title: A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation.
abstract: Belatacept, an inhibitor of the CD28-CD80/86 costimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus far, no biomarker for belatacept-resistant rejection has been validated. In this randomized-controlled trial, acute rejection rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated.
  
  
  
  Forty kidney transplant recipients were 1:1 randomized to belatacept or tacrolimus combined with basiliximab, mycophenolate mofetil, and prednisolone. The 1-year incidence of biopsy-proven acute rejection was monitored. Potential biomarkers, namely, CD8CD28, CD4CD57PD1, and CD8CD28 end-stage terminally differentiated memory T cells were measured pretransplantation and posttransplantation and correlated to rejection. Pharmacodynamic monitoring of belatacept was performed by measuring free CD86 on monocytes.
  
  
  
  The rejection incidence was higher in belatacept-treated than tacrolimus-treated patients: 55% versus 10% (P = 0.006). All 3 graft losses, due to rejection, occurred in the belatacept group. Although 4 of 5 belatacept-treated patients with greater than 35 cells CD8CD28 end-stage terminally differentiated memory T cells/μL rejected, median pretransplant values of the biomarkers did not differ between belatacept-treated rejectors and nonrejectors. In univariable Cox regressions, the studied cell subsets were not associated with rejection-risk. CD86 molecules on circulating monocytes in belatacept-treated patients were saturated at all timepoints.
  
  
  
  Belatacept-based immunosuppressive therapy resulted in higher and more severe acute rejection compared with tacrolimus-based therapy. This trial did not identify cellular biomarkers predictive of rejection. In addition, the CD28-CD80/86 costimulatory pathway appeared to be sufficiently blocked by belatacept and did not predict rejection.
authors.affiliation: 1 Division of Nephrology and Kidney Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 2 Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 3 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. 4 Department of Biostatistics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
authors.forename: Gretchen N
authors.initials: GN
authors.lastname: de Graav
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.forename: Marian C
authors.initials: MC
authors.lastname: Clahsen-van Groningen
authors.forename: Rens
authors.initials: R
authors.lastname: Kraaijeveld
authors.forename: Marjolein
authors.initials: M
authors.lastname: Dieterich
authors.forename: Wenda
authors.initials: W
authors.lastname: Verschoor
authors.forename: Jan H
authors.initials: JH
authors.lastname: von der Thusen
authors.forename: Dave L
authors.initials: DL
authors.lastname: Roelen
authors.forename: Monique
authors.initials: M
authors.lastname: Cadogan
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van de Wetering
authors.forename: Joost
authors.initials: J
authors.lastname: van Rosmalen
authors.forename: Wilem
authors.initials: W
authors.lastname: Weimar
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Hesselink
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000175:diagnosis / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000069594:Abatacept; D016559:Tacrolimus