ORIGINAL RESEARCH article
Front. Immunol.
Sec. Alloimmunity and Transplantation
Non-HLA antibody trajectories may predict kidney transplant outcomes
Provisionally accepted
- 1University of California, San Francisco, San Francisco, United States
- 2Research and Development, Werfen, Wakesha, WI, United States
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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. 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. 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, suggesting that non-HLA PRA trajectories may influence graft loss. These findings highlight the dynamic nature of non-HLA antibody responses and support the integration of non-HLA antibody profiling into longitudinal immune monitoring frameworks. Larger multicenter studies are warranted to establish the clinical utility of non-HLA PRA testing across diverse transplant populations.
Keywords: alloimmununity, antibody-mediated rejection (ABMR), Donor-specific antibodies (DSA), Graft outcomes, immune monitoring, Kidney Transplantation, Minor Histocompatibility Antigens, Non-HLA antibodies
Received: 21 Oct 2025; Accepted: 27 Jan 2026.
Copyright: © 2026 Rajalingam, Sigdel, MARUTHAMUTHU, Da Gente, Shoji and Ray. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Raja Rajalingam
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