Skip to main content

Advertisement

SpringerLink
Log in

mTOR inhibitors in pediatric kidney transplantation

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The mammalian target of the rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly being used in pediatric kidney transplantation in different combinations and doses. Several studies have shown beneficial effects of using mTOR inhibitors in children after pediatric renal transplantation. A switch to a low-dose calcineurin inhibitor (CNI) and mTOR inhibitor has been proven to stabilize the glomerular filtration rate. Additionally, de novo studies using a low-dose CNI and an mTOR inhibitor have shown good graft survival and a low number of rejections. Side effects of mTOR inhibitors, such as hyperlipidemia, wound healing problems, and proteinuria, mainly occur if high doses are given and if treatment is not combined with a CNI. Lower doses of mTOR inhibitors do not result in growth impairment or reduced testosterone levels. Treatment with mTOR inhibitors is also associated with a lower number of viral infections, especially cytomegalovirus. Due to their antiproliferative effect, mTOR inhibitors could theoretically reduce the risk of post-transplant lymphoproliferative disease. mTOR inhibitors, especially in combination with low-dose CNIs, can safely be used in children after kidney transplantation as de novo therapy or for conversion from CNI- and mycophenolate mofetil-based regimens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Joosten SA, Sijpkens YW, van Kooten C, Paul LC (2005) Chronic renal allograft rejection: Pathophysiologic considerations. Kidney Int 68:1–13

    Article  CAS  PubMed  Google Scholar 

  2. Offner G, Toenshoff B, Hocker B, Krauss M, Bulla M, Cochat P, Fehrenbach H, Fischer W, Foulard M, Hoppe B, Hoyer PF, Jungraithmayr TC, Klaus G, Latta K, Leichter H, Mihatsch MJ, Misselwitz J, Montoya C, Muller-Wiefel DE, Neuhaus TJ, Pape L, Querfeld U, Plank C, Schwarke D, Wygoda S, Zimmerhackl LB (2008) Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids. Transplantation 86:1241–1248

    Article  CAS  PubMed  Google Scholar 

  3. North American Pediatric Renal Trials and Collaborative Studies (2011) Annual dialysis report. Available at: https://Web.emmes.com/study/ped/annlrept/annualrept2011.pdf

  4. Grenda R, Watson A, Trompeter R, Tonshoff 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 (2010) A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: The TWIST study. Am J Transplant 10:828–836

    Article  CAS  PubMed  Google Scholar 

  5. Cole OJ, Shehata M, Rigg KM (1998) Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc 30:2200–2203

    Article  CAS  PubMed  Google Scholar 

  6. Schuurman HJ, Pally C, Weckbecker G, Schuler W, Bruns C (1999) SDZ RAD inhibits cold ischemia-induced vascular remodeling. Transplant Proc 31:1024–1025

    Article  CAS  PubMed  Google Scholar 

  7. Matsumoto Y, Hof A, Baumlin Y, Muller M, Hof RP (2004) Differential effects of everolimus and cyclosporine A on intimal alpha-actin-positive cell dynamics of carotid allografts in mice. Transplantation 78:345–351

    Article  CAS  PubMed  Google Scholar 

  8. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5:671–688

    Article  CAS  PubMed  Google Scholar 

  9. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6:304–312

    Article  CAS  PubMed  Google Scholar 

  10. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601

    Article  CAS  PubMed  Google Scholar 

  11. Hartford CM, Ratain MJ (2007) Rapamycin: Something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther 82:381–388

    Article  CAS  PubMed  Google Scholar 

  12. Chapman JR, Valantine H, Albanell J, Arns WA, Campistol JM, Eisen H, Frigerio M, Lehmkuhl H, Marcen R, Morris R, Nashan B, Pascual J, Pohanka E, Segovia J, Zuckermann A (2007) Proliferation signal inhibitors in transplantation: Questions at the cutting edge of everolimus therapy. Transplant Proc 39:2937–2950

    Article  CAS  PubMed  Google Scholar 

  13. Gaumann A, Schlitt HJ, Geissler EK (2008) Immunosuppression and tumor development in organ transplant recipients: The emerging dualistic role of rapamycin. Transpl Int 21:207–217

