OBJECTIVE: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. DESIGN: Systematic review and meta-analysis of individual patient data. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. ELIGIBILITY: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. RESULTS: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. CONCLUSIONS: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

Cairo Kidney Center Cairo University Cairo Egypt

Clinic of Dermatology Venerology and Allergology JW Goethe Clinic University of Frankfurt Germany

Department of Nephrology and Transplantation Lund University Malmo Sweden

Department of Nephrology Institutu Klinicke a Experimentalni Mediciny Prague Czech Republic

Department of Nephrology Saint Louis Hospital Paris France

Department of Renal Medicine Addenbrooke's Hospital Cambridge UK

Department of Surgery University of Munich Munich Germany

Division of Nephrology Hospital of J W Goethe Frankfurt Germany

Hospital do Rim e Hipertensao Universidade Federal de Sao Paulo Sao Paulo Brazil

Limites Medical Research Vacallo Switzerland

Maastricht University Medical Centre Maastricht Netherlands

Northwestern University Feinberg School of Medicine Chicago IL USA

Ottawa Hospital Research Institute Ottawa ON Canada

Ottawa Hospital Research Institute Ottawa ON Canada University of Ottawa Ottawa ON Canada

University of Cambridge Department of Surgery NIHR Cambridge Biomedical Research Centre Addenbrooke's Hospital Cambridge UK

University of Manitoba Department of Pediatrics and Child's Health Winnipeg MB Canada

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BMJ. 2014;349:g7543 PubMed

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BMJ. 2014 Nov 25;349:g6808. doi: 10.1136/bmj.g6808. PubMed

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Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LYC, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725-30. PubMed

Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N. A study of the quality of life and cost-utility of renal transplantation. Kidney Int 1996;50:235-42. PubMed

US Renal Data System. USRDS 2013 Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2013.

WHO-ONT collaboration. Global observatory on donation and transplantation. www.transplant-observatory.org/Pages/home.aspx

Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296:2823-31. PubMed

Krynitz B, Edgren G, Lindelöf B, Baecklund E, Brattström C, Wilczek H, Smedby KE. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008—a Swedish population-based study. Int J Cancer 2013;132:1429-38. PubMed

US Renal Data System. USRDS 2012 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases, 2012.

ANZDATA Registry Report 2010, Australia and New Zealand Dialysis and Transplant Registry, Adelaide, South Australia. Australia and New Zealand Dialysis and Transplant Registry, 2010.

Asch WS, Bia MJ. Oncologic issues and kidney transplantation: a review of frequency, mortality, and screening. Adv Chronic Kidney Dis 2014;21:106-13. PubMed

Mackenzie KA, Wells JE, Lynn KL, Simcock JW, Robinson BA, Roake JA, et al. First and subsequent nonmelanoma skin cancers: incidence and predictors in a population of New Zealand renal transplant recipients. Nephrol Dial Transplant 2010;25:300-6. PubMed

Wisgerhof HC, Edelbroek JR, de Fijter JW, Haasnoot GW, Claas FH, Willemze R, et al. Subsequent squamous- and basal-cell carcinomas in kidney-transplant recipients after the first skin cancer: cumulative incidence and risk factors. Transplantation 2010;89:1231-8. PubMed

Zavos G, Karidis NP, Tsourouflis G, Bokos J, Diles K, Sotirchos G, et al. Nonmelanoma skin cancer after renal transplantation: a single-center experience in 1736 transplantations. Int J Dermatol 2011;12:1496-500. PubMed

Khokhar NZ, Altman JK, Platanias LC. Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies. Curr Opin Oncol 2011;23:578-86. PubMed

Kapoor A. Malignancy in kidney transplant recipients. Drugs 2008;68(suppl 1):11-9. PubMed

Campistol JM, Albanell J, Arns W, Boletis I, Dantal J, de Fijter JW, et al. Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance. Nephrol Dial Transplant 2007;22(suppl 1):i36-41. PubMed

Kauffman H, Cherikh W, Cheng Y, Hanto D, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005;80:883-9. PubMed

Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 2006;81:1234-48. PubMed

Campbell S, Walker R, Tai SS, Jiang Q, Russ G. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant 2012;12:1146-56. PubMed

Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012;26:329-39. PubMed

Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75. PubMed

Altman DG, Andersen PK. Calculating the number needed to treat for trials where the outcome is time to an event. BMJ 1999;319:1492-5. PubMed PMC

Flechner S, Glyda M, Cockfield S, Grinyó J, Legendre Ch, Russ G, et al. The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant 2011;11:1633-44. PubMed

Flechner SM, Gurkan A, Hartmann A, Legendre CM, Russ GR, Campistol JM, et al. A randomized, open-label study of sirolimus versus cyclosporine in primary de novo renal allograft recipients. Transplantation 2013;95:1233-41. PubMed

Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000;69:1252-60. PubMed

MacDonald AS, RAPAMUNE Global Study Group. 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;71:271-80. PubMed

Barsoum RS, Morsy AA, Iskander IR, Morgan MM, Fayad TM, Atalla NT, et al. The Cairo kidney center protocol for rapamycin-based sequential immunosuppression in kidney transplant recipients: 2-year outcomes. Exp Clin Transplant 2007;5:649-57. PubMed

