ELEVATE: an innovative study design to assess the efficacy, safety, and evolution of cardiovascular parameters in de novo kidney transplant recipients after early conversion from a calcineurin inhibitor to everolimus

References

• Gurk-Turner C, Manitpisitkul W, Cooper M. A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor. Transplantation. 2012;94(7):659–668.
   PubMed Web of Science ®Google Scholar
• Halleck F, Duerr M, Waiser J, et al. An evaluation of sirolimus in renal transplantation. Expert Opin Drug Metab Toxicol. 2012;8(10):1337–1356.
   PubMed Web of Science ®Google Scholar
• Rostaing L, Kamar N. mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J Nephrol. 2010;23(2):133–142.
   Web of Science ®Google Scholar
• Ponticelli C. Can mTOR inhibitors reduce the risk of late kidney allograft rejection? Transpl Int. 2008;21(1):2–10.
   Web of Science ®Google Scholar
• Gutiérrez-Dalmau A, Campistol JM. The role of proliferation signal inhibitors in post-transplant malignancies. Nephrol Dial Transplant. 2007;22 Suppl 1:i11–i16.
   Google Scholar
• Nashan B, Gaston R, Emery V, et al. Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation. 2012;93(11):1075–1085.
   Web of Science ®Google Scholar
• Suwelack B, Malyar V, Koch M, Sester M, Sommerer C. The influence of immunosuppressive agents on BK virus risk following kidney transplantation, and implications for choice of regimen. Transplant Rev (Orlando). 2012;26(3):201–211.
   Google Scholar
• Seckinger J, Sommerer C, Hinkel UP, Hoffmann O, Zeier M, Schwenger V. Switch of immunosuppression from cyclosporine A to everolimus: impact on pulse wave velocity in stable de-novo renal allograft recipients. J Hypertens. 2008;26(11):2213–2219.
   Web of Science ®Google Scholar
• Joannidès R, Monteil C, de Ligny BH, et al. Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine. Am J Transplant. 2011;11(11):2414–2422.
   Web of Science ®Google Scholar
• Organ Procurement and Transplant Network and Scientific Renal Transplant Registry. Annual Report, 2011. Available from: http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/01_kidney_12.pdf. Accessed January 25, 2014.
   Google Scholar
• Gondos A, Döhler B, Brenner H, Opelz G. Kidney graft survival in Europe and the United States: strikingly different long-term outcomes. Transplantation. 2013;95(2):267–274.
   PubMed Web of Science ®Google Scholar
• Opelz G, Döhler B. Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report. Am J Transplant. 2012;12(8):3031–3038.
   Google Scholar
• Opelz G, Döhler B. Association between steroid dosage and death with a functioning graft after kidney transplantation. Am J Transplant. 2013;13(8):2096–2105.
   Web of Science ®Google Scholar
• Collins AJ, Foley RN, Herzog C, et al. US Renal Data System 2010 Annual Data Report. Am J Kidney Dis. 2011;57 Suppl 1:A8, e1–e526.
   Google Scholar
• Tapiawala SN, Tinckam KJ, Cardella CJ, et al. Delayed graft function and the risk of death with a functioning graft. J Am Soc Nephrol. 2010;21(1):153–161.
   PubMed Web of Science ®Google Scholar
• Ojo A. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 2006;82(5):603–611.
   PubMed Web of Science ®Google Scholar
• Liefeldt L, Budde K. Risk factors for cardiovascular disease in renal transplant recipients and strategies to minimize risk. Transpl Int. 2010;23(2):1191–1204.
   Google Scholar
• Nashan B. Induction therapy and mTOR inhibition: minimizing calcineurin inhibitor exposure in de novo renal transplant patients. Clin Transplant. 2013;27 Suppl 25:16–29.
   Google Scholar
• Valantine H. Is there a role for proliferation signal/mTOR inhibitors in the prevention and treatment of de novo malignancies after heart transplantation? Lessons learned from renal transplantation and oncology. J Heart Lung Transplant. 2007;26(6):557–564.
   Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–456.
   PubMed Web of Science ®Google Scholar
• Zeier M, van der Giet M. Calcineurin inhibitor sparing regimens using m-target of rapamycin inhibitors: an opportunity to improve cardiovascular risk following kidney transplantation? Transpl Int. 2011;24(1):30–42.
   Web of Science ®Google Scholar
• Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Chapman JR, Allen RD. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation. 2004;78(4):557–565.
   PubMed Web of Science ®Google Scholar
• Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349(24):2326–2333.
   PubMedGoogle Scholar
• Ekberg H, van Gelder T, Kaplan B, Bernasconi C. Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation. Transplantation. 2011;92(1):82–87.
   PubMed Web of Science ®Google Scholar
• Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562–2575.
   PubMed Web of Science ®Google Scholar
• Chapman JR, O’Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol. 2005;16(10):3015–3026.
   PubMed Web of Science ®Google Scholar
• Vincenti F, Ramos E, Brattstrom C, et al. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 2001;71(9):1282–1287.
