Advertisement

Immunosuppression for Pediatric Renal Transplantation

  • Jodi M. Smith
  • Thomas L. Nemeth
  • Ruth A. McDonald
Living reference work entry

Abstract

The major advance allowing prolonged graft survival has been the use of immunosuppressive drugs that downregulate the immune response. The immunosuppression that is used varies among centers and evolves with the development of new medications.

Keywords

Acute Rejection Graft Survival Induction Therapy Calcineurin Inhibitor Delay Graft Function 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Feld LG, et al. Renal transplantation in children from 1987–1996: the 1996 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 1997;1(2):146–62.PubMedGoogle Scholar
  2. 2.
    Benfield MR, et al. Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 2003;7(4):321–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Benfield MR, et al. A randomized multicenter trial of OKT3 mAbs induction compared with intravenous cyclosporine in pediatric renal transplantation. Pediatr Transplant. 2005;9(3):282–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Scientific Registry of Transplant Recipients. Annual data report. 2013. http://srtr.transplant.hrsa.gov/annual_reports/2013/Default.aspx
  5. 5.
    Mourad G, et al. Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression. Transplantation. 2001;72(6):1050–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Merion RM, Howell T, Bromberg JS. Partial T-cell activation and anergy induction by polyclonal antithymocyte globulin. Transplantation. 1998;65(11):1481–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Peddi VR, et al. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002;73(9):1514–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Brophy PD, et al. Comparison of polyclonal induction agents in pediatric renal transplantation. Pediatr Transplant. 2001;5(3):174–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Brennan DC, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999;67(7):1011–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Brennan DC, et al. Leukocyte response to thymoglobulin or atgam for induction immunosuppression in a randomized, double-blind clinical trial in renal transplant recipients. Transplant Proc. 1999;31(3B Suppl):16S–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Ault BH, et al. Short-term outcomes of Thymoglobulin induction in pediatric renal transplant recipients. Pediatr Nephrol. 2002;17(10):815–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Khositseth S, et al. Thymoglobulin versus ATGAM induction therapy in pediatric kidney transplant recipients: a single-center report. Transplantation. 2005;79(8):958–63.PubMedCrossRefGoogle Scholar
  13. 13.
    Warejko JK, Hmiel SP. Single-center experience in pediatric renal transplantation using thymoglobulin induction and steroid minimization. Pediatr Transplant. 2014;18(8):816–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Mayes JT, et al. Reexposure to OKT3 in renal allograft recipients. Transplantation. 1988;45(2):349–53.PubMedCrossRefGoogle Scholar
  15. 15.
    Norman DJ, et al. Consensus statement regarding OKT3-induced cytokine-release syndrome and human antimouse antibodies. Transplant Proc. 1993;25(2 Suppl 1):89–92.PubMedGoogle Scholar
  16. 16.
    Shihab FS, Barry JM, Norman DJ. Encephalopathy following the use of OKT3 in renal allograft transplantation. Transplant Proc. 1993;25(2 Suppl 1):31–4.PubMedGoogle Scholar
  17. 17.
    Cole MS, et al. HuM291, a humanized anti-CD3 antibody, is immunosuppressive to T cells while exhibiting reduced mitogenicity in vitro. Transplantation. 1999;68(4):563–71.PubMedCrossRefGoogle Scholar
  18. 18.
    North American Pediatric Renal Trials and Collaborative Studies. Annual transplant report. 2010. https://web.emmes.com/study/ped/annlrept/2010_Report.pdf
  19. 19.
    Calne R, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation. 1999;68(10):1613–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Calne R, et al. Prope tolerance with induction using Campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal allograft recipients. Nippon Geka Gakkai Zasshi. 2000;101(3):301–6.PubMedGoogle Scholar
  21. 21.
