Drugs

, Volume 64, Issue 12, pp 1325–1338 | Cite as

Immunosuppression for Long-Term Maintenance of Renal Allograft Function

Review Article

Abstract

The incidence and severity of acute rejection episodes was markedly reduced by the introduction of new immunosuppressive drug regimens for renal transplantation, resulting in improved graft survival at 1 year. However, only modest improvement has been shown in long-term graft function rates.

This overview evaluates the efficacy of currently used immunosuppressive drugs and drug combinations for long-term maintenance therapy. Prospective controlled trials rarely extend beyond 5 years; therefore, registry data and retrospective reports have also been employed. From currently available data it may be concluded that the initial beneficial effect of ciclosporin (cyclosporin) is lost 10 years after transplantation. Tacrolimus is an alternative to ciclosporin with a different profile of adverse effects and a higher efficacy in acute rejection treatment. For long-term maintenance, projected half-lives of kidney graft function are in favour of tacrolimus. Mycophenolate mofetil (MMF) has been shown to significantly reduce the incidence of early rejections. However, the improved long-term graft survival reported in retrospective studies has still to be confirmed in controlled trials. There is no convincing evidence for superiority of triple therapy including prednisone (or prednisolone), calcineurin inhibitors and azathioprine/MMF over dual therapy without azathioprine/MMF with respect to long-term outcome. Withdrawal of corticosteroids or calcineurin inhibitors clearly reduces adverse drug effects but carries the risk of acute rejection episodes. Avoidance of corticosteroids by using new immunosuppressive drug combinations may be an option to minimise toxic adverse effects in the future.

At present, it seems unjustified to convert renal transplant recipients with stable graft function and tolerable adverse effects from one drug to another solely in expectation of future benefits. Acute early or late rejection episodes and intolerable adverse effects are good reasons for conversions between calcineurin inhibitors or cytotoxic agents. Chronic allograft nephropathy with slowly deteriorating graft function remains an unresolved problem.

Notes

Acknowledgements

The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

References

  1. 1.
    Ojo AO, Hanson JA, Wolfe RA, et al. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307–13PubMedGoogle Scholar
  2. 2.
    First MR, Peddi VR, Weiskittel P, et al. Control of risk factors for cardiovascular disease in long-term renal transplant recipients. Transplant Proc 2001; 33: 3674–5PubMedGoogle Scholar
  3. 3.
    Boucher A, Masse M, Lauzon L, et al. Impact of immunosuppressive regimen on cardiovascular risk factors in kidney transplant recipients. Transplant Proc 2002; 34: 1799–802PubMedGoogle Scholar
  4. 4.
    Krämer BK, Zülke C, Kammerl MC, et al. Cardiovascular risk factors and estimated risk for CAD in a randomized trial comparing calcineurin inhibitors in renal transplantation: the European Tacrolimus vs Cyclosporine Microemulsion Study Group. Am J Transplant 2003; 3: 982–7PubMedGoogle Scholar
  5. 5.
    Gjertson DW. Impact of delayed graft function and acute rejection on graft survival. Transplant Proc 2002; 34: 2432PubMedGoogle Scholar
  6. 6.
    First MR. Renal function as a predictor of long-term graft survival in renal transplant patients. Nephrol Dial Transplant 2003; 18 Suppl. 1: 13–6Google Scholar
  7. 7.
    Paraskevas S, Kandaswamy R, Humar A, et al. Predicting long-term kidney graft survival: can new trials be performed? Transplantation 2003; 75: 1256–9PubMedGoogle Scholar
  8. 8.
    de Bruijne MHJ, Sijpkens YWJ, Paul LC, et al. Predicting kidney graft failure using time-dependent renal function covariates. J Clin Epidemiol 2003; 56: 448–55PubMedGoogle Scholar
  9. 9.
    Kaplan B, Schold J, Meier-Kriesche HU. Poor predictive value of serum creatinine for renal allograft loss. Am J Transplant 2003; 3: 1560–5PubMedGoogle Scholar
  10. 10.
    Grimm PC, Nickerson P, Gough J, et al. Computerized image analysis of Sirius Red-stained renal graft biopsies as a surrogate marker to predict long-term allograft function. J Am Soc Nephrol 2003; 14: 1662–8PubMedGoogle Scholar
  11. 11.
    Yilmaz S, Tomlanovich S, Mathew T, et al. Protocol core needle biopsy and histologic chronic allograft damage index (CADI) as surrogate end point for long-term graft survival in multicenter studies. J Am Soc Nephrol 2003; 14: 773–9PubMedGoogle Scholar
  12. 12.
    Ort D, Kovac W, Debol C. Adrenal cortex. In: Wilson J, Foster D, Kronenberg HM, editors. Williams textbook of endocrinology. 9th ed. Philadelphia (PA): WB Saunders, 1998: 517–604Google Scholar
  13. 13.
    Lerut JP. Avoiding steroids in solid organ transplantation. Transplant Int 2003; 16: 213–24Google Scholar
  14. 14.
    Calne RY. Twenty years’ experience of immunosuppression in organ transplantation. Transplant Proc 1982; 14: 91–7Google Scholar
  15. 15.
    Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000; 47: 85–118PubMedGoogle Scholar
  16. 16.
    Borel JF. Mechanism of action of cyclosporin A and rationale use in nephrotic syndrome. Clin Nephrol 1991; 35 Suppl. 1: S23–30PubMedGoogle Scholar
  17. 17.
    Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK 506. Immunol Today 1992; 13: 36–42Google Scholar
  18. 18.
    Keown P, Niese D. Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation: International Sandimmun Neoral Study Group. Kidney Int 1998; 54: 938–44PubMedGoogle Scholar
  19. 19.
    Pollard SG, Lear PA, Ready AR, et al. Comparison of microemulsion and conventional formulations of cyclosporine A in preventing acute rejection in de novo kidney transplant patients: the UK Neoral Renal Study Group. Transplantation 1999; 68: 1325–31PubMedGoogle Scholar
  20. 20.
    Peters DH, Fitton A, Plosker AF, et al. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746–94PubMedGoogle Scholar
  21. 21.
    Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998; 31: 335–40PubMedGoogle Scholar
  22. 22.
    Taylor HE, Ackman CF, Horowitz I. Canadian clinical trial of antilymphocyte globuline in human cadaver renal transplantation. Can Med Assoc J 1976; 115: 1205–8PubMedGoogle Scholar
  23. 23.
    Bonnefoy-Berard N, Vincent C, Revillard J-P. Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation 1991; 51: 669–73PubMedGoogle Scholar
  24. 24.
    Soulillou JP. Relevant targets for therapy with monoclonal antibodies in allograft transplantation. Kidney Int 1994; 46: 540–53PubMedGoogle Scholar
  25. 25.
    Helderman JH. Review and preview of anti-T-cell antibodies. Transplant Proc 1995; 27: 8–9PubMedGoogle Scholar
