Clinical significance of persistent C4d deposition on sequential protocol biopsies in ABO-incompatible kidney transplantation

Introduction C4d deposition is common after ABO-incompatible (ABOi) kidney transplantation and, unlike ABO-compatible grafts, is not necessarily indicative of antibody-mediated injury. Methods Between 2015 and 2022, 254 ABOi kidney transplantations were performed at our center, and 69 recipients with paired 3-month and 1-year protocol biopsies were classified as persistently C4d-positive (n = 54) or C4d-negative/nonpersistent (n = 15). Pre-transplant background, cellular infiltration, chronic Banff lesions according to the Banff 2019 classification, graft function, and graft survival were compared. Results Baseline anti-A/B titers, ABO combination, donor age, and donor relationship did not differ between the groups, whereas donor sex differed significantly (P = 0.014). Microvascular inflammation, defined as glomerulitis plus peritubular capillaritis ≥2, was observed in 6/54 recipients (11.1%) versus 1/15 (6.7%), and chronic changes, defined as interstitial fibrosis score ≥1, were observed in 27/54 (50.0%) versus 6/15 (40.0%); none of these differences reached statistical significance. Graft function and survival also did not differ significantly, although all four graft losses occurred in the persistent C4d-positive group. Three of these losses were attributable to chronic active antibody-mediated rejection, diagnosed at the 1-year biopsy in one recipient and later in two recipients. Discussion Given the selected cohort and limited statistical power, these findings represent a failure to detect an association rather than evidence of equivalence. They are consistent with accommodation but require confirmation in larger, less-selected cohorts.