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      Long‐Term Outcomes in Belatacept‐ Versus Cyclosporine‐Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT‐EXT, a Phase III Randomized Study

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          Abstract

          In the Belatacept Evaluation of Nephroprotection and Efficacy as First‐Line Immunosuppression Trial–Extended Criteria Donors ( BENEFITEXT), extended criteria donor kidney recipients were randomized to receive belatacept‐based (more intense [ MI] or less intense [ LI]) or cyclosporine‐based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent‐to‐treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 belatacept MI–treated, 138 of 175 belatacept LI–treated and 108 of 184 cyclosporine‐treated patients contributed data to these analyses. Hazard ratios ( HRs) comparing time to death or graft loss were 0.915 (95% confidence interval [ CI] 0.625–1.339; p = 0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI 0.634–1.356; p = 0.70) for belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m 2 for belatacept MI, belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or e GFR <20 mL/min per 1.73 m 2 were 0.754 (95% CI 0.536–1.061; p = 0.10) for belatacept MI versus cyclosporine and 0.706 (95% CI 0.499–0.998; p = 0.05) for belatacept LI versus cyclosporine. Acute rejection rates and safety profiles of belatacept‐ and cyclosporine‐based treatment were similar. De novo donor‐specific antibody incidence was lower for belatacept (p ≤ 0.0001). Relative to cyclosporine, belatacept was associated with similar death and graft loss and improved renal function at 7 years after transplant and had a safety profile consistent with previous reports.

          Abstract

          In patients transplanted with an extended donation criteria kidney, belatacept‐based immunosuppression is associated with a similar death/graft loss and improved renal function at 7 years posttransplant as a cyclosporine‐based immunosuppression, with a safety profile consistent with previous reports.

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          Most cited references39

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          The natural history of chronic allograft nephropathy.

          With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure. We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter. Two distinctive phases of injury were evident as chronic allograft nephropathy evolved. An initial phase of early tubulointerstitial damage from ischemic injury (P<0.05), prior severe rejection (P<0.01), and subclinical rejection (P<0.01) predicted mild disease by one year, which was present in 94.2 percent of patients. Early subclinical rejection was common (affecting 45.7 percent of biopsy specimens at three months), and the risk was increased by the occurrence of a prior episode of severe rejection and reduced by tacrolimus and mycophenolate therapy (both P<0.05) and gradually abated after one year. Both subclinical rejection and chronic rejection were associated with increased tubulointerstitial damage (P<0.01). Beyond one year, a later phase of chronic allograft nephropathy was characterized by microvascular and glomerular injury. Chronic rejection (defined as persistent subclinical rejection for two years or longer) was uncommon (5.8 percent). Progressive high-grade arteriolar hyalinosis with luminal narrowing, increasing glomerulosclerosis, and additional tubulointerstitial damage was accompanied by the use of calcineurin inhibitors. Nephrotoxicity, implicated in late ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings. By 10 years, severe chronic allograft nephropathy was present in 58.4 percent of patients, with sclerosis in 37.3 percent of glomeruli. Tubulointerstitial and glomerular damage, once established, was irreversible, resulting in declining renal function and graft failure. Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes. Copyright 2003 Massachusetts Medical Society
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            Immunosuppressive drugs for kidney transplantation.

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              Belatacept and Long-Term Outcomes in Kidney Transplantation

              In previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study.
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                Author and article information

                Contributors
                antoine.durrbach@bct.aphp.fr
                Journal
                Am J Transplant
                Am. J. Transplant
                10.1111/(ISSN)1600-6143
                AJT
                American Journal of Transplantation
                John Wiley and Sons Inc. (Hoboken )
                1600-6135
                1600-6143
                09 June 2016
                November 2016
                : 16
                : 11 ( doiID: 10.1111/ajt.2016.16.issue-11 )
                : 3192-3201
                Affiliations
                [ 1 ] University Hôpital of Bicêtre Le Kremlin‐Bicêtre France
                [ 2 ] Université Paris‐Saclay Plateau de Saclay France
                [ 3 ] Hospital do Rim Sao Paulo Brazil
                [ 4 ] Mount Sinai Medical Center New York NY
                [ 5 ] Instituto de Nefrología Buenos Aires Argentina
                [ 6 ] University Hospital Toulouse France
                [ 7 ] University Hospitals Leuven Leuven Belgium
                [ 8 ] University of Minnesota Minneapolis MN
                [ 9 ] Medical University of Vienna Vienna Austria
                [ 10 ] Bristol‐Myers Squibb Lawrenceville NJ
                [ 11 ] Bristol‐Myers Squibb Braine‐l'Alleud Belgium
                [ 12 ] University Hospital Bellvitge Barcelona Spain
                Author notes
                [*] [* ]Corresponding author: Antoine Durrbach, antoine.durrbach@ 123456bct.aphp.fr
                Article
                AJT13830
                10.1111/ajt.13830
                5516151
                27130868
                7252bb5d-2f81-4ea3-b9a1-ab7385ebf913
                © 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 22 November 2015
                : 01 April 2016
                : 08 April 2016
                Page count
                Figures: 4, Tables: 3, Pages: 10, Words: 7294
                Funding
                Funded by: Bristol‐Myers Squibb
                Categories
                Original Article
                Original Articles
                Clinical Science
                Custom metadata
                2.0
                ajt13830
                November 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:19.07.2017

                Transplantation
                clinical research/practice,kidney transplantation/nephrology,clinical trial,donors and donation: deceased,donors and donation: extended criteria,donors and donation: donation after circulatory death (dcd),immunosuppressant,fusion proteins and monoclonal antibodies: belatacept

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