Beyond Donor-Specific Antibodies: The Unseen Role of Non-Donor-Specific Anti-human Leukocyte Antigen (HLA) Antibodies in Rejection.

Antibody-mediated rejection (ABMR) is conventionally defined by the presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA), characteristic microvascular injury on allograft biopsy, and evidence of complement activation, most commonly reflected by C4d deposition. We report the case of a 46-year-old woman who underwent a fully HLA-matched live-related kidney transplant with negative crossmatches and no detectable DSA, but with high-mean fluorescence intensity (MFI) non-DSA (NDSA). Sixteen months post-transplant, she developed unexplained graft dysfunction. Allograft biopsy demonstrated moderate-to-severe interstitial inflammation and tubulitis (Banff Grade IA) with associated microvascular inflammation characterized by glomerulitis and peritubular capillaritis, and C4d negativity. In the context of prior high-MFI NDSA and suspicious antibody-mediated features, the patient received combined immune-directed therapy, including corticosteroids, plasmapheresis, intravenous immunoglobulin, rituximab, and optimization of maintenance immunosuppression, resulting in significant improvement in graft function. She remained under continuous follow-up for six months post treatment, with stable graft function, normal serum creatinine levels, and no recurrence of rejection. This case highlights a seronegative ABMR-like phenotype in which NDSA may contribute to graft injury despite negative DSA and C4d, underscoring the limitations of a strictly DSA-centric diagnostic framework.