   PubMed Web of Science ®Google Scholar
• Bemelman FJ, de Maar EF, Press RR, et al. Minimization of maintenance immunosuppression early after renal transplantation: an interim analysis. Transplantation. 2009;88(3):421–428.
   Web of Science ®Google Scholar
• Ekberg H, Grinyó J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant. 2007;7(3):560–570.
   PubMed Web of Science ®Google Scholar
• Hazzan M, Labalette M, Copin MC, et al. Predictive factors of acute rejection after early cyclosporine withdrawal in renal transplant recipients who receive mycophenolate mofetil: results from a prospective, randomized trial. J Am Soc Nephrol. 2005;16(8):2509–2516.
   Web of Science ®Google Scholar
• Ekberg H. Calcineurin inhibitor sparing in renal transplantation. Transplantation. 2008;86(6):761–767.
   PubMed Web of Science ®Google Scholar
• Tedesco Silva H Jr, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant. 2010;10(6):1401–1413.
   PubMed Web of Science ®Google Scholar
• 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;25(5):592–602.
   PubMed Web of Science ®Google Scholar
• 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;88(10):1194–1202.
   PubMed Web of Science ®Google Scholar
• Guba M, Pratschke J, Hugo C, et al; for SMART-Study Group. 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(2):175–183.
   Web of Science ®Google Scholar
• 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;12(10):2744–2753.
   PubMed Web of Science ®Google Scholar
• Lebranchu Y, Thierry A, Toupance O, et al. Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: CONCEPT study. Am J Transplant. 2009;9(5):1115–1123.
   PubMed Web of Science ®Google Scholar
• 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;79(8):897–907.
   PubMed Web of Science ®Google Scholar
• Budde K, Becker T, Arns W, et al; for ZEUS Study Investigators. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011;377(9768):837–847.
   PubMed Web of Science ®Google Scholar
• Wu J, Li H, Huang H, et al. Slope of changes in renal function in the first year post-transplantation and one-yr estimated glomerular filtration rate together predict long-term renal allograft survival. Clin Transplant. 2010;24(6):862–868.
   Web of Science ®Google Scholar
• Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int. 2002;62(1):311–318.
   PubMed Web of Science ®Google Scholar
• Budde K, Lehner F, Sommerer C, et al; for ZEUS Study Investigators. Conversion from cyclosporine to everolimus at 4.5 months post-transplant: 3-year results from the randomized ZEUS study. Am J Transplant. 2012;12(6):1528–1540.
   PubMed Web of Science ®Google Scholar
• Budde K, Witzke O, Sommerer C, et al. Improved renal function of an everolimus/enteric-coated mycophenolate sodium regimen after calcineurin inhibitor withdrawal in de novo renal transplant patients: 5 years follow-up of the ZEUS trial. Am J Transplant. 2013;13 Suppl 5: Abstr 18.
   Google Scholar
• Zeier M, Budde K, Arns W, et al. Efficacy and safety of three different treatment regimens in de novo renal transplant patients: follow-up results of the HERAKLES trial at month 24. Am J Transplant. 2013; 13 Suppl 5:Abstr 495.
   Web of Science ®Google Scholar
• McMullen JR, Sherwood M, Tarnavski O, et al. Inhbition of mTOR signaling with rapamycin regresses cardiac hypertrophy induced by pressure overload. Circulation. 2004;109(24):3050–3055.
   Web of Science ®Google Scholar
• Shioi T, McMullen JR, Tarnvaksi O, et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation. 2003;107(12):1664–1670.
   PubMed Web of Science ®Google Scholar
• Gao XM, Wong G, Wang B, et al. Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens. 2006;24(8):1663–1670.
   Web of Science ®Google Scholar
• Buss SJ, Muenz S, Riffel JH, et al. Beneficial effects of mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol. 2009;54(25):2435–2446.
   PubMed Web of Science ®Google Scholar
• Calò LA, Davis PA, Giacon B, et al. Oxidative stress in kidney transplant patients with calcineurin inhibitor induced hypertension: effect of ramipril. J Cardiovasc Pharmacol. 2002;40(4):625–631.
   PubMed Web of Science ®Google Scholar
• Oflaz H, Turkmen A, Kazancioglu R, et al. The effect of calcineurin inhibitors on endothelial function in renal transplant recipients. Clin Transplant. 2003;17(3):212–216.
   Web of Science ®Google Scholar
• Paoletti E, Amidone M, Cassottana P, et al. Effect of sirolimus on left ventricular hypertrophy in kidney transplant recipients: a 1-year nonrandomized controlled trial. Am J Kidney Dis. 2008;52(2):324–330.
   PubMed Web of Science ®Google Scholar
• Hiemann NE, Wellnhofer E, Lehmkuhl HB, Knosalla C, Hetzer R, Meyer R. Everolimus prevents endomyocardial remodeling after heart transplantation. Transplantation. 2011;92(10):1165–1172.
