Pediatric Drugs

, Volume 13, Issue 1, pp 49–69

Calcineurin Inhibitor-Free Immunosuppression in Pediatric Renal Transplantation

A Viable Option?
Review Article

Abstract

The introduction, in the mid-1980s, of calcineurin inhibitors — namely ciclosporin (cyclosporine) and later tacrolimus — has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity.

To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10–20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking.

At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.

References

  1. 1.
    Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004 Aug; 4(8): 1289–95PubMedCrossRefGoogle Scholar
  2. 2.
    Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. Epub 2010 Oct 25Google Scholar
  3. 3.
    Höcker B, Tonshoff B. Treatment strategies to minimize or prevent chronic allograft dysfunction in pediatric renal transplant recipients: an overview. Paediatr Drugs 2009; 11(6): 381–96PubMedCrossRefGoogle Scholar
  4. 4.
    Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Engl J Med 2003 Dec 11; 349(24): 2326–33PubMedCrossRefGoogle Scholar
  5. 5.
    North American Pediatric Renal Trials and Collaborative Studies 2008 annual report [online]. Available from URL: http://www.NAPRTCS.org [Accessed 2009 Aug]
  6. 6.
    UpToDate. Clinical practice guidelines: table UTD grading criteria [online]. Available from URL: http://www.uptodate.com [Accessed 2010 Feb 18]
  7. 7.
    Benfield MR, Tejani A, Harmon WE, et al. A randomized multicenter trial of OKT3 mAbs induction compared with intravenous cyclosporine in pediatric renal transplantation. Pediatr Transplant 2005 Jun; 9(3): 282–92PubMedCrossRefGoogle Scholar
  8. 8.
    Guba M, Rentsch M, Wimmer CD, et al. Calcineurin-inhibitor avoidance in elderly renal allograft recipients using ATG and basiliximab combined with mycophenolate mofetil. Transpl Int 2008 Jul; 21(7): 637–45PubMedCrossRefGoogle Scholar
  9. 9.
    Khositseth S, Matas A, Cook ME, et al. Thymoglobulin versus ATGAM induction therapy in pediatric kidney transplant recipients: a single-center report. Transplantation 2005 Apr 27; 79(8): 958–63PubMedCrossRefGoogle Scholar
  10. 10.
    Colleen Hastings M, Wyatt RJ, Lau KK, et al. Five years’ experience with thymoglobulin induction in a pediatric renal transplant population. Pediatr Transplant 2006 Nov; 10(7): 805–10PubMedCrossRefGoogle Scholar
  11. 11.
    Baron PW, Ojogho ON, Yorgin P, et al. Comparison of outcomes with low-dose anti-thymocyte globulin, basiliximab or no induction therapy in pediatric kidney transplant recipients: a retrospective study. Pediatr Transplant 2008 Feb; 12(1): 32–9PubMedCrossRefGoogle Scholar
  12. 12.
    Vincenti F, Ramos E, Brattstrom C, et al. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation 2001 May 15; 71(9): 1282–7PubMedCrossRefGoogle Scholar
  13. 13.
    Asberg A, Midtvedt K, Line PD, et al. Calcineurin inhibitor avoidance with daclizumab, mycophenolate mofetil, and prednisolone in DR-matched de novo kidney transplant recipients. Transplantation 2006 Jul 15; 82(1): 62–8PubMedCrossRefGoogle Scholar
  14. 14.
    Abramowicz D, Manas D, Lao M, et al. Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized, controlled study. Transplantation 2002 Dec 27; 74(12): 1725–34PubMedCrossRefGoogle Scholar
  15. 15.
    Schnuelle P, van der Heide JH, Tegzess A, et al. Open randomized trial comparing early withdrawal of either cyclosporine or mycophenolate mofetil in stable renal transplant recipients initially treated with a triple drug regimen. J Am Soc Nephrol 2002 Feb; 13(2): 536–43PubMedGoogle Scholar
  16. 16.
    Smak Gregoor PJ, de Sevaux RG, Ligtenberg G, et al. Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study. J Am Soc Nephrol 2002 May; 13(5): 1365–73PubMedCrossRefGoogle Scholar
