Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) - results of a randomized controlled clinical trial

3C Study Collaborative Group, Richard Haynes, Lisa Blackwell, Natalie Staplin, William G Herrington, Jonathan Emberson, Parminder K Judge, Benjamin C Storey, Martin J Landray, Paul N Harden, Colin Baigent, Peter Friend, 3C Study Collaborative Group, Richard Haynes, Lisa Blackwell, Natalie Staplin, William G Herrington, Jonathan Emberson, Parminder K Judge, Benjamin C Storey, Martin J Landray, Paul N Harden, Colin Baigent, Peter Friend

Abstract

Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short-term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long-term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus-based and 197 to tacrolimus-based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline-adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m2 in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m2 in the tacrolimus group (P = .50). Biopsy-proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus-based therapy, sirolimus-based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088.

Keywords: clinical research/practice; immunosuppressant - calcineurin inhibitor (CNI); immunosuppressant - fusion proteins and monoclonal antibodies: alemtuzumab; immunosuppressant - fusion proteins and monoclonal antibodies: basiliximab/daclizumab; immunosuppressant - mechanistic target of rapamycin (mTOR); immunosuppression/immune modulation; kidney transplantation/nephrology.

© 2017 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Effect of allocation to sirolimus‐based maintenance therapy on transplant function within the first 18 months
Figure 3
Figure 3
Life‐table plot of the effect of allocation to sirolimus‐based maintenance therapy on any biopsy‐proven rejection

References

    1. Meier‐Kriesche HU, Schold JD, Kaplan B. Long‐term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004;4(8):1289‐1295.
    1. 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.
    1. Nankivell BJ, P'Ng CH, O'Connell PJ, Chapman JR. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: comparison of cyclosporine and tacrolimus eras. Transplantation. 2016;100(8):1723‐1731.
    1. Ekberg H. Calcineurin inhibitor sparing in renal transplantation. Transplantation. 2008;86(6):761‐767.
    1. 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.
    1. 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):547‐561.
    1. 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;87(2):233‐242.
    1. Lebranchu Y, Thierry A, Toupance O, Westeel PF, Etienne I, Thervet E, 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.
    1. 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;377(9768):837‐847.
    1. Mulay AV, Cockfield S, Stryker R, Fergusson D, Knoll GA. Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence. Transplantation. 2006;82(9):1153‐1162.
    1. Lim WH, Eris J, Kanellis J, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant. 2014;14(9):2106‐2119.
    1. de Fijter JW, Holdaas H, Oyen O, Sanders JS, Sundar S, Bemelman FJ, et al. Early Conversion From Calcineurin Inhibitor‐ to Everolimus‐Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial. Am J Transplant. 2017;17:1853‐1867.
    1. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin‐cancer prevention in kidney transplantation. N Engl J Med. 2012;367(4):329‐339.
    1. 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;31(10):1317‐1323.
    1. 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;349:g6679.
    1. Ruggenenti P, Perico N, Gotti E, et al. Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury. Transplantation. 2007;84(8):956‐964.
    1. Sutherland AI, Akhtar MZ, Zilvetti M, et al. Alemtuzumab and sirolimus in renal transplantation: six‐year results of a single‐arm prospective pilot study. Am J Transplant. 2014;14(3):677‐684.
    1. 3C Study Collaborative Group . Alemtuzumab‐based induction treatment versus basiliximab‐based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014;384(9955):1684‐1690
    1. Haynes R, Baigent C, Harden P, et al. Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol. Transplantation Res. 2013;2(1):7.
    1. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31(1):103‐115.
    1. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. J Am Med Assoc. 1995;273(5):408‐412.
    1. Rubin D. Multiple imputation for non‐response in surveys. New York: John Wiley; 1987.
    1. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Brit. J Cancer. 1977;35(1):1‐39.
    1. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Brit. J Cancer. 1976;34(6):585‐612.
    1. Silva HT Jr, Felipe CR, Garcia VD, et al. Planned randomized conversion from tacrolimus to sirolimus‐based immunosuppressive regimen in de novo kidney transplant recipients. Am J Transplant. 2013;13(12):3155‐3163.
    1. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long‐term outcomes in kidney transplantation. N Engl J Med. 2016;374(4):333‐343.
    1. Guba M, Pratschke J, Hugo C, 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(2):175‐183.
    1. Heilman RL, Younan K, Wadei HM, et al. Results of a prospective randomized trial of sirolimus conversion in kidney transplant recipients on early corticosteroid withdrawal. Transplantation. 2011;92(7):767‐773.
    1. Pankewycz O, Leca N, Kohli R, et al. Conversion to low‐dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy‐guided study. Transplantation Proc. 2011;43(2):519‐523.
    1. Smith MP, Newstead CG, Ahmad N, et al. Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. Transplantation. 2008;85(4):636‐639.
    1. Matas AJ. Chronic progressive calcineurin nephrotoxicity: an overstated concept. Am J Transplant. 2011;11(4):687‐692.
    1. Calne R, Friend P, Moffatt S, et al. Prope tolerance, perioperative campath 1H, and low‐dose cyclosporin monotherapy in renal allograft recipients. Lancet. 1998;351(9117):1701‐1702.
    1. 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.
    1. Mallat SG, Tanios BY, Itani HS, et al. CMV and BKPyV infections in renal transplant recipients receiving an mTOR inhibitor‐based regimen versus a CNI‐based regimen: a systematic review and meta‐analysis of randomized, controlled trials. Clin J Am Soc Nephrol. 2017;12:1321‐1336.
    1. Gutierrez‐Dalmau A, Campistol JM. Kaposi's sarcoma after renal transplantation. N Engl J Med. 2005;353(8):846‐847.
    1. 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;20(11):2517‐2523.
    1. Diekmann F, Andres A, Oppenheimer F. mTOR inhibitor‐associated proteinuria in kidney transplant recipients. Transplantation Rev. 2012;26(1):27‐29.
    1. Fernandez‐Fresnedo G, Plaza JJ, Sanchez‐Plumed J, Sanz‐Guajardo A, Palomar‐Fontanet R, Arias M. Proteinuria: a new marker of long‐term graft and patient survival in kidney transplantation. Nephrol Dial Transplant. 2004;19(Suppl 3):iii47‐iii51
    1. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta‐analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670‐1681.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться