1,734
Views
80
CrossRef citations to date
0
Altmetric
Reviews

Safety of mTOR inhibitors in adult solid organ transplantation

, &
Pages 303-319 | Received 20 Oct 2015, Accepted 14 Dec 2015, Published online: 28 Jan 2016

Bibliography

  • Shimobayashi M, Hall MN. Making new contacts : the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. Nature Publishing Group. 2014;15(3):155–162.
  • Ponticelli C. The pros and the cons of mTOR inhibitors in kidney transplantation. Expert Rev Clin Immunol. 2014 Feb;10(2):295–305.
  • Peddi VR, Wiseman A, Chavin K, et al. Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation. Transplant Rev (Orlando). 2013 Oct;27(4):97–107.
  • Klintmalm GB, Nashan B. The role of mTOR inhibitors in liver transplantation: reviewing the evidence. J Transplant. 2014 Jan;2014:845438.
  • Ricoult SJH, Manning BD. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep. 2013 Mar 1;14(3):242–251.
  • Lamming DW, Sabatini DM. A central role for mTOR in lipid homeostasis. Cell Metab. 2013 Oct 1;18(4):465–469.
  • MacDonald AS. 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 Jan 27;71(2):271–280.
  • Cybulski N, Polak P, Auwerx J, et al. mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9902–9907.
  • Vítko S, Margreiter R, Weimar W, et al. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant. 2005 Oct;5(10):2521–2530.
  • Cataneo-Dávila A, Zúñiga-Varga J, Correa-Rotter R, et al. Renal function outcomes in kidney transplant recipients after conversion to everolimus-based immunosuppression regimen with CNI reduction or elimination. Transplant Proc. 2009 Dec;41(10):4138–4146.
  • Guba M, Pratschke J, Hugo C, et al. Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36 months after transplantation. Transpl Int. 2012 Apr;25(4):416–423.
  • Mjörnstedt L, Sørensen SS, Von Zur Mühlen B, et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant. 2012 Oct;12(10):2744–2753.
  • Weir MR, Mulgaonkar S, Chan L, et al. Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial. Kidney Int. 2011 Apr;79(8):897–907.
  • Schena FP, Pascoe MD, Alberu J, 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 Jan 27;87(2):233–242.
  • Flechner SM, Glyda M, Cockfield S, et al. The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant. 2011 Aug;11(8):1633–1644.
  • Basic-Jukic N, Kes P, Bubic-Filipi L, et al. Rhabdomyolysis and acute kidney injury secondary to concomitant use of fluvastatin and rapamycin in a renal transplant recipient. Nephrol Dial Transplant. 2010 Jun;25(6):2036; author reply 2036–2037.
  • Hong YA, Kim HD, Jo K, et al. Severe rhabdomyolysis associated with concurrent use of simvastatin and sirolimus after cisplatin-based chemotherapy in a kidney transplant recipient. Exp Clin Transplant. 2014 Apr;12(2):152–155.
  • Dos Santos AG, Guardia AC, Pereira TS, et al. Rhabdomyolysis as a clinical manifestation of association with ciprofibrate, sirolimus, cyclosporine, and pegylated interferon-α in liver-transplanted patients: a case report and literature review. Transplant Proc. 2014 Jan;46(6):1887–1888.
  • ANZDATA Registry. 37th report, chapter 8: transplantation [Internet]. Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia; 2015. [cited 2015 Mar 31]. Available from: http://www.anzdata.org.au
  • USRDS 2014 annual data report. Chapter 7: transplantation [Internet]. United States Renal Data System (USRDS), Washington, USA; 2015. [cited 2015 Mar 31]. Available from: http://www.usrds.org
  • Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014 Jan;349:g6679.
  • Budde K, Becker T, Arns W, et al. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011 Mar 3;377(9768):837–847.
  • Budde K, Lehner F, Sommerer C, et al. Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study. Am J Transplant. 2015 Jan 17;15(1):119–128.
  • Gyurus E, Kaposztas Z, Kahan BD. Sirolimus therapy predisposes to new-onset diabetes mellitus after renal transplantation: a long-term analysis of various treatment regimens. Transplant Proc. 2011 Jun;43(5):1583–1592.