Blydt-Hansen TD, Gibson IW, Birk PE. Histological progression of chronic renal allograft injury comparing sirolimus and mycophenolate mofetil-based protocols. A single-center, prospective, randomized, controlled study. Pediatr Transplant 2010;14:909-18. PubMed

Gallon L, Perico N, Dimitrov BD, Winoto J, Remuzzi G, Leventhal J, et al. Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF. Am J Transplant 2006;6:1617-23. PubMed

Gelens MACJ, Christiaans MHL, Van Heurn ELW, Berg-Loonen EPM, Peutz-Kootstra CJ, Van Hooff JP. High rejection rate during calcineurin inhibitor-free and early steroid withdrawal immunosuppression in renal transplantation. Transplantation 2006;82:1221-3. PubMed

Glotz D, Charpentier B, Abramovicz D, Lang P, Rostaing L, Rifle G, et al. Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids. Transplantation 2010;89:1511-7. PubMed

Guba M, Pratschke J, Hugo C, Krämer BK, Nohr-Westphal C, Brockmann J, et al. Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial. Transplantation 2010;90:175-83. PubMed

Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: Similar efficacy and different toxicity compared with cyclosporine. Transplantation 1999;67:1036-42. PubMed

Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Transplantation 1999;68:1526-32. PubMed

Kahan BD for the Rapamune US Study Group. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet 2000;356:194-202. PubMed

Machado PGP, Felipe CR, Hanzawa NM, Park SI, Garcia R, Alfieri F, et al. An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination. Clin Transplant 2004;18:28-38. PubMed

Salgo R, Gossmann J, Schofer H, Kachel HG, Kuck J, Geiger H, et al. Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre) malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial. Am J Transplant 2010;10:1385-93. PubMed

Schena FP, Pascoe MD, Alberu J, del Carmen Rial M, Oberbauer R, Brennan DC, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009;87:233-42. PubMed

Sampaio EL, Pinheiro-machado PG, Garcia R, Felipe CR, Park SI, Casarini DE, et al. Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen. Clin Transplant 2008;22:141-9. PubMed

Vitko S, Wlodarczyk Z, Kyllonen L, Czajkowski Z, Margreiter R, Backman L, et al. Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study. Am J Transplant 2006;6:531-8. PubMed

Watson CJE, Firth J, Williams PF, Bradley JR, Pritchard N, Chaudhry A, et al. A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation. Am J Transplant 2005;5:2496-503. PubMed

Halleck F, Budde K. Transplantation: sirolimus for secondary SCC prevention in renal transplantation. Nat Rev Nephrol 2012;8:687. PubMed

Letavernier E, Legendre CM. mToR inhibitors-induced proteinuria: mechanisms, significance, and management. Tranplant Rev 2008;22:125-30. PubMed

Halimi JM. Low-grade proteinuria and microalbuminuria in renal transplantation. Transplantation 2013;96:121-30. PubMed

Johnston O, Rose CL, Webster AC, Gill J. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008;19:1411-8. PubMed PMC

Kasiske B, de Mattos A, Flechner S, Gallon L, Meier-Kriesche HU, Weir MR, et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am J Transplant 2008;8:1384-92. PubMed

Knoll G, Muirhead N, Trpeski L, Zhu N, Badovinac K. Patient survival following renal transplant failure in Canada. Am J Transplant 2005;5:1719-24. PubMed

Kaplan B, Meier-Kriesche HU. Death after graft loss: an important late study endpoint in kidney transplantation. Am J Transplant 2002;2:970-4. PubMed

Sharif A, Shabir S, Chand S, Cockwell P, Ball S, Borrows R. Meta-analysis of calcineurin-inhibitor-sparing regimens in kidney transplantation. J Am Soc Nephrol 2011;22:2107-18. PubMed PMC

Pengel L, Liu H, Morris P. Do wound complications or lymphoceles occur more often in solid organ transplant recipients on mTOR inhibitors? A systematic review of randomized controlled trials. Transplant Int 2011;24:1216-30. PubMed

Srinivas TR, Schold JD, Guerra G, Eagan A, Bucci CM, Meier-Kriesche HU. Mycophenolate mofetil/sirolimus compared to other common immunosuppressive regimens in kidney transplantation. Am J Transplant 2007;7:586-94. PubMed

Cortazar F, Molnar MZ, Isakova T, Czira ME, Kovesdy CP, Roth D, et al. Clinical outcomes in kidney transplant recipients receiving long-term therapy with inhibitors of the mammalian target of rapamycin. Am J Transplant 2012;12:379-87. PubMed PMC

Isakova T, Xie H, Messinger S, Cortazar F, Scialla JJ, Guerra G, et al. Inhibitors of mTOR and risks of allograft failure and mortality in kidney transplantation. Am J Transplant 2013;13:100-10. PubMed PMC

Russ GR, Tedesco-Silva H, Kuypers D, Cohney S, Langer RM, Witzke O, et al. Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results. Am J Transplant 2013;13:1746-56. PubMed

Kramer BK, Klinger M, Vitko S, Glyda M, Midtvedt K, Stefoni S, et al. Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial. Transplantation 2012;94:492-8. PubMed

Vincenti F, Tedesco-Silva H, Busque S, O’Connell P, Friedewald J, Cibrik D, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant 2012;12:2446-56. PubMed

Reeves BC, Deeks JJ, Higgins JPT, Wells GA. Including non-randomized studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Wiley-Blackwell, 2008:391-432.