    Knechtle SJ, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant. 2003;3(6):722–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Kirk AD, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation. 2003;76(1):120–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Bartosh SM, Knechtle SJ, Sollinger HW. Campath-1H use in pediatric renal transplantation. Am J Transplant. 2005;5(6):1569–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Moudgil A, Puliyanda D. Induction therapy in pediatric renal transplant recipients: an overview. Paediatr Drugs. 2007;9:323–41.PubMedCrossRefGoogle Scholar
  25. 25.
    Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation. 2005;80:457–65.PubMedCrossRefGoogle Scholar
  26. 26.
    Tan HP, Donaldson J, Ellis D, et al. Pediatric living donor kidney transplantation under alemtuzumab pretreatment and tacrolimus monotherapy: 4-year experience. Transplantation. 2008;86:1725–31.PubMedCrossRefGoogle Scholar
  27. 27.
    Kaabak M, Babenko N, Samsonov D, et al. Alemtuzumab induction in pediatric kidney transplantation. Pediatr Transplant. 2013;17:168–78.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Supe-Markovina K, Melquist JJ, Connolly D, DiCarlo HN, Waltzer WC, Fine RN, Darras FS. Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: a seven-yr experience. Pediatr Transplant. 2014;18(4):363–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Sterkers G, et al. Duration of action of a chimeric interleukin-2 receptor monoclonal antibody, basiliximab, in pediatric kidney transplant recipients. Transplant Proc. 2000;32(8):2757–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Pescovitz MD, et al. Safety and pharmacokinetics of daclizumab in pediatric renal transplant recipients. Pediatr Transplant. 2008;12(4):447–55.PubMedCrossRefGoogle Scholar
  31. 31.
    Smith JM, et al. Decreased risk of renal allograft thrombosis associated with interleukin-2 receptor antagonists: a report of the NAPRTCS. Am J Transplant. 2006;6(3):585–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Offner G, et al. A multicenter, open-label, pharmacokinetic/pharmacodynamic safety, and tolerability study of basiliximab (Simulect) in pediatric de novo renal transplant recipients. Transplantation. 2002;74(7):961–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Sarwal MM, et al. Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in pediatric renal transplantation. Transplantation. 2001;72(1):13–21.PubMedCrossRefGoogle Scholar
  34. 34.
    Strehlau J, et al. Interleukin-2 receptor antibody-induced alterations of ciclosporin dose requirements in paediatric transplant recipients. Lancet. 2000;356(9238):1327–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Swiatecka-Urban A, et al. Basiliximab induction improves the outcome of renal transplants in children and adolescents. Pediatr Nephrol. 2001;16(9):693–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Vester U, et al. Efficacy and tolerability of interleukin-2 receptor blockade with basiliximab in pediatric renal transplant recipients. Pediatr Transplant. 2001;5(4):297–301.PubMedCrossRefGoogle Scholar
  37. 37.
    Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med. 1998;338(25):1813–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Bluestone JA. Is CTLA-4 a master switch for peripheral T cell tolerance? J Immunol. 1997;158(5):1989–93.PubMedGoogle Scholar
  39. 39.
    Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212.PubMedCrossRefGoogle Scholar
  40. 40.
    Thompson CB. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation? Cell. 1995;81(7):979–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Linsley PS, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174(3):561–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Walunas TL, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1(5):405–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Greenwald RJ, et al. CTLA-4 regulates induction of anergy in vivo. Immunity. 2001;14(2):145–55.PubMedCrossRefGoogle Scholar
  44. 44.
    Perez VL, et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity. 1997;6(4):411–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Lin H, et al. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med. 1993;178(5):1801–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Pearson TC, et al. CTLA4-Ig plus bone marrow induces long-term allograft survival and donor specific unresponsiveness in the murine model. Evidence for hematopoietic chimerism. Transplantation. 1996;61(7):997–1004.PubMedCrossRefGoogle Scholar
  47. 47.
    Pearson TC, et al. Transplantation tolerance induced by CTLA4-Ig. Transplantation. 1994;57(12):1701–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Sayegh MH, et al. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med. 1995;181(5):1869–74.PubMedCrossRefGoogle Scholar
  49. 49.
