title: Eculizumab Therapy for Chronic Antibody-Mediated Injury in Kidney Transplant Recipients: A Pilot Randomized Controlled Trial.
abstract: We hypothesized that de novo donor-specific antibody (DSA) causes complement-dependent endothelial cell injury in kidney transplants, as assessed by expression of endothelial cell-associated transcripts (ENDATs), that may be attenuated through complement inhibition. In total, 15 participants (five control, 10 treatment) with DSA and deteriorating renal function were enrolled. The treatment group received 6 mo of eculizumab followed by 6 mo of observation, whereas controls were observed. The primary end point was percentage change in estimated GFR (eGFR) trajectory over the treatment period. The treatment group had an improved eGFR trajectory versus control, based on our predetermined two-sided 0.10 significance level (p = 0.09). Within-subject analysis of treated participants at 6-mo intervals did not show significant change (p = 0.60). Modeling C1q status showed that C1q-positive patients had significantly higher mean eGFR than patients with negative C1q (p = 0.04). Biopsies revealed elevated renal ENDATs in most participants, but ENDATs were not reduced with complement inhibition. Our data suggest that eculizumab treatment may stabilize kidney function in patients with chronic persistent DSA based on our pilot a priori significance threshold. ENDAT expression predicative of acute humoral injury is not reduced with complement inhibition in this chronic setting. Further studies will be necessary to determine which patients may benefit from eculizumab.
authors: Department of Surgery, Yale School of Medicine, New Haven, CT.|Department of Medicine, Yale School of Medicine, New Haven, CT.
authors: S
authors: S
authors: Kulkarni
authors: Department of Immunobiology, Yale School of Medicine, New Haven, CT.
authors: N C
authors: NC
authors: Kirkiles-Smith
authors: Center for Analytical Science, Yale School of Public Health, New Haven, CT.
authors: Y H
authors: YH
authors: Deng
authors: Department of Surgery, Yale School of Medicine, New Haven, CT.|Department of Medicine, Yale School of Medicine, New Haven, CT.
authors: R N
authors: RN
authors: Formica
authors: Department of Pathology, Yale School of Medicine, New Haven, CT.
authors: G
authors: G
authors: Moeckel
authors: Department of Pathology, University of Cambridge, Cambridge, UK.
authors: V
authors: V
authors: Broecker
authors: Department of Surgery, Yale School of Medicine, New Haven, CT.
authors: L
authors: L
authors: Bow
authors: Department of Surgery, Yale School of Medicine, New Haven, CT.
authors: R
authors: R
authors: Tomlin
authors: Department of Immunobiology, Yale School of Medicine, New Haven, CT.|Department of Pathology, Yale School of Medicine, New Haven, CT.
authors: J S
authors: JS
authors: Pober
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002908:Chronic Disease; D003182:Complement C5 / Q000037:antagonists & inhibitors; D051056:Complement Inactivating Agents / Q000627:therapeutic use; D018479:Early Intervention, Educational; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000097:blood*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011379:Prognosis; D012307:Risk Factors; D014019:Tissue Donors; D066027:Transplant Recipients; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; D051056:Complement Inactivating Agents; D007518:Isoantibodies; C481642:eculizumab
keywords: alloantibody; basic (laboratory) research/science; chronic allograft nephropathy; clinical research/practice; clinical trial; complement biology; kidney failure/injury; kidney transplantation/nephrology