Acquisition of C3d‐Binding Activity by De NovoDonor‐Specific HLAAntibodies Correlates With Graft Loss in Nonsensitized Pediatric Kidney Recipients

Alloantibody‐mediated graft injury is a major cause of kidney dysfunction and loss. The complement‐binding ability of de novodonor‐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 dnDSAsand 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 dnDSAsusing 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 dnDSAC1q 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 dnDSAswere better fit to stratify graft loss risk when the different dnDSAcategories were evaluated in combined models because the 10‐year graft survival probability was lower in patients with C3d‐binding dnDSAthan in those without dnDSAsor with C1q+/C3d−or non‐complement‐binding dnDSAs(40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSAremoval or modulation at first confirmed positivity, with treatment intensification guided by dnDSAbiological characteristics. In this longitudinal study of renal transplant recipients, the authors demonstrate that patients with de novo donor‐specific HLA antibodies capable of C3d binding are more likely to develop antibody‐mediated rejection and graft loss, and describe the dynamic and progressive phenomenon of complement‐binding ability acquisition.