    Turka LA, et al. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci U S A. 1992;89(22):11102–5.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Chandraker A, et al. T-cell costimulatory blockade in experimental chronic cardiac allograft rejection: effects of cyclosporine and donor antigen. Transplantation. 1997;63(8):1053–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Russell ME, et al. Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. J Clin Invest. 1996;97(3):833–8.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Chandraker A, et al. Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection. J Clin Invest. 1998;101(11):2309–18.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Kim KS, et al. CD28-B7-mediated T cell costimulation in chronic cardiac allograft rejection: differential role of B7-1 in initiation versus progression of graft arteriosclerosis. Am J Pathol. 2001;158(3):977–86.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10:535–46.PubMedCrossRefGoogle Scholar
  55. 55.
    Durrbach A, Pestana JM, Pearson T, et al. A phase II study of belatacept versus cyclosporine in kidney transplant from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010;10:547–57.PubMedCrossRefGoogle Scholar
  56. 56.
    Rostaing L, Vincenti F, Grinyo J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of BENEFIT study. Am J Transplant. 2013;13:2875–83.PubMedCrossRefGoogle Scholar
  57. 57.
    Charpentier B, Medina Pestana JO, Del C, Rial M, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys. Am J Transplant. 2013;13:2884–91.PubMedCrossRefGoogle Scholar
  58. 58.
    Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra Jr O. Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation. 2003;76(9):1331–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Grenda R, Watson A, Trompeter R, Tönshoff B, Jaray J, Fitzpatrick M, Murer L, Vondrak K, Maxwell H, van Damme-Lombaerts R, Loirat C, Mor E, Cochat P, Milford DV, Brown M, Webb NJ. A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: the TWIST Study. Am J Transplant. 2010;10:828–36.PubMedCrossRefGoogle Scholar
  60. 60.
    Pape L, Offner G, Kreuzer M, Froede K, Drube J, Kanzelmeyer N, Ehrich JH, Ahlenstiel T. De novo therapy with everolimus, low-dose cyclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation. Am J Transplant. 2010;10(10):2349–54.PubMedCrossRefGoogle Scholar
  61. 61.
    Delucchi A, Valenzuela M, Ferrario M, Lillo AM, Guerrero JL, Rodriguez E, Cano F, Cavada G, Godoy J, Rodriguez J, Gonzalez CG, Buckel E, Contreras L. Early steroid withdrawal in pediatric renal transplant on newer immunosuppressive drugs. Pediatr Transplant. 2007;11:743–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Benfield MR, Bartosh S, Ikle D, Warshaw B, Bridges N, Morrison Y, Harmon W. A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant. 2010;10:81–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Shapiro R, Ellis D, Tan HP, Moritz ML, Basu A, Vats AN, Khan AS, Gray EA, Zeevi A, McFeaters C, James G, Grosso MJ, Marcos A, Starzl TE. Antilimphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediatr. 2006;148(6):813–8.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Chavers BM, Chang C, Gillingham KJ, Matas A. Pediatric kidney transplantation using a novel protocol of rapid (6-day) discontinuation of prednisolone: 2-year results. Transplantation. 2009;88(2):237–41.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Calne RY, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2(8151):1033–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Harmon WE, Sullivan EK. Cyclosporine dosing and its relationship to outcome in pediatric renal transplantation. Kidney Int Suppl. 1993;43:S50–5.PubMedGoogle Scholar
  67. 67.
    Neu AM, et al. Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: a NAPRTCS study. Pediatr Transplant. 2003;7(3):217–22.PubMedCrossRefGoogle Scholar
  68. 68.
    Suthanthiran M, et al. Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols. Transplantation. 1993;55(5):1008–13.PubMedCrossRefGoogle Scholar
  69. 69.
    Foley RJ, Hamner RW, Weinman EJ. Serum potassium concentrations in cyclosporine- and azathioprine-treated renal transplant patients. Nephron. 1985;40(3):280–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Chapman JR, et al. Reversibility of cyclosporin nephrotoxicity after three months' treatment. Lancet. 1985;1(8421):128–30.PubMedCrossRefGoogle Scholar
  71. 71.
    Allen RD, Hunnisett AG, Morris PJ. Cyclosporin and magnesium. Lancet. 1985;1(8440):1283–4.PubMedCrossRefGoogle Scholar
  72. 72.
    Crocker JF, et al. Cyclosporin A toxicity in children. Transplant Rev. 1993;7:72.CrossRefGoogle Scholar
  73. 73.
    Thomas DW, et al. Cyclosporin A-induced gingival overgrowth is unrelated to allograft function in renal transplant recipients. J Clin Periodontol. 2001;28(7):706–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Hoyer PF, et al. Conversion from Sandimmune to Neoral and induction therapy with Neoral in pediatric renal transplant recipients. Transplant Proc. 1996;28(4):2259–61.PubMedGoogle Scholar
  75. 75.
    First MR, Alloway R, Schroeder TJ. Development of Sang-35: a cyclosporine formulation bioequivalent to Neoral. Clin Transplant. 1998;12(6):518–24.PubMedGoogle Scholar
  76. 76.
    Schroeder TJ, et al. A generic cyclosporine development program. Transplant Proc. 1997;29(1–2):1235–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Tejani A, et al. Steady improvement in short-term graft survival of pediatric renal transplants: the NAPRTCS experience. Clin Transpl. 1999;95–110.Google Scholar
  78. 78.
    Matas AJ, et al. The importance of early cyclosporine levels in pediatric kidney transplantation. Clin Transplant. 1996;10(6 Pt 1):482–6.PubMedGoogle Scholar
  79. 79.
    Medeiros M, et al. Limited sampling model for area-under-the-curve monitoring in pediatric patients receiving either Sandimmune or Neoral cyclosporin A oral formulations. Pediatr Transplant. 1999;3(3):225–30.PubMedCrossRefGoogle Scholar
  80. 80.
    Barama A., et al. Absorption profiling of cyclosporine therapy for de nova kidney transplantation: a prospective randomized study comparing sparse sampling to trough monitoring [abstract no. 190]. Transplantation. 2000;69(2);Suppl:S162.Google Scholar
  81. 81.
    Dello Strologo L, et al. C2 monitoring: a reliable tool in pediatric renal transplant recipients. Transplantation. 2003;76(2):444–5.PubMedCrossRefGoogle Scholar
  82. 82.
    Ferraresso M, et al. Pharmacokinetic of cyclosporine microemulsion in pediatric kidney recipients receiving A quadruple immunosuppressive regimen: the value of C2 blood levels. Transplantation. 2005;79(9):1164–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Pape L, Ehrich JH, Offner G. Advantages of cyclosporin A using 2-h levels in pediatric kidney transplantation. Pediatr Nephrol. 2004;19(9):1035–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Trompeter R, et al. Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption. Pediatr Transplant. 2003;7(4):282–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Preiss R. P-glycoprotein and related transporters. Int J Clin Pharmacol Ther. 1998;36(1):3–8.PubMedGoogle Scholar
  86. 86.
    Gaston RS. Current and evolving immunosuppressive regimens in kidney transplantation. Am J Kidney Dis. 2006;47(4 Suppl 2):S3–21.PubMedCrossRefGoogle Scholar
  87. 87.
    ShapiroR, et al. The superiority of tacrolimus in renal transplant recipients – the Pittsburgh experience. Clin Transpl. 1995;199–205.Google Scholar
  88. 88.
    McKee M, et al. Initial experience with FK506 (tacrolimus) in pediatric renal transplant recipients. J Pediatr Surg. 1997;32(5):688–90.PubMedCrossRefGoogle Scholar
  89. 89.
    Ellis D. Clinical use of tacrolimus (FK-506) in infants and children with renal transplants. Pediatr Nephrol. 1995;9(4):487–94.PubMedCrossRefGoogle Scholar
  90. 90.
