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.

Alberta Transplant Applied Genomics Centre Edmonton Alberta Canada

Department of Clinical Interventions Department of Nephrology and Kidney Transplantation SPWSZ Hospital Pomeranian Medical University Szczecin Poland

Department of Medicine Division of Nephrology and Transplant Immunology University of Alberta Edmonton Alberta Canada

Department of Nephrology and Transplant Center Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Nephrology Hannover Medical School Hannover Germany

Department of Pathology Medical University of Warsaw Warsaw Poland

Division of Nephrology and Dialysis Department of Medicine 3 Medical University of Vienna Vienna Austria

Division of Nephrology Virginia Commonwealth University Richmond Virginia USA

University of Maryland Baltimore Maryland USA

University of Wisconsin Madison Wisconsin USA

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Am J Transplant. 2022 Dec;22(12):3180-3181. doi: 10.1111/ajt.17136. PubMed

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Transcriptomic Signatures of Antibody-mediated Rejection in Early Biopsies With Negative Histology in HLA-incompatible Kidney Transplantation

Relating Molecular T Cell-mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis