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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Review Article

Immunosuppressive Management of Pediatric Kidney Transplant Recipients

Author(s): Tomáš Seeman*

Volume 26, Issue 28, 2020

Page: [3451 - 3459] Pages: 9

DOI: 10.2174/1381612826666200708133429

Price: $65

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Abstract

Kidney transplantation is a preferable treatment of children with end-stage kidney disease. All kidney transplant recipients, including pediatric need immunosuppressive medications to prevent rejection episodes and graft loss.

Induction therapy is used temporarily only immediately following transplantation while maintenance immunosuppressive drugs are started and given long-term. There is currently no consensus regarding the use of induction therapy in children; its use should be decided based on the immunological risk of the child.

The recent progress shows that the recommended strategy is to use as maintenance immunosuppressive therapy a combination of a calcineurin inhibitor (preferably tacrolimus) with an antiproliferative drug (preferably mycophenolate mofetil) with steroids that can be withdrawn early or late in low-risk children. The mTOR-inhibitors (sirolimus, everolimus) are used rarely in pediatrics because of common side effects and no evidence of a benefit over calcineurin inhibitors. The use of calcineurin inhibitors, mycophenolate, and mTOR-inhibitors should be followed by therapeutic drug monitoring.

Immunosuppressive therapy of acute rejection consists of high-dose steroids and/or anti-lymphocyte antibodies (T-cell mediated rejection) or plasma exchange, intravenous immunoglobulines and/or rituximab (antibodymediated rejection).

The future strategies for research are mainly precise characterisation of children needing induction therapy, more specific indications for mTOR-inhibitors and for the far future, the possibility to reach the immuno tolerance.

Keywords: Corticosteroids, calcineurin inhibitors, tacrolimus, cyclosporine, antiproliferative drugs, mycophenolate mofetil, azathioprine, sirolimus, everolimus, rituximab.

