What is the calcineurin inhibitor of choice for pediatric renal transplantation?
Jameela A. Kari,
Richard S. Trompeter,
Jameela A. Kari
Pediatrics Department, King AbdulAziz University Hospital, Jeddah, Saudi Arabia
Search for more papers by this authorRichard S. Trompeter
Renal Unit, Gt Ormond St Hospital for Children NHS Trust, London, UK
Search for more papers by this authorJameela A. Kari,
Richard S. Trompeter,
Jameela A. Kari
Pediatrics Department, King AbdulAziz University Hospital, Jeddah, Saudi Arabia
Search for more papers by this authorRichard S. Trompeter
Renal Unit, Gt Ormond St Hospital for Children NHS Trust, London, UK
Search for more papers by this authorDr Richard S. Trompeter, Renal Office, Gt Ormond St Hospital for Children NHS Trust, Gt Ormond St, London WC1N 3JH, UK
Tel.: 44 20 7813 8346
Fax: 44 20 7829 8841
E-mail: [email protected] or [email protected]
Abstract
Abstract: Cyclosporine microemulsion (CyA) and tacrolimus (Tac) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. In the majority of patients, these calcineurin inhibitors have been used in combination with other immunosuppressive drugs, such as azathioprine or mycophenolate mofetil (MMF). In this review we will address the question of what calcineurin inhibitor we should use in an individual pediatric renal transplant patient. Well-designed randomized studies in children showed no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However Tac is significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population when used in conjunction with azathioprine and corticosteroids. This difference disappears when calcineurin inhibitors are used in combination with MMF as both Tac and CyA produce similar rejection rates and graft survival. However, Tac is associated with improved graft function at 1 and 2 yr post-transplant. Adverse events of hypomagnesaemia and diarrhea seem to be higher in Tac group whereas hypertrichosis, flu syndrome and gum hyperplasia occurs more frequently in the CyA group. The incidence of post-transplant diabetes mellitus was almost identical between Tac and CyA treated patients. The recommendation drawn from the available data is that both CyA and Tac can be used safely and effectively in children. However Tac may be preferable to CyA because of steroid sparing effect and less hirsutism. We recommend that cyclosporine should be chosen when patients experience Tac-related adverse events. Nevertheless, the best calcineurin inhibitor should be decided on individual patients according to variable risk factors, such as risk of rejection in sensitized patient or delayed graft function. The possibility of adverse events should also be considered.
References
- 1 Benfield MR, McDonald RA, Bartosh S, Ho PL, Harmon W. Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2003: 7: 321–335.
- 2 Cecka JM, Gjertson DW, Terasaki PI. Pediatric renal transplantation: a review of the UNOS data. United Network for Organ Sharing. Pediatr Transplant 1997: 1: 55–64.
- 3 Gjertson DW, Cecka JM, Terasaki PI. The Relative effects of FK506 and cyclosporine on short- and long-term kidney graft survival. Transplantation 1995: 60: 1384–1388.
- 4 Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 1976: 6: 468–475.
- 5 Starzl TE, Iwatsulki S, Malatack JJ et al. Liver and kidney transplantation in children receiving cyclosporin A and steroids. J Pediatr 1982: 100: 681–686.
- 6 Hamawy MM. Molecular actions of calcineurin inhibitors. Drug News Perspect 2003: 16: 277–282.
- 7 Dunn CJ, Wagstaff AJ, Perry CM, Plosker GL, Goa KL. Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ transplantation. Drugs 2001: 61: 1957–2016.
- 8 Cooney GF, Habucky K, Hoppu K. Cyclosporin pharmacokinetics in paediatric transplant recipients. Clin Pharmacokinet 1997: 32: 481–495.
- 9 Ettenger RB. Age and the immune response in pediatric renal transplantation. Eur J Pediatr 1992: 151(Suppl. 1): S7–S8.
- 10 Kino T, Hatanaka H, Miyata S et al. FK-506, a novel immunosuppressant isolated from a streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987: 40: 1256–1265.