    Article  CAS  PubMed  Google Scholar 

  14. Gupta P, Kaufman S, Fishbein TM (2005) Sirolimus for solid organ transplantation in children. Pediatr Transplant 9:269–276

    Article  CAS  PubMed  Google Scholar 

  15. Hymes LC, Warshaw BL (2005) Sirolimus in pediatric patients: Results in the first 6 months post-renal transplant. Pediatr Transplant 9:520–522

    Article  CAS  PubMed  Google Scholar 

  16. Ettenger RB, Grimm EM (2001) Safety and efficacy of TOR inhibitors in pediatric renal transplant recipients. Am J Kidney Dis 38:S22–S28

    Article  CAS  PubMed  Google Scholar 

  17. Pape L, Ahlenstiel T, Ehrich JH, Offner G (2007) Reversal of loss of glomerular filtration rate in children with transplant nephropathy after switch to everolimus and low-dose cyclosporine A. Pediatr Transplant 11:291–295

    Article  CAS  PubMed  Google Scholar 

  18. Federal Drug Administration. Available at: http://www.acessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed 25 Apr 2013

  19. European Medicines Agency. Available at: http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d123. Accessed 25 Apr 2013

  20. Garcia CD, Bittencourt VB, Alves AB, Garcia VD, Tumelero A, Antonello JS, Malheiros D (2006) Conversion to sirolimus in pediatric renal transplantation recipients. Transplant Proc 38:1901–1903

    Article  CAS  PubMed  Google Scholar 

  21. Vilalta R, Vila A, Nieto J, Callis L (2003) Rapamycin use and rapid withdrawal of calcineurin inhibitors in pediatric renal transplantation. Transplant Proc 35:703–704

    Article  CAS  PubMed  Google Scholar 

  22. MacDonald AS (2003) Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas, and kidney transplantation. Transplant Proc 35:201S–208S

    Article  CAS  PubMed  Google Scholar 

  23. Falger JC, Mueller T, Arbeiter K, Boehm M, Regele H, Balzar E, Aufricht C (2006) Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy. Pediatr Transplant 10:565–569

    Article  CAS  PubMed  Google Scholar 

  24. Ibanez JP, Monteverde ML, Diaz MA, Goldberg J, Turconi AF (2007) Sirolimus in chronic allograft nephropathy in pediatric recipients. Pediatr Transplant 11:777–780

    Article  CAS  PubMed  Google Scholar 

  25. Hymes LC, Warshaw BL, Amaral SG, Greenbaum LA (2008) Tacrolimus withdrawal and conversion to sirolimus at three months post-pediatric renal transplantation. Pediatr Transplant 12:773–777

    Article  CAS  PubMed  Google Scholar 

  26. Weintraub L, Li L, Kambham N, Alexander S, Concepcion W, Miller K, Wong C, Salvatierra O, Sarwal M (2008) Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation. Pediatr Transplant 12:541–549

    Article  PubMed  Google Scholar 

  27. Ettenger R, Hoyer PF, Grimm P, Webb N, Loirat C, Mahan JD, Mentser M, Niaudet P, Offner G, Vandamme-Lombaerts R, Hexham JM, Everolimus Pediatric Study Group (2008) Multicenter trial of everolimus in pediatric renal transplant recipients: Results at three year. Pediatr Transplant 12:456–463

    Article  CAS  PubMed  Google Scholar 

  28. Pape L, Offner G, Kreuzer M, Froede K, Drube J, Kanzelmeyer N, Ehrich JH, Ahlenstiel T (2010) De novo therapy with everolimus, low-dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation. Am J Transplant 10:2349–2354

    Article  CAS  PubMed  Google Scholar 

  29. Pape L, Lehner F, Blume C, Ahlenstiel T (2011) Pediatric kidney transplantation followed by de novo therapy with everolimus, low-dose cyclosporine A, and steroid elimination: 3-year data. Transplantation 92:658–662