  26. 26.
    The Canadian Multicentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation: analysis at three years. N Engl J Med 1986; 314: 1219–25Google Scholar
  27. 27.
    Calne RY, for the European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: 5-year follow-up of a multicenter trial. Lancet 1987; 330: 506–7Google Scholar
  28. 28.
    Hariharan S, Johnson CP, Breshnahan BA, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000; 342: 605–12PubMedGoogle Scholar
  29. 29.
    Meier-Kriesche H-U, Ojo AO, Port FK, et al. Survival improvement among patients with end-stage renal disease: trends over time for transplant recipients and wait-list patients. J Am Soc Nephrol 2001; 12: 1293–6PubMedGoogle Scholar
  30. 30.
    Ferguson RM, Henry ML, Elkhammas EA, et al. Twenty years of renal transplantation at Ohio State University: the results of five areas of immunosuppression. Am J Surg 2003; 186: 306–11PubMedGoogle Scholar
  31. 31.
    Ponticelli C, Villa M, Cesana B, et al. Risk factors for late kidney allograft failure. Kidney Int 2002; 62: 1848–54PubMedGoogle Scholar
  32. 32.
    Pascual M, Theruvath T, Kawai T, et al. Strategies to improve long-term outcome after renal transplantation. N Engl J Med 2002; 346: 580–90PubMedGoogle Scholar
  33. 33.
    Beveridge T, Calne RY. Cyclosporine (Sandimmun) in cadaveric renal transplantation: ten-year follow-up of a multicenter trial: European Multicentre Trial Group. Transplantation 1995; 59: 1568–70PubMedGoogle Scholar
  34. 34.
    Ponticelli C, Civati G, Tarantino A, et al. Randomized study with cyclosporine in kidney transplantation: 10-year follow-up. Am Soc Nephrol 1996; 7: 792–7Google Scholar
  35. 35.
    Knight RJ, Kerman RH, Welsh M, et al. Chronic rejection in primary allograft recipients under cyclosporine-prednisone immunosuppressive therapy. Transplantation 1991; 51: 355–9PubMedGoogle Scholar
  36. 36.
    Marcen R, Pascual J, Teruel JL, et al. Outcome of cadaveric renal transplant patients treated for 10 years with cyclosporine: is chronic allograft nephropathy the major cause of late graft loss? Transplantation 2001; 72: 57–62PubMedGoogle Scholar
  37. 37.
    Grimbert P, Baron C, Fruchaud G, et al. Long-term results of a prospective randomised study comparing two immunosuppressive regimens, one with and one without CsA, in low risk renal transplant recipients. Transplant Int 2002; 15: 550–5Google Scholar
  38. 38.
    Helderman JH, vanBuren DH, Amend WJC, et al. Chronic immunosuppression of the renal transplant patient. J Am Soc Nephrol 1994; 4: S2–9PubMedGoogle Scholar
  39. 39.
    Montagnino G, Tarantino A, Segolini GP, et al. Long-term results of a randomized study comparing three immunosuppressive schedules with cyclosporine in cadaveric kidney transplantation. J Am Soc Nephrol 2001; 12: 2163–9PubMedGoogle Scholar
  40. 40.
    Nishikawa E, Terasaki PI. Annual trends in kidney transplantation. Clin Transpl 2001; 15: 247–69Google Scholar
  41. 41.
    Stoves J, Newstead CG. Variability of cyclosporine exposure and its relevance to chronic allograft nephropathy: a case control study. Transplantation 2002; 74: 1794–7PubMedGoogle Scholar
  42. 42.
    Marcen R, Pascual J, Tato A, et al. Comparison of CO and C2 cyclosporine monitoring in long-term renal transplant recipients. Transplant Proc 2003; 35: 1780–2PubMedGoogle Scholar
  43. 43.
    Shapiro R, Jordan M, Scantlebury V, et al. A prospective, randomized trial of FK-506 in renal transplantation: a comparison between double- and triple-drug therapy. Clin Transplant 1994; 8: 508–15PubMedGoogle Scholar
  44. 44.
    Chang RWS, Snowdon S, Palmer A, et al. European randomized trial of dual versus triple tacrolimus-based regimens for control of acute rejection in renal allograft recipients. Transplant Int 2001; 14: 384–90Google Scholar
  45. 45.
    Pascual J, Ortuno J, for the Spanish and Italian Tacrolimus Study Group. Simple tacrolimus-based immunosuppressive regimens following renal transplantation: a large multicenter comparison between double and triple therapy. Transplant Proc 2002; 34: 89–91PubMedGoogle Scholar
  46. 46.
    Garcia I, for the Spanish and Italian Tacrolimus Study Group. Efficacy and safety of dual versus triple tacrolimus-based therapy in kidney transplantation: two-year follow up. Transplant Proc 2002; 34: 1638–9PubMedGoogle Scholar
  47. 47.