  • Johnston O, Rose CL, Webster AC, et al. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol. 2008 Jul;19(7):1411–1418.
  • Murakami N, Riella LV, Funakoshi T. Risk of metabolic complications in kidney transplantation after conversion to mTOR inhibitor: a systematic review and meta-analysis. Am J Transplant. 2014 Oct;14(10):2317–2327.
  • Syed NA, Khandelwal RL. Reciprocal regulation of glycogen phosphorylase and glycogen synthase by insulin involving phosphatidylinositol-3 kinase and protein phosphatase-1 in HepG2 cells. Mol Cell Biochem. 2000 Aug;211(1–2):123–136.
  • Bussiere CT, Lakey JRT, Shapiro AMJ, et al. The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia. 2006 Oct;49(10):2341–2349.
  • Kwon G, Marshall CA, Liu H, et al. Glucose-stimulated DNA synthesis through mammalian target of rapamycin (mTOR) is regulated by KATP channels: effects on cell cycle progression in rodent islets. J Biol Chem. 2006 Feb 10;281(6):3261–3267.
  • Barlow AD, Nicholson ML, Herbert TP. Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms. Diabetes. 2013 Aug;62(8):2674–2682.
  • Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev. 2002 Apr;23(2):201–229.
  • Mittelman SD, Bergman RN. Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin. Am J Physiol Endocrinol Metab. 2000 Sep;279(3):E630–E637.
  • Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol. 2005 Oct;16(10):3128–3135.
  • Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007 Dec 20;357(25):2562–2575.
  • Diekmann F, Gutiérrez-Dalmau A, López S, et al. Influence of sirolimus on proteinuria in de novo kidney transplantation with expanded criteria donors: comparison of two CNI-free protocols. Nephrol Dial Transplant. 2007 Aug;22(8):2316–2321.
  • Franco AFV, Martini D, Abensur H, et al. Proteinuria in transplant patients associated with sirolimus. Transplant Proc. 2007 Mar;39(2):449–452.
  • Vogelbacher R, Wittmann S, Braun A, et al. The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation. 2007 Dec 15;84(11):1492–1499.
  • Aliabadi AZ, Pohanka E, Seebacher G, et al. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant. 2008 Apr;8(4):854–861.
  • Pinheiro HS, Amaro TA, Braga AM, et al. Post-rapamycin proteinuria: incidence, evolution, and therapeutic handling at a single center. Transplant Proc. 2006 Dec;38(10):3476–3478.
  • Straathof-Galema L, Wetzels JFM, Dijkman HBPM, et al. Sirolimus-associated heavy proteinuria in a renal transplant recipient: evidence for a tubular mechanism. Am J Transplant. 2006 Mar;6(2):429–433.
  • Stephany BR, Augustine JJ, Krishnamurthi V, et al. Differences in proteinuria and graft function in de novo sirolimus-based vs. calcineurin inhibitor-based immunosuppression in live donor kidney transplantation. Transplantation. 2006 Aug 15;82(3):368–374.
  • Wiseman AC, McCague K, Kim Y, et al. The effect of everolimus versus mycophenolate upon proteinuria following kidney transplant and relationship to graft outcomes. Am J Transplant. 2013 Feb;13(2):442–449.
  • Roodnat JI, Mulder PG, Rischen-Vos J, et al. Proteinuria after renal transplantation affects not only graft survival but also patient survival. Transplantation. 2001 Aug 15;72(3):438–444.
  • Langer RM, Hené R, Vitko S, et al. Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation. Transpl Int. 2012 May;25(5):592–602.
  • Büchler M, Caillard S, Barbier S, et al. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am J Transplant. 2007 Nov;7(11):2522–2531.
  • Sterneck M, Kaiser GM, Heyne N, et al. Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation. Am J Transplant. 2014 Mar;14(3):701–710.
  • Asrani SK, Wiesner RH, Trotter JF, et al. De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000–2003 phase II prospective randomized trial. Am J Transplant. 2014 Feb;14(2):356–366.
  • Fischer L, Klempnauer J, Beckebaum S, et al. A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation–PROTECT. Am J Transplant. 2012 Jul;12(7):1855–1865.
