Immunosuppressive Medications in Kidney Transplantation

  • Lavjay ButaniEmail author


While acute rejection and short-term graft survival have improved in the modern era of renal transplantation, gains in long-term graft survival have been more limited. This is, in part, due to the nephrotoxic effect of many posttransplant medications, such as the calcineurin inhibitors. Moreover, side effects of other immunosuppressive medications such as corticosteroids have contributed to significant morbidity and mortality, especially from their effects on cardiovascular health. The past two decades have seen much innovation in the use of immunosuppressive strategies to facilitate minimal exposure to these potent but potentially toxic medications. This chapter discusses some of the common immunosuppressive medications and strategies that are being used for induction and maintenance therapy in children and adolescents following transplantation.


Transplantation Steroid minimization Induction Maintenance Pediatric Rejection 


  1. 1.
    Hricik DE, Almawi WY, Strom TB. Trends in the use of glucocorticoids in renal transplantation. Transplantation. 1994;57(7):979–89.CrossRefGoogle Scholar
  2. 2.
    Hricik DE, Whalen CC, Lautman J, Bartucci MR, Moir EJ, Mayes JT, et al. Withdrawal of steroids after renal transplantation – clinical predictors of outcome. Transplantation. 1992;53(1):41–5.CrossRefGoogle Scholar
  3. 3.
    NAPRTCS Annual Report. [Internet]. 2014. [Cited March 18, 2017]. Available from:
  4. 4.
    Kidney Disease: Improving Global Outcomes Transplant Work G. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1–155.Google Scholar
  5. 5.
    Hill P, Cross NB, Barnett AN, Palmer SC, Webster AC. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017;1:CD004759.PubMedGoogle Scholar
  6. 6.
    Baron PW, Ojogho ON, Yorgin P, Sahney S, Cutler D, Ben-Youssef R, 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;12(1):32–9.CrossRefGoogle Scholar
  7. 7.
    Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, Halloran P, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med. 1998;338(3):161–5.CrossRefGoogle Scholar
  8. 8.
    Sollinger H, Kaplan B, Pescovitz MD, Philosophe B, Roza A, Brayman K, et al. Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection. Transplantation. 2001;72(12):1915–9.CrossRefGoogle Scholar
  9. 9.
    Clark G, Walsh G, Deshpande P, Koffman G. Improved efficacy of basiliximab over antilymphocyte globulin induction therapy in paediatric renal transplantation. Nephrol Dial Transplant. 2002;17(7):1304–9.CrossRefGoogle Scholar
  10. 10.
    Thomusch O, Wiesener M, Opgenoorth M, Pascher A, Woitas RP, Witzke O, et al. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial. Lancet. 2016;388(10063):3006–16.CrossRefGoogle Scholar
  11. 11.
    Kirk AD, Hale DA, Mannon RB, Kleiner DE, Hoffmann SC, Kampen RL, 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.CrossRefGoogle Scholar
  12. 12.
    Calne R, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation. 1999;68(10):1613–6.CrossRefGoogle Scholar
  13. 13.
    Kim IK, Choi J, Vo AA, Kang A, Patel M, Toyoda M, et al. Safety and efficacy of alemtuzumab induction in highly sensitized pediatric renal transplant recipients. Transplantation. 2017;101(4):883–9.CrossRefGoogle Scholar
  14. 14.
    Supe-Markovina K, Melquist JJ, Connolly D, DiCarlo HN, Waltzer WC, Fine RN, et al. Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: a seven-yr experience. Pediatr Transplant. 2014;18(4):363–8.CrossRefGoogle Scholar
  15. 15.
    Serrano OK, Friedmann P, Ahsanuddin S, Millan C, Ben-Yaacov A, Kayler LK. Outcomes associated with steroid avoidance and alemtuzumab among kidney transplant recipients. Clin J Am Soc Nephrol. 2015;10(11):2030–8.CrossRefGoogle Scholar
  16. 16.
