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Growth of kidney-transplanted pediatric patients treated with sirolimus

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Abstract

Experimental findings indicate that sirolimus (SRL) inhibits longitudinal growth by mechanisms potentially related to its inhibitory effects on both cell proliferation and expression of vascular endothelial growth factor (VEGF). The aim of this study was to investigate the growth pattern of kidney-transplanted children treated with SRL in a multicenter observational clinical study. Height, change in height SD (Δ height) and growth velocity of pediatric patients with renal transplant were calculated at 0, 6, 12, and 24 months after starting SRL. Controls of kidney-transplanted children not treated with SRL were matched by age, gender, renal function, and dose of corticosteroids. Sixty-eight children (34 SRL, 34 controls) were enrolled in the study. Nephrotoxicity was the most frequent indication to start therapy with SRL. SRL exerted an adverse effect on growth as demonstrated by significantly lower (p < 0.05) growth velocity (cm/year) and smaller change in height SD in the SRL group after 6 (4.08 vs. 6.56 and –0.05 vs. 0.14), 12 (4.44 vs. 6.11 and –0.03 vs. 0.28) and 24 (4.53 vs. 6.03 and –0.04 vs. 0.53) months of treatment. This study suggests that SRL therapy may interfere with growth of kidney-transplanted children. This undesirable effect needs to be taken into account when considering a switch to SRL and confirmed in further prospective trials including larger number of patients.

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Abbreviations

SRL:

Sirolimus

GFR:

Glomerular filtration rate

mTOR:

Mammalian target of rapamycin

VEGF:

Vascular endothelial growth factor

Δ Height:

Change in height SD

CNIs:

Calcineurin inhibitors

rhGH:

Recombinant human growth hormone

References

  1. Sehgal SN (2003) Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35:7S–14S

    Article  CAS  Google Scholar 

  2. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

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

    Article  Google Scholar 

  5. Höcker B, Feneberg R, Köpf S, Weber LT, Waldherr R, Wühl E, Tönshoff B (2006) SRL-based immunosuppression vs. CNI minimization in pediatric renal transplant recipients with chronic CNI nephrotoxicity. Pediatr Transplant 10:593–601

    Article  Google Scholar 

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

    Article  Google Scholar 

  7. Mota A, Arias M, Taskinen EI, Paavonen T, Brault Y, Legendre C, Claesson K, Castagneto M, Campistol JM, Hutchison B, Burke JT, Yilmaz S, Häyry P, Neylan JF (2004) Sirolimus-based therapy following early Cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 4:953–961

    Article  CAS  Google Scholar 

  8. 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  Google Scholar 

  9. Mathew T, Kreis H, Friend P (2004) Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant 18:446–449

    Article  Google Scholar 

  10. Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G (2005) Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 352:1317–1323

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Alvarez-García O, García-López E, Loredo V, Gil-Peña H, Rodríguez-Suárez J, Ordóñez FA, Carbajo-Pérez E, Santos F (2010) Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate. Kidney Int 78:561–568

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  16. Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin N Amst 34:571–590

    Article  CAS  Google Scholar 

  17. Tanner JM, Marshall WA, Healy MJ, Goldstein H (1983) Assessment of skeletal maturity and prediction of adult height (tw2 method). 2nd edn. Academic Press, New York

    Google Scholar 

  18. Fine RN (2010) Etiology and treatment of growth retardation in children with chronic kidney disease and end-stage renal disease: a historical perspective. Pediatr Nephrol 25:725–732

    Article  Google Scholar 

  19. Nissel R, Brázda I, Feneberg R, Wigger M, Greiner C, Querfeld U, Haffner D (2004) Effect of renal transplantation in childhood on longitudinal growth and adult height. Kidney Int 66:792–800

    Article  Google Scholar 

  20. Grenda R, Watson A, Trompeter R, Tönshoff 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  Google Scholar 

  21. Ferraris JR, Pasqualini T, Alonso G, Legal S, Sorroche P, Galich A, Coccia P, Ghezzi L, Ferraris V, Karabatas L, Guida C, Jasper H (2010) A study on strategies for improving growth and body composition after renal transplantation. Pediatr Nephrol 25:753–762

    Article  Google Scholar 

  22. Li L, Chang A, Naesens M, Kambham N, Waskerwitz J, Martin J, Wong C, Alexander S, Grimm P, Concepcion W, Salvatierra O, Sarwal MM (2009) Steroid-free immunosuppression since 1999: 129 pediatric renal transplants with sustained graft and patients benefits. Am J Transplant 9:1362–1372

    Article  CAS  Google Scholar 

  23. Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra O Jr (2003) Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation 76:1331–1339

    Article  CAS  Google Scholar 

  24. Grenda R (2010) Effects of steroid avoidance and novel protocols on growth in paediatric renal transplant patients. Pediatr Nephrol 25:747–752

    Article  Google Scholar 

  25. Tejani A, Fine R, Alexander S, Harmon W, Stablein D (1993) Factors predictive of sustained growth in children after renal transplantation. J Pediatr 122:397–402

    Article  CAS  Google Scholar 

  26. Harambat J, Cochat P (2009) Growth after renal transplantation. Pediatr Nephrol 24:1297–1306

    Article  Google Scholar 

  27. North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) 2008 annual report. Available at: https://doi.org/web.emmes. com/study/ped/annlrept/annlrept.html. Accessed 8 Oct 2009.

  28. Alvarez-Garcia O, Garcia-Lopez E, Loredo V, Gil-Peña H, Rodriguez J, Ordoñez FA, Santos F (2010) Growth hormone (GH) administration improves longitudinal growth in rats with growth retardation induced by rapamycin. Pediatr Nephrol 25:31A

    Google Scholar 

  29. Warshaw BL, Hymes LC (2010) Linear growth in pediatric renal transplant recipients is similar with sirolimus vs. calcineurin inhibitors. Presented at the American Transplant Congress, San Diego (CA) 2010 (abstract).

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Acknowledgements

The study was funded by the Instituto de Salud Carlos III from the Spanish Ministry of Science and Innovation and by the Fundación Nutrición y Crecimiento.

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Authors and Affiliations

  1. Hospital Universitario Central de Asturias, Villamil s/n, 33006, Oviedo, Asturias, Spain

    David González & Fernando Santos

  2. Santo Antonio Children’s Hospital, Porto Alegre, Brazil

    Clotilde D. García

  3. Hospital Luis Calvo Mackenna, Santiago, Chile

    Marta Azócar

  4. Royal Sick Children’s Hospital, Glasgow, Scotland, United Kingdom

    Simon Waller

  5. Hospital Universitario La Paz, Madrid, Spain

    Angel Alonso

  6. Hospital de Cruces, Baracaldo, Vizcaya, Spain

    Gema Ariceta

  7. Hospital Universitario Fundación Santafé, Bogota, Colombia

    Natalia Mejía

  8. University of Oviedo, Oviedo, Asturias, Spain

    Fernando Santos

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  1. David González
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  2. Clotilde D. García
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  3. Marta Azócar
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  4. Simon Waller
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  7. Natalia Mejía
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  8. Fernando Santos
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Correspondence to Fernando Santos.

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González, D., García, C.D., Azócar, M. et al. Growth of kidney-transplanted pediatric patients treated with sirolimus. Pediatr Nephrol 26, 961–966 (2011). https://doi.org/10.1007/s00467-011-1811-3

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  • DOI: https://doi.org/10.1007/s00467-011-1811-3

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