  • Zuckermann A, Keogh A, Crespo-Leiro MG, et al. Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency. Am J Transplant. 2012 Sep;12(9):2487–2497.
  • De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant. 2012 Dec;12(11):3008–3020.
  • Saliba F, De Simone P, Nevens F, et al. Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant. 2013 Jul;13(7):1734–1745.
  • Letavernier E, Bruneval P, Vandermeersch S, et al. Sirolimus interacts with pathways essential for podocyte integrity. Nephrol Dial Transplant. 2009 Feb;24(2):630–638.
  • Guba M, Von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002 Feb;8(2):128–135.
  • Servais A, Meas-Yedid V, Toupance O, et al. Interstitial fibrosis quantification in renal transplant recipients randomized to continue cyclosporine or convert to sirolimus. Am J Transplant. 2009 Dec;9(11):2552–2560.
  • Diekmann F, Budde K, Oppenheimer F, et al. Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant. 2004 Nov;4(11):1869–1875.
  • Bumbea V, Kamar N, Ribes D, et al. Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant. 2005 Nov;20(11):2517–2523.
  • Gutiérrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008 Aug 7;359(6):584–592.
  • Uhlmann D, Weber T, Ludwig S, et al. Long-term outcome of conversion to sirolimus monotherapy after liver transplant. Exp Clin Transplant. 2012 Feb;10(1):30–38.
  • Wadei HM, Zaky ZS, Keaveny AP, et al. Proteinuria following sirolimus conversion is associated with deterioration of kidney function in liver transplant recipients. Transplantation. 2012 May 27;93(10):1006–1012.
  • Oroszlán M, Bieri M, Ligeti N, et al. Sirolimus and everolimus reduce albumin endocytosis in proximal tubule cells via an angiotensin II-dependent pathway. Transpl Immunol. 2010 Jul;23(3):125–132.
  • Cai Y, Chen Y, Zheng S, et al. Sirolimus damages podocytes in rats with protein overload nephropathy. J Nephrol. 2011 Jan;24(3):307–312.
  • Saurina A, Campistol JM, Piera C, et al. Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria. Nephrol Dial Transplant. 2006 Feb;21(2):488–493.
  • Stallone G, Infante B, Pontrelli P, et al. Sirolimus and proteinuria in renal transplant patients: evidence for a dose-dependent effect on slit diaphragm-associated proteins. Transplantation. 2011 May 15;91(9):997–1004.
  • Van Den Akker JM, Wetzels JFM, Hoitsma AJ. Proteinuria following conversion from azathioprine to sirolimus in renal transplant recipients. Kidney Int. 2006 Oct;70(7):1355–1357.
  • Ponticelli C, Banfi G. Thrombotic microangiopathy after kidney transplantation. Transpl Int. 2006 Oct;19(10):789–794.
  • Reig Mezquida JP, Jover AS, Ansótegui Barrera E, et al. Thrombotic microangiopathy associated with tacrolimus in lung transplantation. Arch Bronconeumol. 2015 May;51(5):e23–e24.
  • Al-Nouri ZL, Reese JA, Terrell DR, et al. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015 Jan 22;125(4):616–618.
  • Nava F, Cappelli G, Mori G, et al. Everolimus, cyclosporine, and thrombotic microangiopathy: clinical role and preventive tools in renal transplantation. Transplant Proc. 2014 Sep;46(7):2263–2268.
  • Langer RM, Van Buren CT, Katz SM, et al. De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine-sirolimus combination. Transplantation. 2002 Mar 15;73(5):756–760.
  • Yılmaz VT, Koçak H, Avcı AB, et al. Thrombotic thrombocytopenic purpura associated with everolimus use in a renal transplant patient. Int Urol Nephrol. 2011 Jun;43(2):581–584.
  • Verbiest A, Pirenne J, Dierickx D. De novo thrombotic microangiopathy after non-renal solid organ transplantation. Blood Rev. 2014 Nov;28(6):269–279.
  • Keller K, Daniel C, Schöcklmann H, et al. Everolimus inhibits glomerular endothelial cell proliferation and VEGF, but not long-term recovery in experimental thrombotic microangiopathy. Nephrol Dial Transplant. 2006 Oct;21(10):2724–2735.