    Sung J, Barry JM, Jenkins R, Rozansky D, Iragorri S, Conlin M, et al. Alemtuzumab induction with tacrolimus monotherapy in 25 pediatric renal transplant recipients. Pediatr Transplant. 2013;17(8):718–25.CrossRefGoogle Scholar
  17. 17.
    Cole E, Maham N, Cardella C, Cattran D, Fenton S, Hamel J, et al. Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients. Transplantation. 2003;75(12):2086–90.CrossRefGoogle Scholar
  18. 18.
    Meier-Kriesche HU, Bonilla-Felix MA, Ferris ME, Swinford R, Kahan BD, Brannan P, et al. A limited sampling strategy for the estimation of neoral AUCs in pediatric patients. Pediatr Nephrol. 1999;13(9):742–7.CrossRefGoogle Scholar
  19. 19.
    Trompeter R, Filler G, Webb NJ, Watson AR, Milford DV, Tyden G, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol. 2002;17(3):141–9.CrossRefGoogle Scholar
  20. 20.
    Wlodarczyk Z, Squifflet JP, Ostrowski M, Rigotti P, Stefoni S, Citterio F, et al. Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant. 2009;9(11):2505–13.CrossRefGoogle Scholar
  21. 21.
    Kramer BK, Charpentier B, Backman L, Silva HT Jr, Mondragon-Ramirez G, Cassuto-Viguier E, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant. 2010;10(12):2632–43.CrossRefGoogle Scholar
  22. 22.
    Guirado L, Cantarell C, Franco A, Huertas EG, Fructuoso AS, Fernandez A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant. 2011;11(9):1965–71.CrossRefGoogle Scholar
  23. 23.
    Sessa A, Esposito A, Iavicoli G, Lettieri E, Ragosta G, Rossano R, et al. Cardiovascular risk factors in renal transplant patients after switch from standard tacrolimus to prolonged-release tacrolimus. Transplant Proc. 2012;44(7):1901–6.CrossRefGoogle Scholar
  24. 24.
    Tremblay S, Nigro V, Weinberg J, Woodle ES, Alloway RR. A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study. Am J Transplant. 2017;17(2):432–42.CrossRefGoogle Scholar
  25. 25.
    Zhao W, Fakhoury M, Baudouin V, Storme T, Maisin A, Deschenes G, et al. Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients. Eur J Clin Pharmacol. 2013;69(2):189–95.CrossRefGoogle Scholar
  26. 26.
    Shihab FS, Bennett WM, Tanner AM, Andoh TF. Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. Transplantation. 1997;64(12):1829–37.CrossRefGoogle Scholar
  27. 27.
    Midtvedt K, Hartmann A, Foss A, Fauchald P, Nordal KP, Rootwelt K, et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril. Transplantation. 2001;72(11):1787–92.CrossRefGoogle Scholar
  28. 28.
    Butani L, Afshinnik A, Johnson J, Javaheri D, Peck S, German JB, et al. Amelioration of tacrolimus-induced nephrotoxicity in rats using juniper oil. Transplantation. 2003;76(2):306–11.CrossRefGoogle Scholar
  29. 29.
    Bergan S, Rugstad HE, Bentdal O, Sodal G, Hartmann A, Leivestad T, et al. Monitored high-dose azathioprine treatment reduces acute rejection episodes after renal transplantation. Transplantation. 1998;66(3):334–9.CrossRefGoogle Scholar
  30. 30.
    Dubus I, Vendrely B, Christophe I, Labouyrie JP, Delmas Y, Bonnet J, et al. Mycophenolic acid antagonizes the activation of cultured human mesangial cells. Kidney Int. 2002;62(3):857–67.CrossRefGoogle Scholar
  31. 31.
    Henne T, Latta K, Strehlau J, Pape L, Ehrich JH, Offner G. Mycophenolate mofetil-induced reversal of glomerular filtration loss in children with chronic allograft nephropathy. Transplantation. 2003;76(9):1326–30.CrossRefGoogle Scholar
  32. 32.
    Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman AB, Cibrik D, Magee JC, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation. 2000;69(11):2405–9.CrossRefGoogle Scholar
  33. 33.