- 11 Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989: 2: 1000–1004.
- 12 Olyaei AJ, De Mattos AM, Bennett WM. Nephrotoxicity of Immunosuppressive Drugs: New Insight and Preventive Strategies. Curr Opin Crit Care 2001: 7: 384–389.
- 13 Tanabe K. Calcineurin inhibitors in renal transplantation: what is the best option? Drugs 2003: 63: 1535–1548.
- 14 Mayer AD, Dmitrewski J, Squifflet JP et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a Report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997: 64: 436–443.
- 15 Chang RW, Snowden S, Palmer A et al. European randomized trial of dual versus triple tacrolimus-based regimens for control of acute rejection in renal allograft recipients. Transpl Int 2001: 14: 384–390.
- 16 Margreiter R. Efficacy and safety of tacrolimus compared with cyclosporin microemulsion in renal transplantation: a randomized multicenter study. Lancet 2002: 359: 741–746.
- 17 Charpentier B, Rostaing L, Berthoux F et al. A Three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation 2003: 75: 844–851.
- 18 Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomized trials. BMJ 1999: 318: 1104–1107.
- 19 Trompeter R, Filler G, Webb NJ et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002: 17: 141–149.
- 20 Jurewicz WA. Tacrolimus versus cyclosporin immunosuppression: long-term outcome in renal transplantation. Nephrol Dial Transplant 2003: 18(Suppl. 1): 7–11.
- 21 Benfield MR, Stablein D, Tejani A. Trends in immunosuppressive therapy: a Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 1999: 3: 27–32.
- 22 Elshihabi I, Chavers B, Donaldson L, Emmett L, Tejani A. Continuing improvement in cadaver donor graft survival in north American children: the 1998 Annual Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 2000: 4: 235–246.
- 23 Trompeter R, Fitzpatrick M, Hutchinson C, Johnston A. 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: 282–288.
- 24 Filler G, Trompeter R, Webb NJ et al. One-year glomerular filtration rate predicts graft survival in pediatric renal recipients: a randomized trial of tacrolimus vs. cyclosporin microemulsion. Transplant Proc 2002: 34: 1935–1938.
- 25 Tejani A, Ho PL, Emmett L, Stablein DM. Reduction in acute rejections decreases chronic rejection graft failure in children: a Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Am J Transplant 2002: 2: 142–147.
- 26 Tejani A, Sullivan EK. The impact of acute rejection on chronic rejection: a Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2000: 4: 107–111.
- 27 Del Castillo D. Analysis of primary and recurrent rejection following renal transplantation in a large, comparative, multicentre trial. Transplant Proc 2001: 33: 1259–1261.
- 28 Sperschneider H. A large multicentre trial to compare the efficacy and safety of tacrolimus with cyclosporine microemulsion following renal transplantation. Transplant Proc 2001: 33: 1279–1281.
- 29 Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of Its use in the management of organ transplantation. Drugs 2003: 63: 1247–1297.
- 30 Murphy GJ, Waller JR, Sandford RS, Furness PN, Nicholson ML. Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis. Br J Surg 2003: 90: 680–686.
- 31 Weber LT, Hocker B, Mehls O, Tonshoff B. Mycophenolate mofetil in pediatric renal transplantation. Minerva Urol Nefrol 2003: 55: 91–99.
- 32 Gonin JM. Maintenance immunosuppression: new agents and persistent dilemmas. Adv Ren Replace Ther 2000: 7: 95–116.
- 33 Virji M, Carter JE, Lirenman DS. Single-center experience with mycophenolate mofetil in pediatric renal transplant recipients. Pediatr Transplant 2001: 5: 293–296.
- 34 Staskewitz A, Kirste G, Tonshoff B et al. Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. German Pediatric Renal Transplantation Study Group. Transplantation 2001: 71: 638–644.
- 35 Jungraithmayr T, Staskewtiz A, Kirste G et al. Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years. Transplantation 2003: 75: 454–461.
