title: Acquisition of C3d-Binding Activity by De Novo Donor-Specific HLA Antibodies Correlates With Graft Loss in Nonsensitized Pediatric Kidney Recipients.
abstract: Alloantibody-mediated graft injury is a major cause of kidney dysfunction and loss. The complement-binding ability of de novo donor-specific antibodies (dnDSAs) has been suggested as a prognostic tool to stratify patients for clinical risk. In this study, we analyzed posttransplant kinetics of complement-fixing dnDSAs and their role in antibody-mediated rejection development and graft loss. A total of 114 pediatric nonsensitized recipients of first kidney allograft were periodically monitored for dnDSAs using flow bead assays, followed by C3d and C1q assay in case of positivity. Overall, 39 patients developed dnDSAs, which were C1q(+) and C3d(+) in 25 and nine patients, respectively. At follow-up, progressive acquisition over time of dnDSA C1q and C3d binding ability, within the same antigenic specificity, was observed, paralleled by an increase in mean fluorescence intensity that correlated with clinical outcome. C3d-fixing dnDSAs were better fit to stratify graft loss risk when the different dnDSA categories were evaluated in combined models because the 10-year graft survival probability was lower in patients with C3d-binding dnDSA than in those without dnDSAs or with C1q(+) /C3d(-) or non-complement-binding dnDSAs (40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSA removal or modulation at first confirmed positivity, with treatment intensification guided by dnDSA biological characteristics.
authors.affiliation: Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Comoli
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, G. Gaslini Institute, Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cioni
authors.affiliation: Clinical Nephrology Unit and Transplant Immunology Research Laboratory, Department of Internal Medicine - DIMI, University of Genova, Genova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tagliamacco
authors.affiliation: Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Quartuccio
authors.affiliation: Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Innocente
authors.affiliation: Vascular and Endovascular Unit and Kidney Transplant Surgery Unit, University of Genova, IRCCS San Martino University Hospital IST, Genova, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Fontana
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, G. Gaslini Institute, Genova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Trivelli
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, G. Gaslini Institute, Genova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Magnasco
authors.affiliation: Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Nocco
authors.affiliation: Biometry and Statistics Service, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Klersy
authors.affiliation: Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rubert
authors.affiliation: Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ramondetta
authors.affiliation: Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zecca
authors.affiliation: Clinical Nephrology Unit and Transplant Immunology Research Laboratory, Department of Internal Medicine - DIMI, University of Genova, Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Garibotto
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, G. Gaslini Institute, Genova, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: Ghiggeri
authors.affiliation: Transplantation Immunology, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cardillo
authors.affiliation: Clinical Nephrology Unit and Transplant Immunology Research Laboratory, Department of Internal Medicine - DIMI, University of Genova, Genova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Nocera
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, G. Gaslini Institute, Genova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ginevri
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015933:Complement C3d / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D006085:Graft Survival; D006680:HLA Antigens / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D007518:Isoantibodies / Q000276:immunology / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D014019:Tissue Donors; D055815:Young Adult
chemical_list: D006680:HLA Antigens; D007518:Isoantibodies; D015933:Complement C3d
keywords: alloantibody; clinical research/practice; immunobiology; immunosuppression/immune modulation; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; monitoring: immune; rejection: antibody-mediated (ABMR)