    Shaw LM, et al. Current opinions on therapeutic drug monitoring of immunosuppressive drugs. Clin Ther. 1999;21(10):1632–52. discussion 1631.PubMedCrossRefGoogle Scholar
  91. 91.
    Eidelman BH, et al. Neurologic complications of FK 506. Transplant Proc. 1991;23(6):3175–8.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Neu AM, et al. Evaluation of neurotoxicity in pediatric renal transplant recipients treated with tacrolimus (FK506). Clin Transplant. 1997;11(5 Pt 1):412–4.PubMedGoogle Scholar
  93. 93.
    Filler G, et al. Tacrolimus reversibly reduces insulin secretion in paediatric renal transplant recipients. Nephrol Dial Transplant. 2000;15(6):867–71.PubMedCrossRefGoogle Scholar
  94. 94.
    Ciancio G, et al. Post-transplant lymphoproliferative disease in kidney transplant patients in the new immunosuppressive era. Clin Transplant. 1997;11(3):243–9.PubMedGoogle Scholar
  95. 95.
    Dharnidharka VR, et al. Mycophenolate, tacrolimus and post-transplant lymphoproliferative disorder: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 2002;6(5):396–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Eades SK, Boineau FG, Christensen ML. Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea. Pediatr Transplant. 2000;4(1):63–6.PubMedCrossRefGoogle Scholar
  97. 97.
    MacPhee IA, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant. 2004;4(6):914–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Kausman JY, Patel B, Marks SD. Standard dosing of tacrolimus leads to overexposure in pediatric renal transplantation recipients. Pediatr Transplant. 2008;12(3):329–35.PubMedCrossRefGoogle Scholar
  99. 99.
    McDonald RA, et al. Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant. 2008;8(5):984–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Filler G, et al. Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant. 2005;9(4):498–503.PubMedCrossRefGoogle Scholar
  101. 101.
    Dharnidharka VR, et al. Post-transplant lymphoproliferative disorder in the United States: young Caucasian males are at highest risk. Am J Transplant. 2002;2(10):993–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation. 2005;80(2 Suppl):S254–64.PubMedCrossRefGoogle Scholar
  103. 103.
    Bunchman T, et al. The use of mycophenolate mofetil suspension in pediatric renal allograft recipients. Pediatr Nephrol. 2001;16(12):978–84.PubMedCrossRefGoogle Scholar
  104. 104.
    Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis. 2001;38(6 Suppl 6):S25–35.PubMedCrossRefGoogle Scholar
  105. 105.
    Granger DK. Enteric-coated mycophenolate sodium: results of two pivotal global multicenter trials. Transplant Proc. 2001;33(7–8):3241–4.PubMedCrossRefGoogle Scholar
  106. 106.
    Pape L, et al. Improved gastrointestinal symptom burden after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in kidney transplanted children. Pediatr Transplant. 2008;12(6):640–2.PubMedCrossRefGoogle Scholar
  107. 107.
    Vilalta Casas R, et al. Mycophenolic Acid reaches therapeutic levels whereas mycophenolate mofetil does not. Transplant Proc. 2006;38(8):2400–1.PubMedCrossRefGoogle Scholar
  108. 108.
    Tsaroucha AK, et al. Levels of mycophenolic acid and its glucuronide derivative in the plasma of liver, small bowel and kidney transplant patients receiving tacrolimus and cellcept combination therapy. Transpl Immunol. 2000;8(2):143–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation. 1995;60(3):225–32.PubMedCrossRefGoogle Scholar
  110. 110.
    Browne BJ. The Tricontinental Mycophenolate Mofetil Trial. Transplantation. 1996;62(11):1697.PubMedCrossRefGoogle Scholar
  111. 111.
    Ettenger R, et al. The long-term use of mycophenolate mofetil in pediatric renal transplantation. A report of the pediatric MMF study group. Transplantation. 1999;67(7):S124.CrossRefGoogle Scholar
  112. 112.
    Seikaly MG. Mycophenolate mofetil–is it worth the cost? The in-favor opinion. Pediatr Transplant. 1999;3(1):79–82.PubMedCrossRefGoogle Scholar
  113. 113.
    Borrows R, et al. Mycophenolic acid 12-h trough level monitoring in renal transplantation: association with acute rejection and toxicity. Am J Transplant. 2006;6(1):121–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Tredger JM, Brown NW. Mycophenolate: better value through monitoring? Transplantation. 2006;81(4):507–8.PubMedCrossRefGoogle Scholar
  115. 115.
    Tredger JM, et al. Monitoring mycophenolate in liver transplant recipients: toward a therapeutic range. Liver Transpl. 2004;10(4):492–502.PubMedCrossRefGoogle Scholar
  116. 116.
    Yamani MH, et al. The impact of routine mycophenolate mofetil drug monitoring on the treatment of cardiac allograft rejection. Transplantation. 2000;69(11):2326–30.PubMedCrossRefGoogle Scholar
  117. 117.
    Mourad M, et al. Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem. 2001;47(1):88–94.PubMedGoogle Scholar
  118. 118.
    Le Meur Y, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7(11):2496–503.PubMedCrossRefGoogle Scholar
  119. 119.
    Van Gelder T., S. H.T. A prospective randomized study comparing fixed dose vs. concentration controlled MMF regimens for de nova patients following renal transplantation (the FDCC trial). Am J Transplant. 2006;6:343.Google Scholar
  120. 120.
    Bloom R, Naraghi R, et al. OPTICENTP trial: interim results of 6-month efficacy and safety of monitoring mycophenolate mofetil (MMF) in combincation with DNI in renal transplatation. Am J Transplant. 2006;6:344.Google Scholar
  121. 121.
    Filler G. Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy. Transpl Int. 2004;17(3):120–5.PubMedGoogle Scholar
  122. 122.
    Sehgal SN, et al. Rapamycin: a novel immunosuppressive macrolide. Med Res Rev. 1994;14(1):1–22.PubMedCrossRefGoogle Scholar
  123. 123.
    Kim HS, et al. Effects of cyclosporine and rapamycin on immunoglobulin production by preactivated human B cells. Clin Exp Immunol. 1994;96(3):508–12.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Ferraresso M, et al. Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats. J Immunol. 1994;153(7):3307–18.PubMedGoogle Scholar
  125. 125.
    Aagaard-Tillery KM, Jelinek DF. Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin. Cell Immunol. 1994;156(2):493–507.PubMedCrossRefGoogle Scholar
  126. 126.
    Dumont FJ, et al. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol. 1990;144(1):251–8.PubMedGoogle Scholar
  127. 127.
    Cao W, et al. Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis. Inhibition of basic fibroblast growth factor and platelet-derived growth factor action and antagonism of rapamycin by FK506. Transplantation. 1995;59(3):390–5.PubMedCrossRefGoogle Scholar
  128. 128.
    Marx SO, et al. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res. 1995;76(3):412–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Kahan BD, et al. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation. 1999;68(10):1526–32.PubMedCrossRefGoogle Scholar
  130. 130.
    Kahan BD, et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation. 1998;66(8):1040–6.PubMedCrossRefGoogle Scholar
  131. 131.
    Kahan BD, Camardo JS. Rapamycin: clinical results and future opportunities. Transplantation. 2001;72(7):1181–93.PubMedCrossRefGoogle Scholar
  132. 132.
    Schachter AD, et al. Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant. 2004;8(2):171–7.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Sindhi R, et al. Pharmacodynamics of sirolimus in transplanted children receiving tacrolimus. Transplant Proc. 2002;34(5):1960.PubMedCrossRefGoogle Scholar
  134. 134.
    MacDonald A, et al. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22(Suppl B):B101–21.PubMedCrossRefGoogle Scholar
  135. 135.
    Brattstrom C, et al. Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation. 1998;65(9):1272–4.PubMedCrossRefGoogle Scholar
  136. 136.