  • Mulgaonkar S, Kaufman DB. Conversion from calcineurin inhibitor-based immunosuppression to mammalian target of rapamycin inhibitors or belatacept in renal transplant recipients. Clin Transplant. 2014 Nov;28(11):1209–1224.
  • Cortina G, Trojer R, Waldegger S, et al. De novo tacrolimus-induced thrombotic microangiopathy in the early stage after renal transplantation successfully treated with conversion to everolimus. Pediatr Nephrol. 2015 Apr;30(4):693–697.
  • Ekberg H, Bernasconi C, Noldeke J, et al. Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study. Nephrol Dial Transplant. 2010 Jan 26;25(6):2004–2010.
  • Oberbauer R, Kreis H, Johnson RWG, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation. 2003 Jul 27;76(2):364–370.
  • Augustine JJ, Knauss TC, Schulak JA, et al. Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients. Am J Transplant. 2004 Dec;4(12):2001–2006.
  • Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004 Dec 23;351(26):2715–2729.
  • Su L, Tam N, Deng R, et al. Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis. Int Urol Nephrol. 2014 Oct;46(10):2035–2044.
  • Flechner SM, Goldfarb D, Solez K, et al. Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs. Transplantation. 2007 May 15;83(7):883–892.
  • Friend P, Russ G, Oberbauer R, et al. Incidence of anemia in sirolimus-treated renal transplant recipients: the importance of preserving renal function. Transpl Int. 2007 Sep;20(9):754–760.
  • Diekmann F, Rovira J, Diaz-Ricart M, et al. mTOR inhibition and erythropoiesis: microcytosis or anaemia? Nephrol Dial Transplant. 2012 Feb;27(2):537–541.
  • Büchler M, Hurault De Ligny B, Madec C, et al. Induction therapy by anti-thymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. Clin Transplant. 2003 Dec;17(6):539–545.
  • Humar A, Snydman D. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009 Dec;9(Suppl 4):S78–S86.
  • Crough T, Khanna R. Immunobiology of human cytomegalovirus: from bench to bedside. Clin Microbiol Rev. 2009 Jan;22(1):76–98.
  • Staras SAS, Dollard SC, Radford KW, et al. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis. 2006 Nov 1;43(9):1143–1151.
  • Poglitsch M, Weichhart T, Hecking M, et al. CMV late phase-induced mTOR activation is essential for efficient virus replication in polarized human macrophages. Am J Transplant. 2012 Jun;12(6):1458–1468.
  • Rittà M, Costa C, Solidoro P, et al. Everolimus-based immunosuppressive regimens in lung transplant recipients: impact on CMV infection. Antiviral Res. 2015 Jan;113:19–26.
  • Ghassemieh B, Ahya VN, Baz MA, et al. Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation. J Heart Lung Transplant. 2013 Jul;32(7):701–706.
  • Kobashigawa J, Ross H, Bara C, et al. Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation. Transpl Infect Dis. 2013 Apr 26;15(2):150–162.
  • Hill JA, Hummel M, Starling RC, et al. A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus. Transplantation. 2007 Dec 15;84(11):1436–1442.
  • Brennan DC, Legendre C, Patel D, et al. Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant. 2011 Nov;11(11):2453–2462.
  • Andrassy J, Hoffmann VS, Rentsch M, et al. Is cytomegalovirus prophylaxis dispensable in patients receiving an mTOR inhibitor-based immunosuppression? A systematic review and meta-analysis. Transplantation. 2012 Dec 27;94(12):1208–1217.
  • Andrews PA, Emery VC, Newstead C. Summary of the British Transplantation Society guidelines for the prevention and management of CMV disease after solid organ transplantation. Transplantation. 2011 Dec 15;92(11):1181–1187.
  • Kotton CN, Kumar D, Caliendo AM, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013 Aug 27;96(4):333–360.
  • Razonable RR, Humar A. Cytomegalovirus in solid organ transplantation. Am J Transplant. 2013 Mar;13(Suppl 4):93–106.
  • Koch M, Wiech T, Marget M, et al. De novo mTOR inhibitor-based immunosuppression in ABO-incompatible kidney transplantation. Clin Transplant. 2015 Nov;29(11):1021–1028.
