title: Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.
abstract: Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.
authors.affiliation: Department of Surgery, Johns Hopkins Medical Institute, Baltimore, MD.
authors.forename: R A
authors.initials: RA
authors.lastname: Montgomery
authors.affiliation: Department of Surgery, Johns Hopkins Medical Institute, Baltimore, MD.
authors.forename: B J
authors.initials: BJ
authors.lastname: Orandi
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institute, Baltimore, MD.
authors.forename: L
authors.initials: L
authors.lastname: Racusen
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institute, Baltimore, MD.
authors.forename: A M
authors.initials: AM
authors.lastname: Jackson
authors.affiliation: Department of Surgery, Johns Hopkins Medical Institute, Baltimore, MD.
authors.forename: J M
authors.initials: JM
authors.lastname: Garonzik-Wang
authors.affiliation: Transplant Nephrology, St. Vincent's Hospital, Los Angeles, Los Angeles, CA.
authors.forename: T
authors.initials: T
authors.lastname: Shah
authors.affiliation: Transplant Surgery, University of Cincinnati, Cincinnati, OH.
authors.forename: E S
authors.initials: ES
authors.lastname: Woodle
authors.affiliation: Department of Nephrology, Medical University Hospital, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sommerer
authors.affiliation: Research and Development, Lexington, MA.
authors.forename: D
authors.initials: D
authors.lastname: Fitts
authors.affiliation: Research and Development, Lexington, MA.
authors.forename: K
authors.initials: K
authors.lastname: Rockich
authors.affiliation: Research and Development, Lexington, MA.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Research and Development, Lexington, MA.
authors.forename: M E
authors.initials: ME
authors.lastname: Uknis
mesh_terms: D050718:Complement C1 Inhibitor Protein / Q000494:pharmacology*; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D007518:Isoantibodies / Q000009:adverse effects*; D007676:Kidney Failure, Chronic / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010956:Plasmapheresis; D011379:Prognosis; D012307:Risk Factors
chemical_list: D050718:Complement C1 Inhibitor Protein; D051056:Complement Inactivating Agents; D016756:Immunoglobulins, Intravenous; D007518:Isoantibodies
keywords: clinical research/practice; clinical trial; kidney transplantation/nephrology; rejection: antibody-mediated (ABMR)