    Groth CG, 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(7):1036–42.PubMedCrossRefGoogle Scholar
  137. 137.
    Weintraub L, et al. Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation. Pediatr Transplant. 2008;12(5):541–9.PubMedCrossRefGoogle Scholar
  138. 138.
    Bumbea V, et al. Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant. 2005;20(11):2517–23.PubMedCrossRefGoogle Scholar
  139. 139.
    Lai WJ, et al. Is sirolimus a safe alternative to reduce or eliminate calcineurin inhibitors in chronic allograft nephropathy in kidney transplantation? Transplant Proc. 2004;36(7):2056–7.PubMedCrossRefGoogle Scholar
  140. 140.
    Haydar AA, et al. Sirolimus-induced pneumonitis: three cases and a review of the literature. Am J Transplant. 2004;4(1):137–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Weiner SM, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome–a single-centre experience and review of the literature. Nephrol Dial Transplant. 2007;22(12):3631–7.PubMedCrossRefGoogle Scholar
  142. 142.
    Stallone G, et al. Addition of sirolimus to cyclosporine delays the recovery from delayed graft function but does not affect 1-year graft function. J Am Soc Nephrol. 2004;15(1):228–33.PubMedCrossRefGoogle Scholar
  143. 143.
    Lieberthal W, et al. Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. Am J Physiol Renal Physiol. 2001;281(4):F693–706.PubMedGoogle Scholar
  144. 144.
    Lieberthal W, Koh JS, Levine JS. Necrosis and apoptosis in acute renal failure. Semin Nephrol. 1998;18(5):505–18.PubMedGoogle Scholar
  145. 145.
    Witzgall R, et al. Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest. 1994;93(5):2175–88.PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Campistol JM, Sacks SH. Mechanisms of nephrotoxicity. Transplantation. 2000;69(12 Suppl):SS5–10.PubMedGoogle Scholar
  147. 147.
    Zuber J, et al. Sirolimus may reduce fertility in male renal transplant recipients. Am J Transplant. 2008;8(7):1471–9.PubMedCrossRefGoogle Scholar
  148. 148.
    El-Sabrout R, et al. Rejection-free protocol using sirolimus-tacrolimus combination for pediatric renal transplant recipients. Transplant Proc. 2002;34(5):1942–3.PubMedCrossRefGoogle Scholar
  149. 149.
    Montgomery SP, et al. Efficacy and toxicity of a protocol using sirolimus, tacrolimus and daclizumab in a nonhuman primate renal allotransplant model. Am J Transplant. 2002;2(4):381–5.PubMedCrossRefGoogle Scholar
  150. 150.
    Kreis H, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation. 2000;69(7):1252–60.PubMedCrossRefGoogle Scholar
  151. 151.
    Mital D, Podlasek W, Jensik SC. Sirolimus-based steroid-free maintenance immunosuppression. Transplant Proc. 2002;34(5):1709–10.PubMedCrossRefGoogle Scholar
  152. 152.
    Schwarz C, Oberbauer R. Calcineurin inhibitor sparing in renal transplantation. Curr Opin Organ Transplant. 2006;11:632–6.CrossRefGoogle Scholar
  153. 153.
    Kahan BD. The potential role of rapamycin in pediatric transplantation as observed from adult studies. Pediatr Transplant. 1999;3(3):175–80.PubMedCrossRefGoogle Scholar
  154. 154.
    Hymes LC, Warshaw BL. Sirolimus in pediatric patients: results in the first 6 months post-renal transplant. Pediatr Transplant. 2005;9(4):520–2.PubMedCrossRefGoogle Scholar
  155. 155.
    Wu MS, Chang CT, Hung CC. Rapamycin in patients with chronic renal allograft dysfunction. Clin Transplant. 2005;19(2):236–42.PubMedCrossRefGoogle Scholar
  156. 156.