    Filler G, Zimmering M, Mai I. Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression. Pediatr Nephrol. 2000;14(2):100–4.CrossRefGoogle Scholar
  34. 34.
    Weber LT, Shipkova M, Armstrong VW, Wagner N, Schutz E, Mehls O, et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: a report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol. 2002;13(3):759–68.PubMedGoogle Scholar
  35. 35.
    Filler G, Feber J, Lepage N, Weiler G, Mai I. Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children. Pediatr Transplant. 2002;6(5):411–8.CrossRefGoogle Scholar
  36. 36.
    Mycophenolate mofetil in cadaveric renal transplantation. US Renal Transplant Mycophenolate Mofetil Study Group. Am J Kidney Dis. 1999;34(2):296–303.Google Scholar
  37. 37.
    Jungraithmayr T, Staskewitz A, Kirste G, Boswald M, Bulla M, Burghard R, et al. Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years. Transplantation. 2003;75(4):454–61.CrossRefGoogle Scholar
  38. 38.
    Butani L, Palmer J, Baluarte HJ, Polinsky MS. Adverse effects of mycophenolate mofetil in pediatric renal transplant recipients with presumed chronic rejection. Transplantation. 1999;68(1):83–6.CrossRefGoogle Scholar
  39. 39.
    Sollinger HW, Sundberg AK, Leverson G, Voss BJ, Pirsch JD. Mycophenolate mofetil versus enteric-coated mycophenolate sodium: a large, single-center comparison of dose adjustments and outcomes in kidney transplant recipients. Transplantation. 2010;89(4):446–51.CrossRefGoogle Scholar
  40. 40.
    Salvadori M, Holzer H, de Mattos A, Sollinger H, Arns W, Oppenheimer F, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant. 2004;4(2):231–6.CrossRefGoogle Scholar
  41. 41.
    Ettenger R, Bartosh S, Choi L, Zhu W, Niederberger W, Campestrini J, et al. Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients. Pediatr Transplant. 2005;9(6):780–7.CrossRefGoogle Scholar
  42. 42.
    Niaudet P, Charbit M, Loirat C, Lapeyraque AL, Tsimaratos M, Cailliez M, et al. Enteric-coated mycophenolate sodium in de novo pediatric renal transplant patients. Pediatr Nephrol. 2009;24(2):395–402.CrossRefGoogle Scholar
  43. 43.
    Budde K, Curtis J, Knoll G, Chan L, Neumayer HH, Seifu Y, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant. 2004;4(2):237–43.CrossRefGoogle Scholar
  44. 44.
    Schubert M, Venkataramanan R, Holt DW, Shaw LM, McGhee W, Reyes J, et al. Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients. Am J Transplant. 2004;4(5):767–73.CrossRefGoogle Scholar
  45. 45.
    Schachter AD, Meyers KE, Spaneas LD, Palmer JA, Salmanullah M, Baluarte J, et al. Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant. 2004;8(2):171–7.CrossRefGoogle Scholar
  46. 46.
    Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet. 2000;356(9225):194–202.CrossRefGoogle Scholar
  47. 47.
    McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MacDonald AS. Sirolimus-tacrolimus combination immunosuppression. Lancet. 2000;355(9201):376–7.CrossRefGoogle Scholar
  48. 48.
    Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, 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.CrossRefGoogle Scholar
  49. 49.
    Hong JC, Kahan BD. Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation. 2000;69(10):2085–90.CrossRefGoogle Scholar
  50. 50.
    Stallone G, Di Paolo S, Schena A, Infante B, Battaglia M, Ditonno P, 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.CrossRefGoogle Scholar
  51. 51.
    Smith KD, Wrenshall LE, Nicosia RF, Pichler R, Marsh CL, Alpers CE, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol. 2003;14(4):1037–45.CrossRefGoogle Scholar
  52. 52.
    Majewski M, Korecka M, Joergensen J, Fields L, Kossev P, Schuler W, et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation. 2003;75(10):1710–7.CrossRefGoogle Scholar
  53. 53.