    Article  CAS  PubMed  Google Scholar 

  30. Schachter AD, Benfield MR, Wyatt RJ, Grimm PC, Fennell RS, Herrin JT, Lirenman DS, McDonald RA, Munoz-Arizpe R, Harmon WE (2006) Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co-therapy. Pediatr Transplant 10:914–919

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. El-Sabrout R, Delaney V, Qadir M, Butt F, Hanson P, Butt KM (2003) Sirolimus in combination with tacrolimus or mycophenolate mofetil for minimizing acute rejection risk in renal transplant recipients—a single center experience. Transplant Proc 35:89S–94S

    Article  CAS  PubMed  Google Scholar 

  32. Ibanez JP, Monteverde ML, Goldberg J, Diaz MA, Turconi A (2005) Sirolimus in pediatric renal transplantation. Transplant Proc 37:682–684

    Article  CAS  PubMed  Google Scholar 

  33. Iorember FM, Patel HP, Ohana A, Hayes JR, Mahan JD, Baker PB, Rajab A (2010) Steroid avoidance using sirolimus and cyclosporine in pediatric renal transplantation: One year analysis. Pediatr Transplant 14:93–99

    Article  PubMed  Google Scholar 

  34. Sindhi R (2003) Sirolimus in pediatric transplant recipients. Transplant Proc 35:113S–114S

    Article  CAS  PubMed  Google Scholar 

  35. Benfield MR, Bartosh S, Ikle D, Warshaw B, Bridges N, Morrison Y, Harmon W (2010) A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant 10:81–88

    Article  CAS  PubMed  Google Scholar 

  36. Alvarez-Garcia O, Carbajo-Perez E, Garcia E, Gil H, Molinos I, Rodriguez J, Ordonez FA, Santos F (2007) Rapamycin retards growth and causes marked alterations in the growth plate of young rats. Pediatr Nephrol 22:954–961

    Article  PubMed  Google Scholar 

  37. Sanchez CP, He YZ (2009) Bone growth during rapamycin therapy in young rats. BMC Pediatr 9:3

    Article  PubMed Central  PubMed  Google Scholar 

  38. Rangel GA, Ariceta G (2009) Growth failure associated with sirolimus: Case report. Pediatr Nephrol 24:2047–2050

    Article  PubMed  Google Scholar 

  39. Hymes LC, Warshaw BL (2011) Linear growth in pediatric renal transplant recipients receiving sirolimus. Pediatr Transplant 15:570–572

    CAS  PubMed  Google Scholar 

  40. Gonzalez D, Garcia CD, Azocar M, Waller S, Alonso A, Ariceta G, Mejia N, Santos F (2011) Growth of kidney-transplanted pediatric patients treated with sirolimus. Pediatr Nephrol 26:961–966

    Article  PubMed  Google Scholar 

  41. Cavanaugh TM, Schoenemen H, Goebel J (2012) The impact of sirolimus on sex hormones in male adolescent kidney recipients. Pediatr Transplant 16:280–285

    Article  CAS  PubMed  Google Scholar 

  42. Tondolo V, Citterio F, Panocchia N, Nanni G, Favi E, Brescia A, Castagneto M (2005) Gonadal function and immunosuppressive therapy after renal transplantation. Transplant Proc 37:1915–1917

    Article  CAS  PubMed  Google Scholar 

  43. Lee S, Coco M, Greenstein SM, Schechner RS, Tellis VA, Glicklich DG (2005) The effect of sirolimus on sex hormone levels of male renal transplant recipients. Clin Transplant 19:162–167

    Article  PubMed  Google Scholar 

  44. Huyghe E, Zairi A, Nohra J, Kamar N, Plante P, Rostaing L (2007) Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: An overview. Transpl Int 20:305–311

    Article  CAS  PubMed  Google Scholar 

  45. Kaczmarek I, Groetzner J, Adamidis I, Landwehr P, Mueller M, Vogeser M, Gerstorfer M, Uberfuhr P, Meiser B, Reichart B (2004) Sirolimus impairs gonadal function in heart transplant recipients. Am J Transplant 4:1084–1088

    Article  CAS  PubMed  Google Scholar 

  46. Rovira J, Diekmann F, Ramirez-Bajo MJ, Banon-Maneus E, Moya-Rull D, Campistol JM (2012) Sirolimus-associated testicular toxicity: Detrimental but reversible. Transplantation 93:874–879

    Article  CAS  PubMed  Google Scholar 

  47. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF, ELITE-Symphony Study (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357:2562–2575

    Article  CAS  PubMed  Google Scholar 

  48. Ekberg H, Bernasconi C, Tedesco-Silva H, Vitko S, Hugo C, Demirbas A, Acevedo RR, Grinyo J, Frei U, Vanrenterghem Y, Daloze P, Halloran P (2009) Calcineurin inhibitor minimization in the symphony study: Observational results 3 years after transplantation. Am J Transplant 9:1876–1885

    Article  CAS  PubMed  Google Scholar 

  49. Nashan B, Gaston R, Emery V, Saemann MD, Mueller NJ, Couzi L, Dantal J, Shihab F, Mulgaonkar S, Seun Kim Y, Brennan DC (2012) Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation 93:1075–1085

    Article  CAS  PubMed  Google Scholar 

  50. Brennan DC, Legendre C, Patel D, Mange K, Wiland A, McCague K, Shihab FS (2011) Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: Pooled analysis of three clinical trials. Am J Transplant 11:2453–2462

    Article  CAS  PubMed  Google Scholar 

  51. Cullis B, D’Souza R, McCullagh P, Harries S, Nicholls A, Lee R, Bingham C (2006) Sirolimus-induced remission of posttransplantation lymphoproliferative disorder. Am J Kidney Dis 47:e67–e72

    Article  PubMed  Google Scholar 

  52. Pascual J (2007) Post-transplant lymphoproliferative disorder–the potential of proliferation signal inhibitors. Nephrol Dial Transplant 22[Suppl 1]:i27–i35

    Article  CAS  PubMed  Google Scholar 

  53. Zaltzman JS, Prasad R, Chun K, Jothy S (2005) Resolution of renal allograft-associated post-transplant lymphoproliferative disorder with the introduction of sirolimus. Nephrol Dial Transplant 20:1748–1751

    Article  PubMed  Google Scholar 

  54. Chiurchiu C, Carreno CA, Schiavelli R, Petrone H, Balaguer C, Trimarchi H, Pujol GS, Novoa P, Acosta F, Gonzalez C, Arriola M, Massari PU, Argentinian Registry of Everolimus Treated Renal Transplant Recipients (2010) Results of the conversion to everolimus in renal transplant recipients with posttransplantation malignancies. Transplant Proc 42:277–279

    Article  CAS  PubMed  Google Scholar 

  55. Jimenez-Rivera C, Avitzur Y, Fecteau AH, Jones N, Grant D, Ng VL (2004) Sirolimus for pediatric liver transplant recipients with post-transplant lymphoproliferative disease and hepatoblastoma. Pediatr Transplant 8:243–248

    Article  CAS  PubMed  Google Scholar 

  56. Augustine JJ, Bodziak KA, Hricik DE (2007) Use of sirolimus in solid organ transplantation. Drugs 67:369–391

    Article  CAS  PubMed  Google Scholar 

  57. Schachter AD, Meyers KE, Spaneas LD, Palmer JA, Salmanullah M, Baluarte J, Brayman KL, Harmon WE (2004) Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 8:171–177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Powell HR, Kara T, Jones CL (2007) Early experience with conversion to sirolimus in a pediatric renal transplant population. Pediatr Nephrol 22:1773–1777

    Article  PubMed  Google Scholar 

  59. Bumbea V, Kamar N, Ribes D, Esposito L, Modesto A, Guitard J, Nasou G, Durand D, Rostaing L (2005) Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant 20:2517–2523

    Article  CAS  PubMed  Google Scholar 

  60. Butani L (2004) Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 78:1362–1366

    Article  PubMed  Google Scholar 

  61. Letavernier E, Bruneval P, Vandermeersch S, Perez J, Mandet C, Belair MF, Haymann JP, Legendre C, Baud L (2009) Sirolimus interacts with pathways essential for podocyte integrity. Nephrol Dial Transplant 24:630–638

    Article  CAS  PubMed  Google Scholar 

  62. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat Med 8:128–135

    Article  CAS  PubMed  Google Scholar 

  63. Oroszlan M, Bieri M, Ligeti N, Farkas A, Meier B, Marti HP, Mohacsi P (2010) Sirolimus and everolimus reduce albumin endocytosis in proximal tubule cells via an angiotensin II-dependent pathway. Transpl Immunol 23:125–132

    Article  CAS  PubMed  Google Scholar 

  64. Valente JF, Hricik D, Weigel K, Seaman D, Knauss T, Siegel CT, Bodziak K, Schulak JA (2003) Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 3:1128–1134

    Article  CAS  PubMed  Google Scholar 

  65. Dean PG, Lund WJ, Larson TS, Prieto M, Nyberg SL, Ishitani MB, Kremers WK, Stegall MD (2004) Wound-healing complications after kidney transplantation: A prospective, randomized comparison of sirolimus and tacrolimus. Transplantation 77:1555–1561

    Article  CAS  PubMed  Google Scholar 

  66. Nashan B, Citterio F (2012) Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: A critical review of the literature. Transplantation 94:547–561

    Article  CAS  PubMed  Google Scholar 

  67. Budde K, Lehner F, Sommerer C, Arns W, Reinke P, Eisenberger U, Wuthrich RP, Scheidl S, May C, Paulus EM, Muhlfeld A, Wolters HH, Pressmar K, Stahl R, Witzke O, ZEUS Study Investigators (2012) Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study. Am J Transplant 12:1528–1540

    Article  CAS  PubMed  Google Scholar 

  68. Van Damme-Lombaerts R, Webb NA, Hoyer PF, Mahan J, Lemire J, Ettenger R, McMahon L, Cambon N, Boger R, Kovarik JM (2002) Single-dose pharmacokinetics and tolerability of everolimus in stable pediatric renal transplant patients. Pediatr Transplant 6:147–152

    Article  PubMed  Google Scholar 

  69. Zimmerman JJ, Kahan BD (1997) Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 37:405–415

    Article  CAS  PubMed  Google Scholar 

  70. Schubert M, Venkataramanan R, Holt DW, Shaw LM, McGhee W, Reyes J, Webber S, Sindhi R (2004) Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients. Am J Transplant 4:767–773

    Article  CAS  PubMed  Google Scholar 

  71. Venkataramanan R, Sindhi R (2006) Sirolimus pharmacokinetic differences between children and adults. Pediatr Transplant 10:872–874

    Article  CAS  PubMed  Google Scholar 

  72. Grimm EM, Kelley PA, Seinford RD, Gitomer JJ, Kahan BD (2000) Sirolimus pharmacokinetics in pediatric renal transplants. Pediatr Transplant 4:S86a

    Article  Google Scholar 

  73. Zimmerman JJ, Harper D, Getsy J, Jusko WJ (2003) Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers. J Clin Pharmacol 43:1168–1176

    Article  CAS  PubMed  Google Scholar 

  74. Vu MD, Qi S, Xu D, Wu J, Fitzsimmons WE, Sehgal SN, Dumont L, Busque S, Daloze P, Chen H (1997) Tacrolimus (FK506) and sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat. Transplantation 64:1853–1856

    Article  CAS  PubMed  Google Scholar 

  75. Brandhorst G, Tenderich G, Zittermann A, Oezpeker C, Koerfer R, Oellerich M, Armstrong VW (2008) Everolimus exposure in cardiac transplant recipients is influenced by concomitant calcineurin inhibitor. Ther Drug Monit 30:113–116

    Article  CAS  PubMed  Google Scholar 

  76. Pascual J, del Castillo D, Cabello M, Pallardo L, Grinyo JM, Fernandez AM, Brunet M (2010) Interaction between everolimus and tacrolimus in renal transplant recipients: A pharmacokinetic controlled trial. Transplantation 89:994–1000