    Hymes LC, et al. Tacrolimus withdrawal and conversion to sirolimus at three months post-pediatric renal transplantation. Pediatr Transplant. 2008;12(7):773–7.PubMedCrossRefGoogle Scholar
  157. 157.
    Streit F, et al. Sensitive and specific quantification of sirolimus (rapamycin) and its metabolites in blood of kidney graft recipients by HPLC/electrospray-mass spectrometry. Clin Chem. 1996;42(9):1417–25.PubMedGoogle Scholar
  158. 158.
    Sirolimus (package insert). Philadelphia: Wyeth Laboratories; 2001.Google Scholar
  159. 159.
    McAlister VC, et al. A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Ther Drug Monit. 2002;24(3):346–50.PubMedCrossRefGoogle Scholar
  160. 160.
    Filler G, Bendrick-Peart J, Christians U. Pharmacokinetics of mycophenolate mofetil and sirolimus in children. Ther Drug Monit. 2008;30(2):138–42.PubMedCrossRefGoogle Scholar
  161. 161.
    Kahan BD, Yakupoglu YK, Schoenberg L, et al. Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients. Transplantation. 2005;80:749–58.PubMedCrossRefGoogle Scholar
  162. 162.
    Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with TOR inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005;80:883–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Pape L, Offner G, Kreuzer M, et al. De novo therapy with everolimus, low-dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation. Am J Transplant. 2010;10:2349–54.PubMedCrossRefGoogle Scholar
  164. 164.
    Pape L, Lehner F, Blume C, Ahlenstiel T. Pediatric kidney transplantation followed by de novo therapy with everolimus, low-dose cyclosporine A, and steroid elimination: 3-year data. Transplantation. 2011;92:658–62.PubMedCrossRefGoogle Scholar
  165. 165.
    Ettenger R, Hoyer PF, Grimm P, et al. Multicenter trial of everolimus in pediatric renal transplant recipients: Results at three years. Pediatr Transplant. 2008;12:456–63.PubMedCrossRefGoogle Scholar
  166. 166.
    Grushkin C, Mahan JD, Mange KC, Hexham JM, Ettenger R. De novo therapy with everolimus and reduced-exposure cyclosporine following pediatric kidney transplantation: a prospective, multicenter, 12-month study. Pediatr Transplant. 2013;17:237–43.PubMedCrossRefGoogle Scholar
  167. 167.
    Ferraresso M, Belingheri M, Ginevri F, Murer L, Dello Strologo L, Cardillo M, Parodi A, Ghirardo G, Guzzo I, Innocente A, Ghio L. Three-yr safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. Pediatr Transplant. 2014;18(4):350–6. doi:10.1111/petr.12261.PubMedCrossRefGoogle Scholar
  168. 168.
    Harmon WE, Stablein DM, Sayegh MH. Trends in immunosuppression strategies in pediatric kidney transplantation. Am J Transplant. 2003;3(Supp 5):285.Google Scholar
  169. 169.
    Orta-Sibu N, et al. Comparison of high-dose intravenous methylprednisolone with low-dose oral prednisolone in acute renal allograft rejection in children. Br Med J (Clin Res Ed). 1982;285(6337):258–60.CrossRefGoogle Scholar
  170. 170.
    Csapo Z, et al. Campath-1H as rescue therapy for the treatment of acute rejection in kidney transplant patients. Transplant Proc. 2005;37(5):2032–6.PubMedCrossRefGoogle Scholar
  171. 171.
    Schneeberger S, et al. Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H. Am J Transplant. 2004;4(8):1372–4.PubMedCrossRefGoogle Scholar
  172. 172.
    Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am J Kidney Dis. 2001;38(6 Suppl 6):S2–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jodi M. Smith
    • 1
  • Thomas L. Nemeth
    • 2
  • Ruth A. McDonald
    • 1
  1. 1.Division of Nephrology, Seattle Children’sUniversity of WashingtonSeattleUSA
  2. 2.Department of Pharmacy, Seattle Children’sUniversity of WashingtonSeattleUSA

Personalised recommendations