    Pascual J, Segoloni G, Gonzales Molina M, et al. Comparison between a two-drug regimen with tacrolimus and steroids and a triple one with azathioprine in kidney transplantation: results of a European trial with 3-year follow up. Transplant Proc 2003; 35: 1701–3PubMedGoogle Scholar
  48. 48.
    Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997; 63: 977–83PubMedGoogle Scholar
  49. 49.
    Jensik SC; the FK 506 Kidney Transplant Study Group. Tacrolimus (FK 506) in kidney transplantation: three year survival results of the US multicenter, randomized, comparative trial. Transplant Proc 1988; 30: 1216–8Google Scholar
  50. 50.
    Meier-Kriesche HU, Kaplan B. Cyclosporine microemulsion and tacrolimus are associated with decreased chronic allograft failure and improved long-term graft survival as compared with Sandimmune. Am J Transplant 2002; 2: 100–4PubMedGoogle Scholar
  51. 51.
    Murphy GJ, Waller JR, Sandford RS, etal. Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis. Br J Surg 2003; 90: 680–6PubMedGoogle Scholar
  52. 52.
    Pascual J, Marcén R, Burgos FJ, et al. One-center comparison between primary immunosuppression based on Neoral cyclosporin and tacrolimus for renal transplantation. Transplant Proc 2002; 34: 94–5PubMedGoogle Scholar
  53. 53.
    Jurewicz WA. Tacrolimus versus cyclosporin immunosuppression: long-term outcome in renal transplantation. Nephrol Dial Transplant 2003; 18 Suppl. 1: 7–11Google Scholar
  54. 54.
    Vincenti F, Jensik SC, Filo RS, et al. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation 2002; 73: 775–82PubMedGoogle Scholar
  55. 55.
    Mayer AD. Chronic rejection and graft half-life: five-year follow-up of the European tacrolimus multicenter renal study. Transplant Proc 2002; 34: 1491–2PubMedGoogle Scholar
  56. 56.
    Neu AM, Ho PL, Fine RN, et al. Tacrolimus vs cyclosporine A as primary immunosuppression in pediatric renal transplantation: a NAPRTCS study. Pediatr Transplant 2003; 7: 217–22PubMedGoogle Scholar
  57. 57.
    Claesson K, Mayer AD, Squifflet J-P, et al. Lipoprotein patterns in renal transplant patients: a comparison between FK 506 and cyclosporine A patients. Transplant Proc 1998; 30: 1292–4PubMedGoogle Scholar
  58. 58.
    Friemann S, Feurig E, Padberg W, et al. Improvement of nephrotoxicity, hypertension, and lipid metabolism after conversion of kidney transplant recipients from cyclosporine to tacrolimus. Transplant Proc 1998; 30: 1240–2PubMedGoogle Scholar
  59. 59.
    McCune TR, Thacker II LR, Peters TG, et al. Effects of tacrolimus on hyperlipidemia after successful renal transplantation. Transplantation 1998; 65: 87–92PubMedGoogle Scholar
  60. 60.
    Copley JB, Staffeld C, Lindberg J, et al. Cyclosporine to tacrolimus: effect on hypertension and lipid profiles in renal allografts. Transplant Proc 1998; 30: 1254–6PubMedGoogle Scholar
  61. 61.
    Ligtenberg G, Hené RJ, Blankestijn PJ, et al. Cardiovascular risk factors in renal transplant patients: cyclosporin A versus tacrolimus. J Am Soc Nephrol 2001; 12: 368–73PubMedGoogle Scholar
  62. 62.
    Thorp M, DeMattos A, Bennett W, et al. The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia, hirsutism and cholesterol. Transplantation 2000; 69: 1218–24PubMedGoogle Scholar
  63. 63.
    Maes BD, Kuypers D, Messiaen T, et al. Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors. Transplantation 2001; 72: 1655–61PubMedGoogle Scholar
  64. 64.
    Binet I, Nickeleit V, Hirsch HH, et al. Polyoma viras disease under new immunosuppressive drags: a cause of renal graft dysfunction and graft loss. Transplantation 1999; 67: 918–22PubMedGoogle Scholar
  65. 65.
    Lazzaro C, McKechnie T, McKenna M. Tacrolimus versus cyclosporin in renal transplantation in Italy: cost-minimisation and cost-effectiveness analyses. J Nephrol 2002; 15: 580–8PubMedGoogle Scholar
  66. 66.
    Scott LJ, McKeage K, Keam SJ, et al. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003; 63(12): 1247–97PubMedGoogle Scholar
  67. 67.
    Tanabe K. Calcineurin inhibitors in renal transplantation: what is the best option? Drags 2003; 63(15): 1535–48Google Scholar
  68. 68.
    Vanrenterghem Y. Vascular rejection with tacrolimus and potential long-term graft outcome. Transplant Proc 1999; 31 Suppl. 7A: 86S–7SPubMedGoogle Scholar
  69. 69.
