Introduction Donor-specific HLA antibodies (DSAs) are well-established mediators of antibody-mediated rejection (AMR), but growing evidence suggests that non-HLA antibodies may also contribute to kidney allograft dysfunction. However, the clinical utility of non-HLA antibody testing remains limited due to assay variability and undefined pathogenic thresholds. Methods In this longitudinal study, we evaluated 167 deceased-donor kidney transplant recipients at UCSF using a multiplex Luminex assay to quantify IgG reactivity against 88 non-HLA antigens in paired pre- and post-transplant serum samples (n = 334). Patients were stratified by HLA-DSA status and graft outcome. The non-HLA panel reactive antibody (PRA) percentage was defined as the proportion of positive beads among the 88 tested antigens. Results Global non-HLA PRA declined significantly from pre- to post-transplant (9% to 6%; P = 0.0010) only among recipients with functioning grafts, driven by reduced reactivity to signaling, cytoskeletal, and immune-related antigens. Elevated pre-transplant non-HLA PRA was associated with prior sensitization, IgA nephropathy, and African American ancestry, but was independent of age, ABO type, and HLA cPRA. AMR occurred primarily in recipients with both preformed and de novo DSA, while no rejection was observed in DSA-negative recipients. Death-censored graft survival varied across groups, and neither preformed nor de novo DSA consistently predicted outcomes. Discussion These findings suggest that longitudinal trajectories of non-HLA PRA, rather than staticmeasurements or DSA status alone, may influence graft loss. The dynamic nature of non-HLA antibody responses and supports integration of non-HLA antibody profiling into longitudinal immune monitoring frameworks. Larger multicenter studies are needed to define clinically meaningful threshold and estabilish the utility of non-HLA PRA testing across diverse transplant populations.
Rajalingam et al. (Tue,) studied this question.