title: Detection of C3d-binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection predicts renal graft loss.
abstract: Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLA antibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P<0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR <30 ml/min per 1.73 m(2) (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss.
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; Institut National de la Santé et de la Recherche Médicale U1111, Lyon, France; Unité de Formation et de Recherche Lyon Est, Université de Lyon, Lyon, France;
authors.forename: Antoine
authors.initials: A
authors.lastname: Sicard
authors.affiliation: Laboratoire d'Histocompatibilité, Etablissement Français du Sang, Lyon, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ducreux
authors.affiliation: Laboratoire d'anatomopathologie, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France;
authors.forename: Maud
authors.initials: M
authors.lastname: Rabeyrin
authors.affiliation: Service de Néphrologie Transplantation Dialyse, Université de Bordeaux, Bordeaux, France;
authors.forename: Lionel
authors.initials: L
authors.lastname: Couzi
authors.affiliation: Laboratoire d'anatomopathologie, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France;
authors.forename: Brigitte
authors.initials: B
authors.lastname: McGregor
authors.affiliation: Unité de Formation et de Recherche Lyon Est, Université de Lyon, Lyon, France; Service d'Urologie et Transplantation, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France;
authors.forename: Lionel
authors.initials: L
authors.lastname: Badet
authors.affiliation: Unité de Formation et de Recherche Lyon Est, Université de Lyon, Lyon, France; Laboratoire d'anatomopathologie, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France;
authors.forename: Jean Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Service de Néphrologie Transplantation Dialyse, Université de Bordeaux, Bordeaux, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelet
authors.affiliation: Laboratoire d'anatomopathologie, and.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lepreux
authors.affiliation: Laboratoire d'immunologie et immunogénétique, Centre Hospitalier Universitaire, Hôpital Pellegrin, Bordeaux, France;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Visentin
authors.affiliation: Service de Néphrologie Transplantation Dialyse, Université de Bordeaux, Bordeaux, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Merville
authors.affiliation: Service d'Immunologie Biologique, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France; and Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; Institut National de la Santé et de la Recherche Médicale U1111, Lyon, France; Unité de Formation et de Recherche Lyon Est, Université de Lyon, Lyon, France;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Morelon
authors.affiliation: Laboratoire d'immunologie et immunogénétique, Centre Hospitalier Universitaire, Hôpital Pellegrin, Bordeaux, France;
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Taupin
authors.affiliation: Laboratoire d'Histocompatibilité, Etablissement Français du Sang, Lyon, France;
authors.forename: Valérie
authors.initials: V
authors.lastname: Dubois
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France; Institut National de la Santé et de la Recherche Médicale U1111, Lyon, France; Unité de Formation et de Recherche Lyon Est, Université de Lyon, Lyon, France; olivier.thaunat@chu-lyon.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Thaunat
mesh_terms: D000328:Adult; D000888:Antibodies, Anti-Idiotypic / Q000097:blood* / Q000276:immunology; D001706:Biopsy; D015331:Cohort Studies; D015922:Complement C1q / Q000378:metabolism; D015933:Complement C3d / Q000378:metabolism*; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D014019:Tissue Donors
chemical_list: D000888:Antibodies, Anti-Idiotypic; D006680:HLA Antigens; D015922:Complement C1q; D015933:Complement C3d
keywords: acute rejection; antibody-mediated rejection; complement; donor-specific antibodies; transplant outcomes; transplantation