Acquisition of C3d‐Binding Activity by De Novo Donor‐Specific HLA Antibodies Correlates With Graft Loss in Nonsensitized Pediatric Kidney Recipients

Abstract

These authors contributed equally to this work.Alloantibody-mediated graft injury is a major cause of kidney dysfunction and loss. The complementbinding 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 complementfixing 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 À 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.

Detection of HLA Antibodies in Organ Transplant Recipients – Triumphs and Challenges of the Solid Phase Bead Assay

“…The apparent greater association of rejection with C3d than with C1q may be a reflection of the stage of the complement cascade at which these assays are focused. As indicated by Comoli et al (70), the presence of C1q does not predict whether the complement cascade will proceed, or just result in C4 deposition on the cell surface. The downstream production of C3d may more accurately predict complete complement activation.…”

“…Comoli et al (70) in a recent paper presented results of posttransplant testing monitoring for the appearance of de novo donor-specific antibodies. Positivity in the C3d assay did not predict graft rejection at the first appearance of de novo DSA but at the time of rejection there was a strong correlation.…”

From Humoral Theory to Performant Risk Stratification in Kidney Transplantation

“…Growing evidence supports the notion that the capacity of anti-HLA DSA to bind complement significantly improves our ability to predict ABMR and allograft loss. The clinical relevance of posttransplant complement-binding anti-HLA DSA detected using C1q or C3d assays has been recently shown by several groups in kidney transplantation in the United States and in Europe [18, 20–27] and has also been extended to other solid transplant organs, including heart [19, 30], liver [55], and lung [56]. In the study by Loupy et al [24], posttransplant C1q-binding anti-HLA DSA detected within the first year after transplantation were found to be an independent determinant of allograft loss with a 4.8-fold increased risk.…”

The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies

“…Even C3d+ patients with a low MFI had reduced GS. Similarly, Comoli et al studied 114 nonsensitized, pediatric, first kidney transplant recipients and found that 39 developed dnDSA at a median of 25 months [99]. Of these, 25 were C1q-positive, and 9 were additionally C3d-positive.…”