  17. 17.
    Ekberg H, Grinyo J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant 2007 Mar; 7(3): 560–70PubMedCrossRefGoogle Scholar
  18. 18.
    Dudley C, Pohanka E, Riad H, et al. Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the “creeping creatinine” study. Transplantation 2005 Feb 27; 79(4): 466–75PubMedCrossRefGoogle Scholar
  19. 19.
    Harmon W, Meyers K, Ingelfinger J, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol 2006 Jun; 17(6): 1735–45PubMedCrossRefGoogle Scholar
  20. 20.
    Pascual J, Bloom D, Torrealba J, et al. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effect on T-regulatory cells. Am J Transplant 2008 Jul; 8(7): 1529–36PubMedCrossRefGoogle Scholar
  21. 21.
    Ellis D, Shapiro R, Moritz M, et al. Renal transplantation in children managed with lymphocyte depleting agents and low-dose maintenance tacrolimus monotherapy. Transplantation 2007 Jun 27; 83(12): 1563–70PubMedCrossRefGoogle Scholar
  22. 22.
    Halloran P, Mathew T, Tomlanovich S, et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 1997 Jan 15; 63(1): 39–47PubMedCrossRefGoogle Scholar
  23. 23.
    Jungraithmayr T, Staskewitz A, Kirste G, et al., German Pediatric Renal Transplantation Study Group. Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years. Transplantation 2003 Feb 27; 75(4): 454–61PubMedCrossRefGoogle Scholar
  24. 24.
    Abramowicz D, Del Carmen Rial M, Vitko S, et al. Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen: results of a five-year, prospective, randomized study. J Am Soc Nephrol 2005 Jul; 16(7): 2234–40PubMedCrossRefGoogle Scholar
  25. 25.
    Cransberg K, Cornelissen M, Lilien M, et al. Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk. Transplantation 2007 Apr 27; 83(8): 1041–7PubMedCrossRefGoogle Scholar
  26. 26.
    Krischock L, Gullett A, Bockenhauer D, et al. Calcineurin-inhibitor free immunosuppression with mycophenolate mofetil and corticosteroids in paediatric renal transplantation improves renal allograft function without in creasing acute rejection. Pediatr Transplant 2009 Jun; 13(4): 475–81PubMedCrossRefGoogle Scholar
  27. 27.
    David-Neto E, Araujo LM, Lemos FC, et al. Introduction of mycophenolate mofetil and cyclosporin reduction in children with chronic transplant nephropathy. Pediatr Transplant 2001 Aug; 5(4): 302–9PubMedCrossRefGoogle Scholar
  28. 28.
    Kerecuk L, Horsfield C, Taylor J. Improved long-term graft function in pediatric transplant renal recipients with chronic allograft nephropathy. Pediatr Transplant 2009 May; 13(3): 324–31PubMedCrossRefGoogle Scholar
  29. 29.
    Filler G, Gellermann J, Zimmering M, et al. Effect of adding mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity. Transpl Int 2000; 13(3): 201–6PubMedCrossRefGoogle Scholar
  30. 30.
    Tapia E, Franco M, Sanchez-Lozada LG, et al. Mycophenolate mofetil prevents arteriolopathy and renal injury in subtotal ablation despite persistent hypertension. Kidney Int 2003 Mar; 63(3): 994–1002PubMedCrossRefGoogle Scholar
  31. 31.
    Kuypers DR. Benefit-risk assessment of sirolimus in renal transplantation. Drug Saf 2005; 28(2): 153–81PubMedCrossRefGoogle Scholar
  32. 32.
    Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006 Aug; 5(8): 671–88PubMedCrossRefGoogle Scholar
  33. 33.
    Rubinsztein DC, Gestwicki JE, Murphy LO, et al. Potential therapeutic applications of autophagy. Nat Rev Drug Discov 2007 Apr; 6(4): 304–12PubMedCrossRefGoogle Scholar
  34. 34.
    Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Aktdependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004 Jun; 10(6): 594–601PubMedCrossRefGoogle Scholar
  35. 35.
    Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther 2007 Oct; 82(4): 381–8PubMedCrossRefGoogle Scholar
  36. 36.
