title: A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients.
abstract: BACKGROUND
  Antibody-mediated rejection (AMR) is a severe form of rejection, mediated primarily by antibody-dependent complement (C) activation. C1 inhibitor (C1-INH, Berinert) inhibits the classical and lectin pathways of C activation. We performed a randomized, placebo-controlled study using C1-INH in highly sensitized renal transplant recipients for prevention of AMR.
  
  
  METHODS
  Twenty highly sensitized patients desensitized with IVIG+rituximab±plasma exchange were enrolled and randomized 1:1 to receive plasma-derived human C1-INH (20 IU/kg/dose) versus placebo intraoperatively, then twice weekly for 7 doses. Renal function, adverse events (AEs)/serious AEs, C3, C4, and C1-INH levels were monitored and C1q+ HLA antibodies were also blindly assessed.
  
  
  RESULTS
  One patient in the C1-INH group versus 2 patients in the placebo group developed serious AEs, but none were related to study drug. Delayed graft function developed in 1 C1-INH subject and 4 in the placebo. The C1-INH trough levels increased with C1-INH treatment. C3 and C4 levels also increased significantly in the C1-INH group compared to placebo. No C1-INH patient developed AMR during the study. Two patients developed AMR after the study. Three placebo patients developed AMR, one during the study. C1q+ donor specific antibodies were reduced in 2 C1-INH treated patients tested, while immunoglobulin G DSA levels showed decreased binding for both groups.
  
  
  CONCLUSIONS
  The C1-INH appears safe in the posttransplant period. The C1-INH treatment may reduce ischemia-reperfusion injury. The C1-INH also resulted in significant elevations of C1-INH levels, C3, C4, and reduced C1q+ HLA antibodies. Taken together, the combination of antibody reduction and C1-INH may prove useful in prevention of AMR. Further controlled studies are warranted.
authors.affiliation: 1 Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA. 2 Immunogenetics Laboratory, University of Pittsburgh Medical Center, Pittsburgh, PA. 3 Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA. 4 HLA & Immunogenetics Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA. 5 Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Vo
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Jua
authors.initials: J
authors.lastname: Choi
authors.forename: Kristen
authors.initials: K
authors.lastname: Cisneros
authors.forename: Mieko
authors.initials: M
authors.lastname: Toyoda
authors.forename: Joseph
authors.initials: J
authors.lastname: Kahwaji
authors.forename: Alice
authors.initials: A
authors.lastname: Peng
authors.forename: Rafael
authors.initials: R
authors.lastname: Villicana
authors.forename: Dechu
authors.initials: D
authors.lastname: Puliyanda
authors.forename: Nancy
authors.initials: N
authors.lastname: Reinsmoen
authors.forename: Mark
authors.initials: M
authors.lastname: Haas
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D003167:Complement Activation / Q000187:drug effects*; D050718:Complement C1 Inhibitor Protein / Q000009:adverse effects / Q000627:therapeutic use*; D015922:Complement C1q / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects*; D015141:Los Angeles; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D050718:Complement C1 Inhibitor Protein; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D015922:Complement C1q