MTOR Inhibitors in Pediatric Kidney Transplantation

Overview

Journal Pediatr Nephrol

Specialties Nephrology
Pediatrics

Date 2013 Jun 7

PMID 23740036

Citations 16

Authors

Lars Pape

Thurid Ahlenstiel

Affiliations

Soon will be listed here.

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.

Citing Articles

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Role of brentuximab vedotin plus sirolimus in the treatment of classical Hodgkin lymphoma type post-transplant lymphoproliferative disorder: a case-based review.

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A Pediatric Case of Sirolimus-Associated Pneumonitis After Kidney Transplantation.

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References

Battaglia M, Stabilini A, Tresoldi E . Expanding human T regulatory cells with the mTOR-inhibitor rapamycin. Methods Mol Biol. 2011; 821:279-93. DOI: 10.1007/978-1-61779-430-8_17. View

Venkataramanan R, Sindhi R . Sirolimus pharmacokinetic differences between children and adults. Pediatr Transplant. 2006; 10(8):872-4. DOI: 10.1111/j.1399-3046.2006.00600.x. View

Araki K, Turner A, Shaffer V, Gangappa S, Keller S, Bachmann M . mTOR regulates memory CD8 T-cell differentiation. Nature. 2009; 460(7251):108-12. PMC: 2710807. DOI: 10.1038/nature08155. View

Yang K, Neale G, Green D, He W, Chi H . The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol. 2011; 12(9):888-97. PMC: 3158818. DOI: 10.1038/ni.2068. View

Nashan B, Gaston R, Emery V, Saemann M, Mueller N, Couzi L . Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation. 2012; 93(11):1075-85. DOI: 10.1097/TP.0b013e31824810e6. View

Alvarez-Garcia O, Carbajo-Perez E, Garcia E, Gil H, Molinos I, Rodriguez J . Rapamycin retards growth and causes marked alterations in the growth plate of young rats. Pediatr Nephrol. 2007; 22(7):954-61. PMC: 7064183. DOI: 10.1007/s00467-007-0456-8. View

Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A . Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007; 357(25):2562-75. DOI: 10.1056/NEJMoa067411. View

Schachter A, Benfield M, Wyatt R, Grimm P, Fennell R, Herrin J . Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co-therapy. Pediatr Transplant. 2006; 10(8):914-9. PMC: 1636453. DOI: 10.1111/j.1399-3046.2006.00541.x. View

Zimmerman J, Kahan B . Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol. 1997; 37(5):405-15. DOI: 10.1002/j.1552-4604.1997.tb04318.x. View

10.

Brandhorst G, Tenderich G, Zittermann A, Oezpeker C, Koerfer R, Oellerich M . Everolimus exposure in cardiac transplant recipients is influenced by concomitant calcineurin inhibitor. Ther Drug Monit. 2008; 30(1):113-6. DOI: 10.1097/FTD.0b013e318161a335. View

11.

Zuckermann A, Manito N, Epailly E, Fiane A, Bara C, Delgado J . Multidisciplinary insights on clinical guidance for the use of proliferation signal inhibitors in heart transplantation. J Heart Lung Transplant. 2008; 27(2):141-9. DOI: 10.1016/j.healun.2007.08.014. View

12.

Ettenger R, Hoyer P, Grimm P, Webb N, Loirat C, Mahan J . Multicenter trial of everolimus in pediatric renal transplant recipients: results at three year. Pediatr Transplant. 2008; 12(4):456-63. DOI: 10.1111/j.1399-3046.2007.00832.x. View

13.

Vu M, Qi S, Xu D, Wu J, Fitzsimmons W, Sehgal S . Tacrolimus (FK506) and sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat. Transplantation. 1998; 64(12):1853-6. DOI: 10.1097/00007890-199712270-00039. View

14.

Huyghe E, Zairi A, Nohra J, Kamar N, Plante P, Rostaing L . Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. Transpl Int. 2007; 20(4):305-11. DOI: 10.1111/j.1432-2277.2006.00423.x. View

15.

Weintraub L, Li L, Kambham N, Alexander S, Concepcion W, Miller K . Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation. Pediatr Transplant. 2008; 12(5):541-9. DOI: 10.1111/j.1399-3046.2007.00847.x. View

16.

Brennan D, Legendre C, Patel D, Mange K, Wiland A, McCague K . Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant. 2011; 11(11):2453-62. DOI: 10.1111/j.1600-6143.2011.03674.x. View

17.

Benfield M, Bartosh S, Ikle D, Warshaw B, Bridges N, Morrison Y . A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant. 2009; 10(1):81-8. DOI: 10.1111/j.1600-6143.2009.02767.x. View

18.

Hartford C, Ratain M . Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007; 82(4):381-8. DOI: 10.1038/sj.clpt.6100317. View

19.

Joosten S, Sijpkens Y, van Kooten C, Paul L . Chronic renal allograft rejection: pathophysiologic considerations. Kidney Int. 2005; 68(1):1-13. DOI: 10.1111/j.1523-1755.2005.00376.x. View

20.

Nashan B, Citterio F . Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature. Transplantation. 2012; 94(6):547-61. DOI: 10.1097/TP.0b013e3182551021. View