  • Sheng L, Jun S, Jianfeng L, et al. The effect of sirolimus-based immunosuppression vs. conventional prophylaxis therapy on cytomegalovirus infection after liver transplantation. Clin Transplant. 2015 Jun;29(6):555–559.
  • Tedesco-Silva H, Felipe C, Ferreira A, et al. Reduced incidence of cytomegalovirus infection in kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Am J Transplant. 2015 Oct;15(10):2655–2664.
  • Brennan DC, Aguado JM, Potena L, et al. Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence and potential mechanisms. Rev Med Virol. 2013 Mar;23(2):97–125.
  • Mjörnstedt L, Schwartz Sørensen S, Von Zur Mühlen B, et al. Renal function three years after early conversion from a calcineurin inhibitor to everolimus: results from a randomized trial in kidney transplantation. Transpl Int. 2015 Jan;28(1):42–51.
  • Budde K, Lehner F, Sommerer C, et al. Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study. Am J Transplant. 2012 Jul;12(6):1528–1540.
  • Tedesco-Silva H, Vitko S, Pascual J, et al. 12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. Transpl Int. 2007 Jan;20(1):27–36.
  • Kean JM, Rao S, Wang M, et al. Seroepidemiology of human polyomaviruses. PLoS Pathog. 2009 Mar;5(3):e1000363.
  • Jacobi J, Prignitz A, Büttner M, et al. BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition. BMC Nephrol. 2013 Jan;14:207.
  • Morelon E, Stern M, Israël-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation. 2001 Sep 15;72(5):787–790.
  • Singer SJ, Tiernan R, Sullivan EJ. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med. 2000 Dec 14;343(24):1815–1816.
  • McWilliams TJ, Levvey BJ, Russell PA, et al. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. J Heart Lung Transplant. 2003 Feb;22(2):210–213.
  • Atkinson BJ, Cauley DH, Ng C, et al. Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes. BJU Int. 2014 Mar;113(3):376–382.
  • Duran I, Siu LL, Oza AM, et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer. 2006 Aug;42(12):1875–1880.
  • White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010 Aug 1;182(3):396–403.
  • Maroto JP, Hudes G, Dutcher JP, et al. Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol. 2011 May 1;29(13):1750–1756.
  • Bouvier G, Cellerin L, Henry B, et al. Everolimus associated interstitial pneumonitis: 3 case reports. Respir Med CME. 2009 Jan;2(4):181–184.
  • Akata K, Yatera K, Ishimoto H, et al. Two cases of everolimus-associated interstitial pneumonia in patients with renal cell carcinoma. Intern Med. 2011 Jan;50(24):3013–3017.
  • Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Oct 15;116(18):4256–4265.
  • Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765–2772.
  • Carreño CA, Gadea M. Case report of a kidney transplant recipient converted to everolimus due to malignancy: resolution of bronchiolitis obliterans organizing pneumonia without everolimus discontinuation. Transplant Proc. 2007 Apr;39(3):594–595.
  • Pham P-T-T, Pham P-CT, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation. 2004 Apr 27;77(8):1215–1220.
  • Weiner SM, Sellin L, Vonend O, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome – a single-centre experience and review of the literature. Nephrol Dial Transplant. 2007 Dec;22(12):3631–3637.
  • Champion L, Stern M, Israël-Biet D, et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med. 2006 Apr 4;144(7):505–509.
  • Khalife WI, Kogoj P, Kar B. Sirolimus-induced alveolar hemorrhage. J Heart Lung Transplant. 2007 Jun;26(6):652–657.
  • Kahan BD, Knight R, Schoenberg L, et al. Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience. Transplant Proc. 2003 May;35(3):S25–S34.
  • Schwarz MI, Fontenot AP. Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis. Clin Chest Med. 2004 Mar;25(1):133–140.
  • Kirby S, Satoskar A, Brodsky S, et al. Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens. Diagn Pathol. BioMed Central Ltd. 2012;7(1):25.
  • Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998 Feb 13;273(7):3963–3966.
  • Blommaart EF, Luiken JJ, Blommaart PJ, et al. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem. 1995 Feb 3;270(5):2320–2326.
  • Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011 Feb;13(2):132–141.