    Article  CAS  PubMed  Google Scholar 

  77. Marin-Casino M, Crespo M, Mateu-de Antonio J, Pascual J (2011) Monitoring sirolimus levels: How does it affect the immunoassay used? Nefrologia 31:359–361

    CAS  PubMed  Google Scholar 

  78. Coentrao L, Carvalho C, Sampaio S, Oliveira JG, Pestana MI (2010) Relationship between everolimus blood concentration assessed using the innofluor certican fluorescence polarization immunoassay and the architect i system sirolimus chemiluminescent microparticle immunoassay. Transplant Proc 42:1867–1869

    Article  CAS  PubMed  Google Scholar 

  79. Katzman SD, O’Gorman WE, Villarino AV, Gallo E, Friedman RS, Krummel MF, Nolan GP, Abbas AK (2010) Duration of antigen receptor signaling determines T-cell tolerance or activation. Proc Natl Acad Sci USA 107:18085–18090

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12:295–303

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Thomson AW, Turnquist HR, Raimondi G (2009) Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 9:324–337

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Yang K, Neale G, Green DR, He W, Chi H (2011) The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 12:888–897

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Gulen MF, Kang Z, Bulek K, Youzhong W, Kim TW, Chen Y, Altuntas CZ, Sass Bak-Jensen K, McGeachy MJ, Do JS, Xiao H, Delgoffe GM, Min B, Powell JD, Tuohy VK, Cua DJ, Li X (2010) The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 32:54–66

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Battaglia M, Stabilini A, Tresoldi E (2012) Expanding human T regulatory cells with the mTOR-inhibitor rapamycin. Methods Mol Biol 821:279–293

    Article  CAS  PubMed  Google Scholar 

  86. Brouard S, Puig-Pey I, Lozano JJ, Pallier A, Braud C, Giral M, Guillet M, Londono MC, Oppenheimer F, Campistol JM, Soulillou JP, Sanchez-Fueyo A (2010) Comparative transcriptional and phenotypic peripheral blood analysis of kidney recipients under cyclosporin A or sirolimus monotherapy. Am J Transplant 10:2604–2614

    Article  CAS  PubMed  Google Scholar 

  87. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460:108–112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Araki K, Youngblood B, Ahmed R (2010) The role of mTOR in memory CD8 T-cell differentiation. Immunol Rev 235:234–243

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Pascual J, Boletis IN, Campistol JM (2006) Everolimus (certican) in renal transplantation: A review of clinical trial data, current usage, and future directions. Transplant Rev (Orlando) 20:1–18

    Article  Google Scholar 

  90. Zuckermann A, Manito N, Epailly E, Fiane A, Bara C, Delgado JF, Lehmkuhl H, Ross H, Eisen H, Chapman J, Valantine H (2008) Multidisciplinary insights on clinical guidance for the use of proliferation signal inhibitors in heart transplantation. J Heart Lung Transplant 27:141–149

    Article  PubMed  Google Scholar 

  91. Lexicomp (2013) Lexicomp Online™. Available at: http://www.uptodate.com/contents/everolimus-drug-information?source=search_result&search=everolimus&selectedTitle=1%7E80#F7710406. Lexi-Drugs Online™, Lexicomp Inc., Hudson. Accessed 25 Apr 2013

  92. Lexicomp (2013) Lexicomp Online™. Available at: http://www.uptodate.com/contents/sirolimus-drug-information?source=search_result&search=sirolimus&selectedTitle=1%7E150#F221195. Lexi-Drugs Online™, Lexicomp, Inc., Hudson. Accessed 25 Apr 2013

Download references

Conflict of interest

The authors are supported by research grants from Novartis Pharmaceuticals.

Author information

Authors and Affiliations

  1. Department of Pediatric Nephrology, Hepatology and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany

    Lars Pape & Thurid Ahlenstiel

Authors
  1. Lars Pape
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thurid Ahlenstiel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lars Pape.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pape, L., Ahlenstiel, T. mTOR inhibitors in pediatric kidney transplantation. Pediatr Nephrol 29, 1119–1129 (2014). https://doi.org/10.1007/s00467-013-2505-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-013-2505-9

Keywords

Search

Navigation