart recipients: a randomized study. Transplantation. 2010;89(2):263–5.

    PubMed  Google Scholar 

  143. Potena L, Prestinenzi P, Bianchi IG, et al. Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: long-term follow-up of the SHIRAKISS randomized, prospective study. J Heart Lung Transplant. 2012;31(6):565–70.

    PubMed  Google Scholar 

  144. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation. 2003;108(1):48–53.

    CAS  PubMed  Google Scholar 

  145. Arora S, Gude E, Sigurdardottir V, et al. Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: the significance of baseline glomerular filtration rate. J Heart Lung Transplant. 2012;31(3):259–65.

    PubMed  Google Scholar 

  146. Celik S, Doesch AO, Konstandin MH, et al. Increased incidence of acute graft rejection on calcineurin inhibitor-free immunosuppression after heart transplantation. Transplant Proc. 2011;43(5):1862–7.

    CAS  PubMed  Google Scholar 

  147. González-Vílchez F, Vázquez de Prada JA, Paniagua MJ, et al. Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation. Clin Transplant. 2013;27(6):E649–58.

    PubMed  Google Scholar 

  148. Gonzalez-Vilchez F, Vazquez de Prada JA, Almenar L, et al. Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation. J Heart Lung Transplant. 2012;31(3):288–95.

    PubMed  Google Scholar 

  149. Arora S, Ueland T, Wennerblom B, et al. Effect of everolimus introduction on cardiac allograft vasculopathy–results of a randomized, multicenter trial. Transplantation. 2011;92(2):235–43.

    CAS  PubMed  Google Scholar 

  150. Segovia J, Gómez-Bueno M, Goicolea J, et al. Effect of everolimus in patients with established cardiac allograft vasculopathy: results of a randomized, multicenter intravascular ultrasound study. J Heart Lung Transplant. 2012;31:S75.

    Google Scholar 

  151. Segovia J, Fernández-Yáñez J, González-Vílchez FJ, et al. Clinical effects of introducing everolimus in the immunosuppressive regimen of patients with established cardiac allograft vasculopathy (CAV): efficacy analysis of a randomized, multicenter study. J Heart Lung Transplant. 2012;31:S121.

    Google Scholar 

  152. Pérez-Rojas JM, Bobadilla NA. Novel action of aldosterone in CsA nephrotoxicity [in Spanish]. Rev Invest Clin. 2005;57(2):147–55.

    PubMed  Google Scholar 

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Acknowledgments

We recognize the collaborations from Dr. Mercedes González-Vílchez and Dr. Emilio Rodrigo for the critical reading of the manuscript. The authors are partly supported by an unrestricted grant from the Instituto de Investigacion Valdecilla (IDIVAL).

Dr. Francisco González Vílchez has received lecture fees and mentoring honoraria from Novartis; lecture fees and advisory honoraria from Astellas.

Dr. Jose A. Vázquez de Prada declares no relevant conflicts of interest.

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  1. Heart Failure and Transplantation Unit, Cardiology Service, Instituto de Investigación Valdecilla (IDIVAL), University Hospital Marqués de Valdecilla, 39008, Santander, Spain

    Francisco González-Vílchez & José Antonio Vázquez de Prada

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  1. Francisco González-Vílchez
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  2. José Antonio Vázquez de Prada
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Correspondence to Francisco González-Vílchez.

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González-Vílchez, F., Vázquez de Prada, J.A. Chronic Renal Insufficiency in Heart Transplant Recipients: Risk Factors and Management Options. Drugs 74, 1481–1494 (2014). https://doi.org/10.1007/s40265-014-0274-9

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