- 36 Neu AM, Ho PL, Fine RN, Furth SL, Fivush BA. Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: a NAPRTCS Study. Pediatr Transplant 2003: 7: 217–222.
- 37 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: 834–841.
- 38 Ahsan N, Johnson C, Gonwa T et al. Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years. Transplantation 2001: 72: 245–250.
- 39 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: 2048–2053.
- 40 Bunnapradist S, Daswani A, Takemoto SK. Graft survival following living-donor renal transplantation: a comparison of tacrolimus and cyclosporine microemulsion with mycophenolate mofetil and steroids. Transplantation 2003: 76: 10–15.
- 41 Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf 2001: 24: 645–663.
- 42 Ganschow R, Lyons M, Kemper MJ, Burdelski M. B-Cell dysfunction and depletion using mycophenolate mofetil in a pediatric combined liver and kidney graft recipient. Pediatr Transplant 2001: 5: 60–63.
- 43 Fruhwirth M, Fischer H, Simma B, Ellemunter H. Elevated tacrolimus trough levels in association with mycophenolate mofetil-induced diarrhea: a case report. Pediatr Transplant 2001: 5: 132–134.
- 44 Dharnidharka VR, Ho PL, Stablein DM, Harmon WE, Tejani AH. Mycophenolate, Tacrolimus and post-transplant lymphoproliferative disorder: a Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2002: 6: 396–399.
- 45 Loirat C, Niaudet P. The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Pediatr Nephrol 2003: 18: 1095–1101.
- 46 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: 5: 302–309.
- 47 Nashan B. Early Clinical Experience With a Novel Rapamycin Derivative. Ther Drug Monit 2002: 24: 53–58.
- 48 Hoyer PF, Ettenger R, Kovarik JM et al. Everolimus in pediatric De nova renal transplant patients. Transplantation 2003: 75: 2082–2085.
- 49 Vester U, Kranz B, Wehr S, Boger R, Hoyer PF. Everolimus (Certican) in combination with neoral in pediatric renal transplant recipients: interim analysis after 3 months. Transplant Proc 2002: 34: 2209–2210.
- 50 El Sabrout R, Weiss R, Butt F et al. Rejection-free protocol using sirolimus-tacrolimus combination for pediatric renal transplant recipients. Transplant Proc 2000: 34: 1942–1943.
- 51 Sindhi R. Sirolimus in pediatric transplant recipients. Transplant Proc 2003: 35: S113–S114.
- 52 Vilalta R, Vila A, Nieto J, Callis L. Rapamycin use and rapid withdrawal of calcineurin inhibitors in pediatric renal transplantation. Transplant Proc 2003: 35: 703–704.
- 53 Kahan BD. Two-year results of multicenter phase III trials on the effect of the addition of sirolimus to cyclosporine-based immunosuppressive regimens in renal transplantation. Transplant Proc 2003: 35: S37–S51.
- 54 MacDonald AS. A Worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001: 71: 271–280.
- 55 Hricik DE, Anton HA, Knauss TC et al. Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids. Transplantation 2002: 74: 189–193.
- 56 Friemann S, Feuring E, Padberg W, Ernst W. Improvement of nephrotoxicity, hypertension, and lipid Metabolism after conversion of kidney transplant recipients from cyclosporine to tacrolimus. Transplant Proc 1998: 30: 1240–1242.
- 57 Grewal HP, Thistlethwaite JR Jr, Loss GE et al. Corticosteroid cessation 1 week following renal transplantation using tacrolimus/mycophenolate mofetil based immunosuppression. Transplant Proc 1998: 30: 1378–1379.
- 58 Van Hooff JP, Van Duijnhoven EM, Christiaans MH. Tacrolimus and glucose metabolism. Transplant Proc 1999: 31: 49S–50S.
- 59 Tanabe K, Ishikawa N, Shimizu et al. Japanese Single-center experience of kidney transplantation under tacrolimus immunosuppression. Transplant Proc 2000: 32: 1696–1699.
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