  • Howard L, Gopalan D, Griffiths M, et al. Sirolimus-induced pulmonary hypersensitivity associated with a CD4 T-cell infiltrate. Chest. 2006 Jun;129(6):1718–1721.
  • Farkas L, Farkas D, Ask K, et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest. 2009 May;119(5):1298–1311.
  • Borensztajn K, Crestani B, Kolb M. Idiopathic pulmonary fibrosis: from epithelial injury to biomarkers–insights from the bench side. Respiration. 2013 Jan;86(6):441–452.
  • Chatterjee S, Heukamp LC, Siobal M, et al. Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest. American Society for Clinical Investigation. 2013 Apr 1;123(4):1732–1740.
  • Chen Y-H, Pan S-L, Wang J-C, et al. Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer. Strahlenther Onkol. 2014 Nov;190(12):1154–1162.
  • Diekmann F, Rovira J, Carreras J, et al. Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass. J Am Soc Nephrol. 2007 Oct 1;18(10):2653–2660.
  • Pedroso SL, Martins LS, Sousa S, et al. Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus. Transpl Int. 2007 Mar;20(3):291–296.
  • ANZDATA Registry. 36th report, chapter 8: transplantation. Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2014. Available from: http://www.anzdata.org.au
  • Engels EA, Pfeiffer RM, Fraumeni JF, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011 Nov 2;306(17):1891–1901.
  • Guba M, Graeb C, Jauch K-W, et al. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation. 2004 Jun 27;77(12):1777–1782.
  • Hibberd AD, Trevillian PR, Wlodarczyk JH, et al. Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a population-based retrospective cohort study. Transplantation. 2013 Jan 15;95(1):122–127.
  • Lim WH, Turner RM, Chapman JR, et al. Acute rejection, T-cell-depleting antibodies, and cancer after transplantation. Transplantation. 2014 Apr 27;97(8):817–825.
  • Vignot S, Faivre S, Aguirre D, et al. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005 Apr;16(4):525–537.
  • Muthukkumar S, Ramesh TM, Bondada S. Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells. Transplantation. 1995 Aug 15;60(3):264–269.
  • Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol. 2006 Feb;17(2):581–589.
  • Alberú J, Pascoe MD, Campistol JM, et al. Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation. 2011 Aug 15;92(3):303–310.
  • Yanik EL, Gustafson SK, Kasiske BL, et al. Sirolimus use and cancer incidence among US kidney transplant recipients. Am J Transplant. 2015 Jan;15(1):129–136.
  • Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003 Apr 24;348(17):1681–1691.
  • Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011 Aug;65(2):253–261; quiz 262.
  • Brenneisen P, Sies H, Scharffetter-Kochanek K. Ultraviolet-B irradiation and matrix metalloproteinases: from induction via signaling to initial events. Ann N Y Acad Sci. 2002 Nov;973:31–43.
  • Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012 Jul 26;367(4):329–339.
  • Campbell SB, Walker R, Tai SS, et al. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant. 2012 May;12(5):1146–1156.
  • Hoogendijk-Van Den Akker JM, Harden PN, Hoitsma AJ, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013 Apr 1;31(10):1317–1323.
  • Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet. 2000 Jul 15;356(9225):194–202.
  • Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant. 2006 May;6(5 Pt 1):986–992.
  • Grim SA, Slover CM, Sankary H, et al. Risk factors for wound healing complications in sirolimus-treated renal transplant recipients. Transplant Proc. 2006 Dec;38(10):3520–3523.
  • Hulbert AL, Delahunty AJ, Rajab A, et al. The utilization of sirolimus and the impact on wound-healing complications in obese kidney transplant recipients. Clin Transplant. 2013 Jan;27(4):E521–E527.
  • Salvadori M, Scolari MP, Bertoni E, et al. Everolimus with very low-exposure cyclosporine A in de novo kidney transplantation: a multicenter, randomized, controlled trial. Transplantation. 2009 Nov 27;88(10):1194–1202.
  • Cooper M, Wiseman AC, Zibari G, et al. Wound events in kidney transplant patients receiving de novo everolimus: a pooled analysis of three randomized controlled trials. Clin Transplant. 2013 Jan;27(6):E625–E635.
  • Humar R, Kiefer FN, Berns H, et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. Faseb J. 2002 Jun 1;16(8):771–780.
  • Jia J, Dellinger A, Bulusu A, et al. Direct evidence of target inhibition with anti-VEGF, EGFR, and mTOR therapies in a clinical model of wound healing. Clin Cancer Res. 2015 Aug 1;21(15):3442–3452.
  • Akselband Y, Harding MW, Nelson PA. Rapamycin inhibits spontaneous and fibroblast growth factor beta-stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc. 1991 Dec;23(6):2833–2836.
  • Tiong HY, Flechner SM, Zhou L, et al. A systematic approach to minimizing wound problems for de novo sirolimus-treated kidney transplant recipients. Transplantation. 2009 Jan 27;87(2):296–302.
  • Flechner SM, Zhou L, Derweesh I, et al. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients. Transplantation. 2003 Dec 27;76(12):1729–1734.
  • Campistol JM, De Fijter JW, Nashan B, et al. Everolimus and long-term outcomes in renal transplantation. Transplantation. 2011 Aug 15;92(3 Suppl):S3–S26.
  • Nashan B. mTOR inhibitors and their role in modern concepts of immunosuppression. World J Surg. 2014 Dec;38(12):3199–3201.
  • Koch M, Kantas A, Ramcke K, et al. Surgical complications after kidney transplantation: different impacts of immunosuppression, graft function, patient variables, and surgical performance. Clin Transplant. 2015 Mar;29(3):252–260.
  • Nashan B, Citterio F. Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation. Transplant J. 2012 Sep 27;94(6):547–561.
  • Zaza G, Tomei P, Ria P, et al. Systemic and nonrenal adverse effects occurring in renal transplant patients treated with mTOR inhibitors. Clin Dev Immunol. 2013 Jan;2013:1–13.
  • Moro JA, Almenar L, Martínez-Dolz L, et al. mTOR inhibitors and unilateral edema. Rev Española Cardiol. 2008 Sep;61(9):987–988.
  • Pascual J, Boletis IN, Campistol JM. Everolimus (Certican) in renal transplantation: a review of clinical trial data, current usage, and future directions. Transplant Rev. 2006 Jan;20(1):1–18.
  • Ersoy A, Koca N. Everolimus-induced lymphedema in a renal transplant recipient: a case report. Exp Clin Transplant. 2012 Jun;10(3):296–298.
  • Mäkinen T, Jussila L, Veikkola T, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med. 2001 Feb;7(2):199–205.
  • Gharbi C, Gueutin V, Izzedine H. Oedema, solid organ transplantation and mammalian target of rapamycin inhibitor/proliferation signal inhibitors (mTOR-I/PSIs). Clin Kidney J. 2014 Apr;7(2):115–120.
  • Sánchez-Fructuoso AI, Ruiz JC, Pérez-Flores I, et al. Comparative analysis of adverse events requiring suspension of mTOR inhibitors: everolimus versus sirolimus. Transplant Proc. 2010 Oct;42(8):3050–3052.
  • Van Den Eertwegh AJM, Karakiewicz P, Bavbek S, et al. Safety of everolimus by treatment duration in patients with advanced renal cell cancer in an expanded access program. Urology. 2013 Jan;81(1):143–149.
  • Mahé E, Morelon E, Lechaton S, et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation. 2005 Mar 27;79(4):476–482.
  • Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014 Jul;28(3):126–133.
  • Boers-Doets CB, Raber-Durlacher JE, Treister NS, et al. Mammalian target of rapamycin inhibitor-associated stomatitis. Future Oncol. 2013 Dec;9(12):1883–1892.
  • Reitamo S, Spuls P, Sassolas B, et al. Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial. Br J Dermatol. 2001 Sep;145(3):438–445.
  • Mahé E, Morelon E, Lechaton S, et al. Acne in recipients of renal transplantation treated with sirolimus: clinical, microbiologic, histologic, therapeutic, and pathogenic aspects. J Am Acad Dermatol. 2006 Jul;55(1):139–142.
  • Campistol JM, De Fijter JW, Flechner SM, et al. mTOR inhibitor-associated dermatologic and mucosal problems. Clin Transplant. 2010 Jan;24(2):149–156.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.