   Web of Science ®Google Scholar
• Topilsky Y, Hasin T, Raichlin E, et al. Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation. Circulation. 2012;125(5):708–720.
   PubMed Web of Science ®Google Scholar
• Raichlin E, Chandrasekaran K, Kremers WK, et al. Sirolimus as primary immunosuppressant reduces left ventricular mass and improves diastolic function of the cardiac allograft. Transplantation. 2008;86(10):1395–1400.
   Web of Science ®Google Scholar
• Kushwaha SS, Raichlin E, Sheinin Y, et al. Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. Eur Heart J. 2008;29(22):2742–2750.
   Web of Science ®Google Scholar
• Murbraech K, Holdaas H, Massey R, Undset LH, Aakhus S. Cardiac response to early conversion from calcineurin inhibitor to everolimus in renal transplant recipients: an echocardiographic substudy of the randomized controlled CENTRAL trial. Transplantation. 2014;97(2):184–188.
   Web of Science ®Google Scholar
• Tarantino G, Capone D. Inhibition of the mTOR pathway: a possible protective role in coronary artery disease. Ann Med. 2013;45(4):348–356.
   Web of Science ®Google Scholar
• Jia L, Hui RT. Everolimus, a promising medical therapy for coronary heart disease? Med Hypotheses. 2009;73(2):153–155.
   Web of Science ®Google Scholar
• Neumayer HH. Introducing everolimus (Certican) in organ transplantation: an overview of preclinical and early clinical developments. Transplantation. 2005;79 Suppl 9:S72–S75.
   Google Scholar
• Viklický O, Zou H, Müller V, Lacha J, Szabó A, Heemann U. SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts. Transplantation. 2000;69(4):497–502.
   Web of Science ®Google Scholar
• Ma KL, Ruan XZ, Powis SH, Moorhead JF, Varghese Z. Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 2007;292(6):H2721–H2728.
   PubMed Web of Science ®Google Scholar
• Baetta R, Granata A, Canavesi M, et al. Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits. J Pharmacol Exp Ther. 2009;328(2):419–425.
   PubMed Web of Science ®Google Scholar
• Gouëffic Y, Potter-Perigo S, Chan CK, et al. Sirolimus blocks the accumulation of hyaluronan (HA) by arterial smooth muscle cells and reduces monocyte adhesion to the ECM. Atherosclerosis. 2007;195(1):23–30.
   Web of Science ®Google Scholar
• Morrisett JD, Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res. 2002;43(8):1170–1180.
   PubMed Web of Science ®Google Scholar
• Mueller MA, Beutner F, Teupser D, Ceglarek U, Thiery J. Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR –/– mice despite severe hypercholesterolemia. Atherosclerosis. 2008;198(1):39–48.
   Web of Science ®Google Scholar
• Martinet W, Verheye S, De Meyer GR. Everolimus-induced mTOR inhibition selectively depletes macrophages in atherosclerotic plaques by autophagy. Autophagy. 2007;3(3):241–244.
   PubMed Web of Science ®Google Scholar
• Chen WQ, Zhong L, Zhang L, et al. Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum lipid levels. Br J Pharmacol. 2009;156(6):941–951.
   PubMed Web of Science ®Google Scholar
• Verheye S, Martinet W, Kockx MM, et al. Selective clearance of macrophages in atherosclerotic plaques by autophagy. J Am Coll Cardiol. 2007;49(6):706–715.
   PubMed Web of Science ®Google Scholar
• Palmerini T, Kirtane AJ, Serruys PW, et al. Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv. 2012;5(3):357–364.
   Web of Science ®Google Scholar
• Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: A randomized, multicenter trial. Am J Transplant. 2013;13(5):1203–1216.
   PubMed Web of Science ®Google Scholar
• Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349(9):847–858.
   PubMed Web of Science ®Google Scholar
• Raichlin E, Bae JH, Khalpey Z, et al. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation. 2007;116(23):2726–2733.
   PubMed Web of Science ®Google Scholar
• Mackey RH, Venkitachalam L, Sutton-Tyrrell K. Calcifications, arterial stiffness and atherosclerosis. Adv Cardiol. 2007;44:234–244.
   PubMedGoogle Scholar
• Clae KJ, Heye S, Bammens B, et al. Aortic calcifications and arterial stiffness as predictors or cardiovascular events in incident renal transplant patients. Transpl Int. 2013;26(10):973–981.
   Web of Science ®Google Scholar
• Tomlinson LA. Methods for assessing arterial stiffness: technical considerations. Curr Opin Nephrol Hypertens. 2012;21(6):655–660.
   PubMed Web of Science ®Google Scholar
• Strózecki P, Adamowicz A, Wlodarczyk Z, Manitius J. The influence of calcineurin inhibitors on pulse wave velocity in renal transplant recipients. Ren Fail. 2007;29(6):679–684.
   Web of Science ®Google Scholar
• Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130(6):461–470.
   PubMed Web of Science ®Google Scholar