« Previous Next »
[1]
Dharnidharka VR, Fiorina P, Harmon WE. Kidney transplantation in children. N Engl J Med 2014; 371(6): 549-58.
[http://dx.doi.org/10.1056/NEJMra1314376] [PMID: 25099579]
[2]
Verghese PS. Pediatric kidney transplantation: a historical review. Pediatr Res 2017; 81(1-2): 259-64.
[http://dx.doi.org/10.1038/pr.2016.207] [PMID: 27732587]
[3]
Murray JE, Merrill JP, Dammin GJ, et al. Study on transplantation immunity after total body irradiation: clinical and experimental investigation. Surgery 1960; 48: 272-84.
[PMID: 14425430]
[4]
Heemann U, Abramowicz D, Spasovski G, Vanholder R. European Renal Best Practice Work Group on Kidney Transplantation. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant 2011; 26(7): 2099-106.
[http://dx.doi.org/10.1093/ndt/gfr169] [PMID: 21555392]
[5]
Webster AC, Ruster LP, McGee R, et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2010; (1): CD003897
[http://dx.doi.org/10.1002/14651858.CD003897.pub3] [PMID: 20091551]
[6]
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(1) CD004759
[http://dx.doi.org/10.1002/14651858.CD004759.pub2] [PMID: 28073178]
[7]
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(4): 321-35.
[http://dx.doi.org/10.1034/j.1399-3046.2003.00029.x] [PMID: 12890012]
[8]
Feld LG, Stablein D, Fivush B, Harmon W, Tejani A. 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.
[PMID: 10084775]
[9]
Grenda R, Watson A, Vondrak K, et al. A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation. Am J Transplant 2006; 6(7): 1666-72.
[http://dx.doi.org/10.1111/j.1600-6143.2006.01367.x] [PMID: 16827869]
[10]
Webb NJ, Prokurat S, Vondrak K, et al. Multicentre prospective randomised trial of tacrolimus, azathioprine and prednisolone with or without basiliximab: two-year follow-up data. Pediatr Nephrol 2009; 24(1): 177-82.
[http://dx.doi.org/10.1007/s00467-008-0931-x] [PMID: 18688657]
[11]
Offner G, Toenshoff B, Höcker B, et al. Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids. Transplantation 2008; 86(9): 1241-8.
[http://dx.doi.org/10.1097/TP.0b013e318188af15] [PMID: 19005406]
[12]
Pape L. State-of-the-art immunosuppression protocols for pediatric renal transplant recipients. Pediatr Nephrol 2017; 34: 187-94.
[http://dx.doi.org/10.1007/s00467-017-3826-x] [PMID: 29067527]
[13]
Grenda R, Watson A, Trompeter R, et al. 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(4): 828-36.
[http://dx.doi.org/10.1111/j.1600-6143.2010.03047.x] [PMID: 20420639]
[14]
Mehrnia A, Le TX, Tamer TR, Bunnapradist S. Effects of acute rejection vs new-onset diabetes after transplant on transplant outcomes in pediatric kidney recipients: analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database. Pediatr Transplant 2016; 20(7): 952-7.
[http://dx.doi.org/10.1111/petr.12790] [PMID: 27578397]
[15]
Martinez-Mier G, Mendez-Lopez MT, Soto-Miranda E, et al. Acute rejection is a strong negative predictor of graft survival in living-donor pediatric renal transplant: 10-year follow-up in a single mexican center. Exp Clin Transplant 2019; 17(2): 170-6.
[http://dx.doi.org/10.6002/ect.2017.0265] [PMID: 30945629]
[16]
Smith JM, Martz K, Blydt-Hansen TD. Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: a report of the North American Pediatric Renal Trials and Collaborative Studies. Pediatr Transplant 2013; 17(2): 149-57.
[http://dx.doi.org/10.1111/petr.12034] [PMID: 23281637]
[17]
Crowson CN, Reed RD, Shelton BA, MacLennan PA, Locke JE. Lymphocyte-depleting induction therapy lowers the risk of acute rejection in African American pediatric kidney transplant recipients. Pediatr Transplant 2017; 21(1)
[http://dx.doi.org/10.1111/petr.12823] [PMID: 27699934]
[18]
Mota C, Martins L, Costa T, et al. Nineteen years of experience utilizing anti-T-Lymphocyte globulin induction in pediatric kidney transplantation. Ann Transplant 2010; 15(4): 84-91.
[PMID: 21183882]
[19]
Trompeter R, Filler G, Webb NJ, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002; 17(3): 141-9.
[http://dx.doi.org/10.1007/s00467-001-0795-9] [PMID: 11956848]
[20]
