Dixon B Kaufman1, E Steve Woodle2, Adele Rike Shields2, John Leone3, Arthur Matas4, Alexander Wiseman5, Patricia West-Thielke6, Ting Sa7, Eileen C King2,7, Rita R Alloway2. 1. University of Wisconsin, Madison, Wisconsin kaufman@surgery.wisc.edu. 2. University of Cincinnati College of Medicine, Cincinnati, Ohio. 3. Tampa General Hospital, Tampa, Florida. 4. University of Minnesota, Minneapolis, Minnesota. 5. University of Colorado, Denver, Colorado. 6. University of Illinois Chicago, Chicago, Illinois. 7. Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio.
Abstract
BACKGROUND AND OBJECTIVES: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. RESULTS: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. CONCLUSIONS: Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Belatacept Early Steroid Withdrawal Trial, NCT01729494.
BACKGROUND AND OBJECTIVES: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. RESULTS: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. CONCLUSIONS: Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Belatacept Early Steroid Withdrawal Trial, NCT01729494.
Authors: A D Kirk; A Guasch; H Xu; J Cheeseman; S I Mead; A Ghali; A K Mehta; D Wu; H Gebel; R Bray; J Horan; L S Kean; C P Larsen; T C Pearson Journal: Am J Transplant Date: 2014-03-31 Impact factor: 8.086
Authors: R Ferguson; J Grinyó; F Vincenti; D B Kaufman; E S Woodle; B A Marder; F Citterio; W H Marks; M Agarwal; D Wu; Y Dong; P Garg Journal: Am J Transplant Date: 2010-11-29 Impact factor: 8.086
Authors: Oscar Kenneth Serrano; Raja Kandaswamy; Kristen Gillingham; Srinath Chinnakotla; Ty B Dunn; Erik Finger; William Payne; Hassan Ibrahim; Aleksandra Kukla; Richard Spong; Naim Issa; Timothy L Pruett; Arthur Matas Journal: Transplantation Date: 2017-10 Impact factor: 4.939
Authors: A Durrbach; J M Pestana; T Pearson; F Vincenti; V D Garcia; J Campistol; M del Carmen Rial; S Florman; A Block; G Di Russo; J Xing; P Garg; J Grinyó Journal: Am J Transplant Date: 2010-03 Impact factor: 8.086
Authors: F Vincenti; B Charpentier; Y Vanrenterghem; L Rostaing; B Bresnahan; P Darji; P Massari; G A Mondragon-Ramirez; M Agarwal; G Di Russo; C-S Lin; P Garg; C P Larsen Journal: Am J Transplant Date: 2010-03 Impact factor: 8.086
Authors: E Steve Woodle; M Roy First; John Pirsch; Fuad Shihab; A Osama Gaber; Paul Van Veldhuisen Journal: Ann Surg Date: 2008-10 Impact factor: 12.969
Authors: Flavio Vincenti; Lionel Rostaing; Joseph Grinyo; Kim Rice; Steven Steinberg; Luis Gaite; Marie-Christine Moal; Guillermo A Mondragon-Ramirez; Jatin Kothari; Martin S Polinsky; Herwig-Ulf Meier-Kriesche; Stephane Munier; Christian P Larsen Journal: N Engl J Med Date: 2016-01-28 Impact factor: 91.245
Authors: R A Bray; H M Gebel; R Townsend; M E Roberts; M Polinsky; L Yang; H-U Meier-Kriesche; C P Larsen Journal: Am J Transplant Date: 2018-04-02 Impact factor: 8.086