    Dharnidharka VR, Schnitzler MA, Chen J, Brennan DC, Axelrod D, Segev DL, et al. Differential risks for adverse outcomes 3 years after kidney transplantation based on initial immunosuppression regimen: a national study. Transpl Int. 2016;29(11):1226–36.CrossRefGoogle Scholar
  54. 54.
    Knoll GA, Kokolo MB, Mallick R, Beck A, Buenaventura CD, Ducharme R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014;349:g6679.CrossRefGoogle Scholar
  55. 55.
    Weir MR, Pearson TC, Patel A, Peddi VR, Kalil R, Scandling J, et al. Long-term follow-up of kidney transplant recipients in the spare-the-nephron-trial. Transplantation. 2017;101(1):157–65.CrossRefGoogle Scholar
  56. 56.
    Mulay AV, Hussain N, Fergusson D, Knoll GA. Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials. Am J Transplant. 2005;5(7):1748–56.CrossRefGoogle Scholar
  57. 57.
    Hoyer PF, Ettenger R, Kovarik JM, Webb NJ, Lemire J, Mentser M, et al. Everolimus in pediatric de nova renal transplant patients. Transplantation. 2003;75(12):2082–5.CrossRefGoogle Scholar
  58. 58.
    Sarwal MM, Ettenger RB, Dharnidharka V, Benfield M, Mathias R, Portale A, et al. Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Am J Transplant. 2012;12(10):2719–29.CrossRefGoogle Scholar
  59. 59.
    Tsampalieros A, Knoll GA, Molnar AO, Fergusson N, Fergusson DA. Corticosteroid use and growth after pediatric solid organ transplantation: a systematic review and meta-analysis. Transplantation. 2017;101(4):694–703.CrossRefGoogle Scholar
  60. 60.
    Webb NJ, Douglas SE, Rajai A, Roberts SA, Grenda R, Marks SD, et al. Corticosteroid-free kidney transplantation improves growth: 2-year follow-up of the TWIST randomized controlled trial. Transplantation. 2015;99(6):1178–85.CrossRefGoogle Scholar
  61. 61.
    Naesens M, Salvatierra O, Benfield M, Ettenger RB, Dharnidharka V, Harmon W, et al. Subclinical inflammation and chronic renal allograft injury in a randomized trial on steroid avoidance in pediatric kidney transplantation. Am J Transplant. 2012;12(10):2730–43.CrossRefGoogle Scholar
  62. 62.
    Li L, Chaudhuri A, Chen A, Zhao X, Bezchinsky M, Concepcion W, et al. Efficacy and safety of thymoglobulin induction as an alternative approach for steroid-free maintenance immunosuppression in pediatric renal transplantation. Transplantation. 2010;90(12):1516–20.CrossRefGoogle Scholar
  63. 63.
    Lau KK, Berg GM, Schjoneman YG, Perez RV, Butani L. Extended experience with a steroid minimization immunosuppression protocol in pediatric renal transplant recipients. Pediatr Transplant. 2010;14(4):488–95.CrossRefGoogle Scholar
  64. 64.
    Weir MR, Anderson L, Fink JC, Gabregiorgish K, Schweitzer EJ, Hoehn-Saric E, et al. A novel approach to the treatment of chronic allograft nephropathy. Transplantation. 1997;64(12):1706–10.CrossRefGoogle Scholar
  65. 65.
    Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349(24):2326–33.CrossRefGoogle Scholar
  66. 66.
    Kreis H, Oberbauer R, Campistol JM, Mathew T, Daloze P, Schena FP, et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol. 2004;15(3):809–17.CrossRefGoogle Scholar
  67. 67.
    Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10(3):535–46.CrossRefGoogle Scholar
  68. 68.
    Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374(4):333–43.CrossRefGoogle Scholar
  69. 69.
    Lerch C, Kanzelmeyer NK, Ahlenstiel-Grunow T, Froede K, Kreuzer M, Drube J, et al. Belatacept after kidney transplantation in adolescents: a retrospective study. Transpl Int. 2017;30:494–501.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of California Davis Medical CenterSacramentoUSA

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