    Briggs D, Dudley C, Pattison J, et al. Effects of immediate switch from cyclosporine microemulsion to tacrolimus at first acute rejection in renal allograft recipients: European Tacrolimus Renal Rejection Study Group. Transplantation 2003; 75: 2058–63PubMedGoogle Scholar
  70. 70.
    European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet 1995; 345: 1321–5Google Scholar
  71. 71.
    The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029–37Google Scholar
  72. 72.
    The US Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection of primary cadaveric kidney transplants: status of the MYC 1866 study at 1 year. Transplant Proc 1997; 29: 348–9Google Scholar
  73. 73.
    European Mycophenolate Mofetil Cooperative Study Group. Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. Transplantation 1999; 68: 391–6Google Scholar
  74. 74.
    US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil in cadaveric renal transplantation. Am J Kidney Dis 1999; 34: 296–303Google Scholar
  75. 75.
    Mathew TH. A blinded long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years: Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1998; 65: 1450–4PubMedGoogle Scholar
  76. 76.
    Meier-Kriesche H-U, Steffen BJ, Hochberg AM, et al. Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration. Transplantation 2003; 75: 1341–6PubMedGoogle Scholar
  77. 77.
    Meier-Kriesche H-U, Ojo AO, Leichtman AB, et al. Effect of mycophenolate mofetil on long-term outcomes in African American renal transplant recipients. J Am Soc Nephrol 2000; 11: 2366–70PubMedGoogle Scholar
  78. 78.
    Ojo AO, Meier-Kriesche H-U, Hanson JA, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000; 69: 2405–9PubMedGoogle Scholar
  79. 79.
    Offermann G. Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil. Clin Transplant 2003; 17: 43–6PubMedGoogle Scholar
  80. 80.
    Tuncer M, Giirkan A, Erdogan O, et al. Mycophenolate mofetil in renal transplantation: five years experience. Transplant Proc 2002; 34: 2087–8PubMedGoogle Scholar
  81. 81.
    van Hooff JP, Squifflet J-P, Vanrenterghem Y. Benelux experience with a combination of tacrolimus and mycophenolate mofetil: 4-year results. Transplant Proc 2002; 34: 1591–3PubMedGoogle Scholar
  82. 82.
    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: 834–41PubMedGoogle Scholar
  83. 83.
    Gonwa T, Johnson C, Ahsan N, et al. Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years. Transplantation 2003; 75: 2048–53PubMedGoogle Scholar
  84. 84.
    Pascual M, Curtis J, Delmonico FL, et al. A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation. Transplantation 2003; 75: 1501–5PubMedGoogle Scholar
  85. 85.
    Gotti E, Perico N, Perna A, et al. Renal transplantation: can we reduce calcineurin inhibitor/stop steroids? J Am Soc Nephrol 2003; 14: 755–66PubMedGoogle Scholar
  86. 86.
    Opelz G, Dohler B. Cyclosporine and long-term kidney graft survival. Transplantation 2001; 72: 1267–73PubMedGoogle Scholar
  87. 87.
    Kasiske BL, Chakkera HA, Louis TA, et al. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11: 1910–7PubMedGoogle Scholar
  88. 88.
    McPhee IA, Bradley JA, Briggs JD, et al. Long-term outcome of a prospective randomized trial of conversion from cyclosporine to azathioprine treatment one year after transplantation. Transplantation 1998; 66: 1186–92Google Scholar
  89. 89.
    Kumar DD, Srivastava A, Mandhani A, et al. Cyclosporin A withdrawal in live related renal transplantation: long-term results. Clin Transplant 2001; 15: 136–41PubMedGoogle Scholar
  90. 90.
    Bakker RC, Hollander AAMJ, Mallat MJK, et al. Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy. Kidney Int 2003; 64: 1027–34PubMedGoogle Scholar
  91. 91.
    Smak Gregoor PJH, de Sévaux RGL, Ligtenberg G, et al. Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drag therapy: a randomized, prospective, multicenter study. J Am Soc Nephrol 2002; 13: 1365–73PubMedGoogle Scholar
  92. 92.
    Abramowicz D, Manas D, Lao M, et al. Cyclosporin withdrawal from a mycophenolate containing immunosuppressive regimen in stable kidney transplant recipients: a randomized, controlled study. Transplantation 2002; 74: 1725–34PubMedGoogle Scholar
  93. 93.
    Kuypers DRJ, Evenepoel P, Maes B, et al. The use of an anti-CD25 monoclonal antibody and mycophenolate mofetil enables the use of a low-dose tacrolimus and early withdrawal of steroids in renal transplant recipients. Clin Transplant 2002; 17: 234–41Google Scholar
  94. 94.
