Background and hypothesis: In ABO-incompatible (ABOi) kidney transplantation, C4d deposition is associated with accommodation rather than rejection. Isoagglutinins targeting blood group antigens A/B are also classified as donor-specific antibodies (DSA). Therefore, the diagnosis of antibody-mediated rejection (AMR) relies primarily on microvascular inflammation (MVI). Methods: We analyzed 66 ABOi and 251 ABO-compatible (ABOc) KTRs concerning anti-HLA DSA development. 46 protocol biopsies from ABOi KTRs were classified according to Banff 2022. In addition, 25 ABOi protocol biopsies were assessed by the Molecular Microscope Diagnostics System (MMDx) and compared to ABOc biopsies: (1) 35 DSA-negative, C4d-negative cases with MVI0.05) and showed stable graft function. Molecular AMR classifier scores were significantly lower in ABOi and DSA-negative, C4d-negative ABOc cases with MVI below threshold compared to C4d-positive ABOc and ABOc cases with probable AMR (p=0.007). Notably, C4d drives molecular AMR activity in ABOc biopsies already at C4d1 levels by immunofluorescence (p=0.011) and even in the absence of a histological Banff AMR diagnosis (p=0.003). Conclusion: ABOi transplantation reduces the risk of developing de novo anti-HLA DSA. Banff 2022 criteria may over-diagnose AMR. Biopsy-based transcript diagnostics differentiate anti-HLA- and anti-A/B-mediated alloimmune injury from C4d deposition due to accommodation. Interestingly, C4d deposition drives molecular AMR activity in ABOc biopsies.
Lopez et al. (2025) studied this question.