Filler G, Womiloju T, Feber J, Lepage N, Christians U. Adding sirolimus to tacrolimus-based immunosuppression in pediatric renal transplant recipients reduces tacrolimus exposure. Am J Transplant 2005; 5(8): 2005-10.
[http://dx.doi.org/10.1111/j.1600-6143.2005.00963.x] [PMID: 15996252]
[21]
Holmberg C. Nonadherence after pediatric renal transplantation: detection and treatment. Curr Opin Pediatr 2019; 31(2): 219-25.
[http://dx.doi.org/10.1097/MOP.0000000000000734] [PMID: 30672821]
[22]
Höcker B, Tönshoff B. Calcineurin inhibitor-free immunosuppression in pediatric renal transplantation: a viable option? Paediatr Drugs 2011; 13(1): 49-69.
[http://dx.doi.org/10.2165/11538530-000000000-00000] [PMID: 21162600]
[23]
European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995; 345(8961): 1321-5.
[http://dx.doi.org/10.1016/S0140-6736(95)92534-1] [PMID: 7752752]
[24]
Sollinger HW. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60(3): 225-32.
[http://dx.doi.org/10.1097/00007890-199508000-00003] [PMID: 7645033]
[25]
Wagner M, Earley AK, Webster AC, Schmid CH, Balk EM, Uhlig K. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2015; (12): CD007746
[http://dx.doi.org/10.1002/14651858.CD007746.pub2] [PMID: 26633102]
[26]
Staskewitz A, Kirste G, Tönshoff B, et al. German Pediatric Renal Transplantation Study Group. Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. Transplantation 2001; 71(5): 638-44.
[http://dx.doi.org/10.1097/00007890-200103150-00010] [PMID: 11292293]
[27]
Jungraithmayr TC, Wiesmayr S, Staskewitz A, et al. German Pediatric Renal Transplantation Study Group. Five-year outcome in pediatric patients with mycophenolate mofetil-based renal transplantation. Transplantation 2007; 83(7): 900-5.
[http://dx.doi.org/10.1097/01.tp.0000258587.70166.87] [PMID: 17460560]
[28]
Tönshoff B. Should we monitor mycophenolic acid plasma levels in pediatric renal transplantation? Pediatr Transplant 2015; 19(7): 665-6.
[http://dx.doi.org/10.1111/petr.12605] [PMID: 26435035]
[29]
Le Meur Y, Büchler M, Thierry A, 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.
[http://dx.doi.org/10.1111/j.1600-6143.2007.01983.x] [PMID: 17908276]
[30]
Weber LT, Shipkova M, Armstrong VW, 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.
[PMID: 11856782]
[31]
Guilpain P, Le Jeunne C. [Anti-inflammatory and immunosuppressive properties of corticosteroids]. Presse Med 2012; 41(4): 378-83.
[http://dx.doi.org/10.1016/j.lpm.2012.01.010] [PMID: 22361029]
[32]
Ahsan N, Hricik D, Matas A, et al. Steroid Withdrawal Study Group. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Transplantation 1999; 68(12): 1865-74.
[http://dx.doi.org/10.1097/00007890-199912270-00009] [PMID: 10628766]
[33]
Opelz G, Döhler B, Laux G. Collaborative Transplant Study. Long term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant 2005; 5(4 Pt 1): 720-8.
[http://dx.doi.org/10.1111/j.1600-6143.2004.00765.x] [PMID: 15760395]
[34]
Grenda R. Steroid withdrawal in renal transplantation. Pediatr Nephrol 2013; 28(11): 2107-12.
[http://dx.doi.org/10.1007/s00467-012-2391-6] [PMID: 23288351]
[35]
Höcker B, Weber LT, Feneberg R, et al. Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant 2010; 25(2): 617-24.
[http://dx.doi.org/10.1093/ndt/gfp506] [PMID: 19793929]
[36]
Sarwal MM, Yorgin PD, Alexander S, et al. Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in pediatric renal transplantation. Transplantation 2001; 72(1): 13-21.
[http://dx.doi.org/10.1097/00007890-200107150-00006] [PMID: 11468528]
[37]
Sarwal MM, Ettenger RB, Dharnidharka V, 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.
[http://dx.doi.org/10.1111/j.1600-6143.2012.04145.x] [PMID: 22694755]
[38]
Benfield MR, Bartosh S, Ikle D, et al. A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant 2010; 10(1): 81-8.
[http://dx.doi.org/10.1111/j.1600-6143.2009.02767.x] [PMID: 19663893]
[39]
McDonald RA, Smith JM, Ho M, et al. CCTPT Study Group. Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant 2008; 8(5): 984-9.
[http://dx.doi.org/10.1111/j.1600-6143.2008.02167.x] [PMID: 18416737]
