Molecular diagnosis of ABMR with or without donor‐specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes

We studied the clinical, histologic, and molecular features distinguishing DSA‐negative from DSA‐positive molecularly defined antibody‐mediated rejection (mABMR). We analyzed mABMR biopsies with available DSA assessments from the INTERCOMEX study: 148 DSA‐negative versus 248 DSA‐positive, compared with 864 no rejection (excluding TCMR and Mixed). DSA‐positivity varied with mABMR stage: early‐stage (EABMR) 56%; fully developed (FABMR) 70%; and late‐stage (LABMR) 58%. DSA‐negative patients with mABMR were usually sensitized, 60% being HLA antibody‐positive. Compared with DSA‐positive mABMR, DSA‐negative mABMR was more often C4d‐negative; earlier by 1.5 years (average 2.4 vs. 3.9 years); and had lower ABMR activity and earlier stage in molecular and histology features. However, the top ABMR‐associated transcripts were identical in DSA‐negative versus DSA‐positive mABMR, for example, NK‐associated (e.g., KLRD1 and GZMB) and IFNG‐inducible (e.g., PLA1A). Genome‐wide class comparison between DSA‐negative and DSA‐positive mABMR showed no significant differences in transcript expression except those related to lower intensity and earlier time of DSA‐negative ABMR. Three‐year graft loss in DSA‐negative mABMR was the same as DSA‐positive mABMR, even after adjusting for ABMR stage. Thus, compared with DSA‐positive mABMR, DSA‐negative mABMR is on average earlier, less active, and more often C4d‐negative but has similar graft loss, and genome‐wide analysis suggests that it involves the same mechanisms. Summary Sentence In 398 kidney transplant biopsies with molecular antibody‐mediated rejection, the 150 DSA‐negative cases are earlier, less intense, and mostly C4d‐negative, but use identical molecular mechanisms and have the same risk of graft loss as the 248 DSA‐positive cases. In a population of kidney transplant indication biopsies with a molecular diagnosis of antibody‐mediated rejection, those without compared to those with donor‐specific antibody typically occur earlier, are less active, and are more often C4d‐negative but have similar graft loss risk and, according to genome‐wide analyses, involve the same mechanisms.