    Chapman JR, Valantine H, Albanell J, et al. Proliferation signal inhibitors in transplantation: questions at the cutting edge of everolimus therapy. Transplant Proc 2007 Dec; 39(10): 2937–50PubMedCrossRefGoogle Scholar
  37. 37.
    Gaumann A, Schlitt HJ, Geissler EK. Immunosuppression and tumor development in organ transplant recipients: the emerging dualistic role of rapamycin. Transpl Int 2008 Mar; 21(3): 207–17PubMedCrossRefGoogle Scholar
  38. 38.
    Höcker B, Feneberg R, Kopf S, et al. SRL-based immunosuppression vs. CNI minimization in pediatric renal transplant recipients with chronic CNI nephrotoxicity. Pediatr Transplant 2006 Aug; 10(5): 593–601PubMedCrossRefGoogle Scholar
  39. 39.
    Knight RJ, Villa M, Laskey R, et al. Risk factors for impaired wound healing in sirolimus-treated renal transplant recipients. Clin Transplant 2007 Jul–Aug; 21(4): 460–5PubMedCrossRefGoogle Scholar
  40. 40.
    Stallone G, Infante B, Grandaliano G, et al. Management of side effects of sirolimus therapy. Transplantation 2009 Apr 27; 87(8 Suppl.): S23–6PubMedCrossRefGoogle Scholar
  41. 41.
    Vitko S, Margreiter R, Weimar W, et al. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2005 Oct; 5(10): 2521–30PubMedCrossRefGoogle Scholar
  42. 42.
    Morelon E, Stern M, Israel-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 2001 Sep 15; 72(5): 787–90PubMedCrossRefGoogle Scholar
  43. 43.
    Garrean S, Massad MG, Tshibaka M, et al. Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients. Clin Transplant 2005 Oct; 19(5): 698–703PubMedCrossRefGoogle Scholar
  44. 44.
    Chhajed PN, Dickenmann M, Bubendorf L, et al. Patterns of pulmonary complications associated with sirolimus. Respiration 2006; 73(3): 367–74PubMedCrossRefGoogle Scholar
  45. 45.
    Butani L. Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 2004 Nov 15; 78(9): 1362–6PubMedCrossRefGoogle Scholar
  46. 46.
    Kahan BD. Sirolimus-based immunosuppression: present state of the art. J Nephrol 2004 Nov–Dec; 17Suppl. 8: S32–9PubMedGoogle Scholar
  47. 47.
    Fritsche L, Budde K, Dragun D, et al. Testosterone concentrations and sirolimus in male renal transplant patients. Am J Transplant 2004 Jan; 4(1): 130–1PubMedCrossRefGoogle Scholar
  48. 48.
    Huyghe E, Zairi A, Nohra J, et al. Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. Transpl Int 2007 Apr; 20(4): 305–11PubMedCrossRefGoogle Scholar
  49. 49.
    Tenderich G, Fuchs U, Zittermann A, et al. Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients. Clin Transplant 2007 Jul–Aug; 21(4): 536–43PubMedCrossRefGoogle Scholar
  50. 50.
    Albano L, Berthoux F, Moal MC, et al. Incidence of delayed graft function and wound healing complications after deceased-donor kidney transplantation is not affected by de novo everolimus. Transplantation 2009 Jul 15; 88(1): 69–76PubMedCrossRefGoogle Scholar
  51. 51.
    Pascual J, Boletis IN, Campistol JM. Everolimus (Certican) in renal transplantation: a review of clinical trial data, current usage, and future directions. Transplant Rev 2006; 20(1): 1–18CrossRefGoogle Scholar
  52. 52.
    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 Apr 15; 67(7): 1036–42PubMedCrossRefGoogle Scholar
  53. 53.
    Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000 Apr 15; 69(7): 1252–60PubMedCrossRefGoogle Scholar
  54. 54.
    Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 2006 Mar; 6(3): 514–22PubMedCrossRefGoogle Scholar
  55. 55.
    Flechner SM, Goldfarb D, Solez K, et al. Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs. Transplantation 2007 Apr 15; 83(7): 883–92PubMedCrossRefGoogle Scholar
  56. 56.
    Hamdy AF, Bakr MA, Ghoneim MA. Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients. J Am Soc Nephrol 2008 Jun; 19(6): 1225–32PubMedCrossRefGoogle Scholar
  57. 57.