    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: Rapamune Maintenance Regimen Study Group. Transplantation 2003; 76: 364–70PubMedGoogle Scholar
  95. 95.
    Saunders RN, Bicknell GR, Nicholson ML. The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy. Transplantation 2003; 75: 772–80PubMedGoogle Scholar
  96. 96.
    Gauthier P, Helderman JH. Cyclosporine avoidance. J Am Soc Nephrol 2000; 11: 1933–6PubMedGoogle Scholar
  97. 97.
    Vincente F. Sparing of calcineurin antagonists: the use of interleukin-2 monoclonal antibodies in conjunction with mycophenolate mofetil. Transplant Immunol Lett 2000; 16: 4–6Google Scholar
  98. 98.
    Tran HTB, Acharya MK, Mckay DB, et al. Avoidance of cyclosporine in renal transplantation: effects of daclizumab, mycophenolate mofetil, and steroids. J Am Soc Nephrol 2000; 11: 1903–9PubMedGoogle Scholar
  99. 99.
    Offermann G, Krause PH, Johann D, et al. Late conversion from steroids to azathioprine in cyclosporin-treated renal graft recipients. Transplant Int 1989; 2: 108–12Google Scholar
  100. 100.
    Schulak JA, Mayes JT, Moritz CE, et al. A prospective randomized trial of prednisone versus no prednisone maintenance therapy in cyclosporine-treated and azathioprine-treated renal transplant patients. Transplantation 1990; 49: 327–32PubMedGoogle Scholar
  101. 101.
    Offermann G, Schwarz A, Krause P-H. Long-term effects of steroid withdrawal in kidney transplantation. Transplant Int 1993; 6: 290–2Google Scholar
  102. 102.
    Sivaraman P, Nussbaumer G, Landsberg D. Lack of long-term benefits of steroid withdrawal in renal transplant recipients. Am J Kidney Dis 2001; 37: 1162–9PubMedGoogle Scholar
  103. 103.
    Jensen S, Jackson EC, Riley L, et al. Tacrolimus-based immunosuppression with steroid withdrawal in pediatric kidney transplantation: 4 year experience at a moderate-volume center. Pediatr Transplant 2003; 7: 119–24PubMedGoogle Scholar
  104. 104.
    Birkeland SA. Steroid-free immunosuppression in renal transplantation: a long-term follow up of 100 consecutive patients. Transplantation 2001; 71: 1089–90PubMedGoogle Scholar
  105. 105.
    Hong JC, Kahan BD. Use of anti-CD25 monoclonal antibody in combination with rapamycin to eliminate cyclosporine treatment during the induction phase of immunosuppression. Transplantation 1999; 68: 701–4PubMedGoogle Scholar
  106. 106.
    Shaffer D, Langone A, Nylander WA, et al. A pilot protocol of marginal donor kidneys or with delayed graft function. Clin Transplant 2003; 17 Suppl. 9: 31–4PubMedGoogle Scholar
  107. 107.
    Fuller TF, Freise CE, Serkova N, et al. Sirolimus delays recovery of rat kidney transplants after ischemia-reperfusion injury. Transplantation 2003; 76: 1594–9PubMedGoogle Scholar
  108. 108.
    McTaggart RA, Gottlieb D, Brooks J, et al. Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am J Transplant 2003; 3: 416–23PubMedGoogle Scholar
  109. 109.
    Smith KD, Wrenshall LE, Nicosia RF, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol 2003; 14: 1037–45PubMedGoogle Scholar
  110. 110.
    Davies C. Sirolimus delays renal allograft recovery. Am J Transplant 2003; 3: 363–5Google Scholar
  111. 111.
    Oberbauer R, Kreis H, Campistol JM, et al. Renal function improves significantly after early cyclosporine withdrawal in sirolimus-treated renal transplant recipients: 3-year results of the Rapamune Maintenance Regimen (RMR) Trial [abstract]. J Am Soc Nephrol 2003; 14: 10AGoogle Scholar
  112. 112.
    Paul LC. Chronic allograft nephropathy: an update. Kidney Int 1999; 36: 783–93Google Scholar
  113. 113.
    Prommool S, Jhangri GS, Cockfield SM, et al. Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 2000; 11: 565–73PubMedGoogle Scholar
  114. 114.
    Sijpkens YWJ, Doxiades IIN, van Kemnade FJ, et al. Chronic rejection with or without transplant vasculopathy. Clin Transplant 2003; 17: 163–70PubMedGoogle Scholar
  115. 115.
    Joosten SA, van Kooten C, Paul LC. Pathogenesis of chronic allograft rejection. Transplant Int 2003; 16: 137–45Google Scholar
  116. 116.
    Prasad GVR, Nash MM, McFarlane PA, et al. Renal transplant recipient attitudes toward steroid use and steroid withdrawal. Clin Transplant 2003; 17: 135–9PubMedGoogle Scholar

Copyright information

© Adis data information BV 2004

Authors and Affiliations

  1. 1.Medizinische Klinik IV, Transplant Center, Charitè, Campus Benjamin FranklinUniversitätsmedizin BerlinBerlinGermany

Personalised recommendations