[40]
Harmon W, Meyers K, Ingelfinger J, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol 2006; 17(6): 1735-45.
[http://dx.doi.org/10.1681/ASN.2006010049] [PMID: 16687625]
[41]
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(6): 658-62.
[http://dx.doi.org/10.1097/TP.0b013e3182295bed] [PMID: 21804444]
[42]
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(3): 237-43.
[http://dx.doi.org/10.1111/petr.12035] [PMID: 23279564]
[43]
Ganschow R, Pape L, Sturm E, et al. Growing experience with mTOR inhibitors in pediatric solid organ transplantation. Pediatr Transplant 2013; 17(7): 694-706.
[http://dx.doi.org/10.1111/petr.12147] [PMID: 24004351]
[44]
Diekmann F, Budde K, Oppenheimer F, Fritsche L, Neumayer HH, Campistol JM. Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant 2004; 4(11): 1869-75.
[http://dx.doi.org/10.1111/j.1600-6143.2004.00590.x] [PMID: 15476488]
[45]
Naik MG, Heller KM, Arns W, et al. German Sirolimus Study Group. Proteinuria and sirolimus after renal transplantation: a retrospective analysis from a large German multicenter database. Clin Transplant 2014; 28(1): 67-79.
[http://dx.doi.org/10.1111/ctr.12280] [PMID: 24372584]
[46]
Pape L, Ahlenstiel T. mTOR inhibitors in pediatric kidney transplantation. Pediatr Nephrol 2014; 29(7): 1119-29.
[http://dx.doi.org/10.1007/s00467-013-2505-9] [PMID: 23740036]
[47]
Pape L, Ahlenstiel T, Ehrich JH, Offner G. Reversal of loss of glomerular filtration rate in children with transplant nephropathy after switch to everolimus and low-dose cyclosporine A. Pediatr Transplant 2007; 11(3): 291-5.
[http://dx.doi.org/10.1111/j.1399-3046.2006.00651.x] [PMID: 17430485]
[48]
Filler G, Webb NJ, Milford DV, et al. Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant 2005; 9(4): 498-503.
[http://dx.doi.org/10.1111/j.1399-3046.2005.00334.x] [PMID: 16048603]
[49]
Hymes LC, Warshaw BL, Amaral SG, Greenbaum LA. Tacrolimus withdrawal and conversion to sirolimus at three months post pediatric renal transplantation. Pediatr Transplant 2008; 12(7): 773-7.
[http://dx.doi.org/10.1111/j.1399-3046.2008.00906.x] [PMID: 18282210]
[50]
Brunkhorst LC, Fichtner A, Höcker B, et al. Efficacy and safety of an everolimus- vs. a mycophenolate mofetil-based regimen in pediatric renal transplant recipients. PLoS One 2015; 10(9) e0135439
[http://dx.doi.org/10.1371/journal.pone.0135439] [PMID: 26407177]
[51]
Tönshoff B, Ettenger R, Dello Strologo L, et al. Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial. Am J Transplant 2019; 19(3): 811-22.
[http://dx.doi.org/10.1111/ajt.15081] [PMID: 30125462]
[52]
Schachter AD, Meyers KE, Spaneas LD, et al. Short sirolimus half life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 2004; 8(2): 171-7.
[http://dx.doi.org/10.1046/j.1399-3046.2003.00148.x] [PMID: 15049798]
[53]
Ahlenstiel-Grunow T, Koch A, Großhennig A, et al. A multicenter, randomized, open-labeled study to steer immunosuppressive and antiviral therapy by measurement of virus (CMV, ADV, HSV)-specific T cells in addition to determination of trough levels of immunosuppressants in pediatric kidney allograft recipients (IVIST01-trial): study protocol for a randomized controlled trial. Trials 2014; 15: 324.
[http://dx.doi.org/10.1186/1745-6215-15-324] [PMID: 25127887]
[54]
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9(Suppl. 3): S1-S157.
[http://dx.doi.org/10.1111/j.1600-6143.2009.02834.x]
[55]
Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018; 18(2): 293-307.
[http://dx.doi.org/10.1111/ajt.14625] [PMID: 29243394]
[56]
Billing H, Rieger S, Ovens J, et al. Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients. Transplantation 2008; 86(9): 1214-21.
[http://dx.doi.org/10.1097/TP.0b013e3181880b35] [PMID: 19005402]
[57]
Billing H, Rieger S, Süsal C, et al. IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantation with a 2-year follow-up. Transpl Int 2012; 25(11): 1165-73.
[http://dx.doi.org/10.1111/j.1432-2277.2012.01544.x] [PMID: 22897111]

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