title: A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation.
abstract: Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation is a cause of accelerated graft loss. To evaluate pathogenic antibodies (Abs) in rFSGS, we processed 141 serum samples from 64 patients with and without primary rFSGS and 34 non-FSGS control patients transplanted at four hospitals. We screened about 9000 antigens in pretransplant sera and selected 10 Abs targeting glomerular antigens for enzyme-linked immunosorbent assay (ELISA) validation. A panel of seven Abs (CD40, PTPRO, CGB5, FAS, P2RY11, SNRPB2, and APOL2) could predict posttransplant FSGS recurrence with 92% accuracy. Pretransplant elevation of anti-CD40 Ab alone had the best correlation (78% accuracy) with rFSGS risk after transplantation. Epitope mapping of CD40 with customized peptide arrays and rFSGS sera demonstrated altered immunogenicity of the extracellular CD40 domain in rFSGS. Immunohistochemistry of CD40 demonstrated a differential expression in FSGS compared to non-FSGS controls. Anti-CD40 Abs purified from rFSGS patients were particularly pathogenic in human podocyte cultures. Injection of anti-CD40/rFSGS Ab enhanced suPAR (soluble urokinase receptor)-mediated proteinuria in wild-type mice, yet no sensitizing effect was noted in mice deficient in CD40 or in wild-type mice that received blocking Ab to CD40. In conclusion, a panel of seven Abs can help identify primary FSGS patients at high risk of recurrence before transplantation. Intrarenal CD40 (and possibly other specific glomerular antigens) is an important contributor to FSGS disease pathogenesis. Human trials of anti-CD40 therapies are warranted to evaluate their efficacy for preventing rFSGS and improving graft survival.
authors.affiliation: Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité, INSERM U1171, Réseau Thématique de Recherche et de Soins Centaure, Labex Transplantex, 75015 Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Delville
authors.affiliation: Division of Transplant Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Tara K
authors.initials: TK
authors.lastname: Sigdel
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Transplant Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Szu-Chuan
authors.initials: SC
authors.lastname: Hsieh
authors.affiliation: Peggy and Harold Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, University of Miami School of Medicine, Miami, FL 33146, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
authors.affiliation: Division of Transplant Surgery, University of Miami School of Medicine, Miami, FL 33146, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
authors.affiliation: Department of Pathology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Nephrology and Renal Transplantation, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Naesens
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Nada
authors.initials: N
authors.lastname: Alachkar
authors.affiliation: Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité, INSERM U1171, Réseau Thématique de Recherche et de Soins Centaure, Labex Transplantex, 75015 Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Canaud
authors.affiliation: Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité, INSERM U1171, Réseau Thématique de Recherche et de Soins Centaure, Labex Transplantex, 75015 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.affiliation: Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité, INSERM U1171, Réseau Thématique de Recherche et de Soins Centaure, Labex Transplantex, 75015 Paris, France.
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA. minnie.sarwal@ucsf.edu jochen_reiser@rush.edu.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Division of Transplant Surgery, University of California San Francisco, San Francisco, CA 94143, USA. minnie.sarwal@ucsf.edu jochen_reiser@rush.edu.
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
mesh_terms: D000328:Adult; D000906:Antibodies / Q000097:blood*; D019013:CD40 Antigens / Q000276:immunology; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000503:physiopathology* / Q000601:surgery; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D012008:Recurrence
chemical_list: D000906:Antibodies; D019013:CD40 Antigens