    Durrbach A, Rostaing L, Tricot L, et al. Prospective comparison of the use of sirolimus and cyclosporine in recipients of a kidney from an expanded criteria donor. Transplantation 2008 Feb 15; 85(3): 486–90PubMedCrossRefGoogle Scholar
  58. 58.
    Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007 Dec 20; 357(25): 2562–75PubMedCrossRefGoogle Scholar
  59. 59.
    Hamdy AF, El-Agroudy AE, Bakr MA, et al. Comparison of sirolimus with low-dose tacrolimus versus sirolimus-based calcineurin inhibitor-free regimen in live donor renal transplantation. Am J Transplant 2005 Oct; 5(10): 2531–8PubMedCrossRefGoogle Scholar
  60. 60.
    Lloberas N, Torras J, Alperovich G, et al. Different renal toxicity profiles in the association of cyclosporine and tacrolimus with sirolimus in rats. Nephrol Dial Transplant 2008 Oct; 23(10): 3111–9PubMedCrossRefGoogle Scholar
  61. 61.
    Oberbauer R, Kreis H, Johnson RW, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation 2003 Jul 27; 76(2): 364–70PubMedCrossRefGoogle Scholar
  62. 62.
    Budde K, Becker T, Arns W, et al. Analysis of renal function in everolimus/enteric-coated mycophenolate sodium treated de novo renal transplant recipients after calcineurin inhibitor withdrawal: the ZEUS study [abstract]. Am J Transplant 2009; 9: 259Google Scholar
  63. 63.
    Pietruck F, Becker T, Arns W, et al. Efficacy and safety of an everolimus/enteric-coated mycophenolate sodium regimen after calcineurin inhibitor withdrawal in de novo renal transplant recipients: results of the ZEUS trial [abstract]. Am J Transplant 2009; 9: 499Google Scholar
  64. 64.
    Baboolal K. A phase III prospective, randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients. Transplantation 2003 Apr 27; 75(8): 1404–8PubMedCrossRefGoogle Scholar
  65. 65.
    Stallone G, Infante B, Schena A, et al. Rapamycin for treatment of chronic allograft nephropathy in renal transplant patients. J Am Soc Nephrol 2005 Dec; 16(12): 3755–62PubMedCrossRefGoogle Scholar
  66. 66.
    Watson CJ, Firth J, Williams PF, et al. A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation. Am J Transplant 2005 Oct; 5(10): 2496–503PubMedCrossRefGoogle Scholar
  67. 67.
    Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009 Jan 27; 87(2): 233–42PubMedCrossRefGoogle Scholar
  68. 68.
    Hymes LC, Warshaw BL, Amaral SG, et al. Tacrolimus withdrawal and conversion to sirolimus at three months post-pediatric renal transplantation. Pediatr Transplant 2008 Nov; 12(7): 773–7PubMedCrossRefGoogle Scholar
  69. 69.
    Powell HR, Kara T, Jones CL. Early experience with conversion to sirolimus in a pediatric renal transplant population. Pediatr Nephrol 2007 Oct; 22(10): 1773–7PubMedCrossRefGoogle Scholar
  70. 70.
    Falger JC, Mueller T, Arbeiter K, et al. Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy. Pediatr Transplant 2006 Jun; 10(4): 474–8PubMedCrossRefGoogle Scholar
  71. 71.
    Ibanez JP, Monteverde ML, Diaz MA, et al. Sirolimus in chronic allograft nephropathy in pediatric recipients. Pediatr Transplant 2007 Nov; 11(7): 777–80PubMedCrossRefGoogle Scholar
  72. 72.
    Weintraub L, Li L, Kambham N, et al. Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation. Pediatr Transplant 2008 Aug; 12(5): 541–9PubMedCrossRefGoogle Scholar
  73. 73.
    Diekmann F, Budde K, Oppenheimer F, et al. Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant 2004 Nov; 4(11): 1869–75PubMedCrossRefGoogle Scholar
  74. 74.
    Diekmann F, Budde K, Slowinski T, et al. Conversion to sirolimus for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria. Transpl Int 2008 Feb; 21(2): 152–5PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Division of Pediatric NephrologyUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.University Children’s Hospital HeidelbergHeidelbergGermany

Personalised recommendations