Biopsy-based Transcriptomics in Banff 2022 Antibody Mediated Rejection Categories

Introduction: Biopsy-based transcriptomics (BBT) supports antibody-mediated rejection (AMR) diagnostics, but Banff 2022 probable AMR and donor-specific antibodies (DSA)-/C4d-microvascular inflammation (MVI) remain unvalidated by BBT. Methods: We analyzed 562 kidney allograft biopsies from Prague and Zurich by histology and Molecular Microscope Diagnostic System (MMDx). Biopsies were classified into the following: (i) active AMR-spectrum lesions without transplant glomerulopathy (cg) (active AMR, probable AMR, MVI, DSA-/C4-); (ii) combined active-chronic lesions with cg (chronic-active AMR, probable AMR with cg, MVI, DSA-/C4d-with cg); (iii) chronic AMR, defined by cg without active lesions; and (iv) controls without rejection. Results: Molecular AMR was detected in 24% of probable AMR and 23% of probable AMR with cg biopsies, 43% of MVI, DSA-/C4d-, 51% of active AMR, 56% of MVI, DSA-/C4d-with cg, and 63% of chronic-active AMR, but was rare in chronic AMR (6%). AMR probability classifier (AMRprob) scores were higher in probable AMR than in controls and similar between chronic AMR and controls. AMRprob scores were comparable among active AMR, chronic-active AMR, and MVI, DSA-/C4d-groups, all of which exhibited elevated T cell-mediated rejection (TCMR) prob scores compared with probable AMR and controls. Least absolute shrinkage and selection operator-penalized Cox regression predicting 3-years graft survival trained in the Zurich cohort showed similar performance of molecular (cgprob, ctprob, tprob, acute kidney injury [AKI]score) and histologic model (Banff cg, interstitial inflammation [ci], tubular atrophy [ct], and tubulitis [t]) (concordance 0.84 vs. 0.82), with the external validation in the Prague cohort (0.78 vs. 0.75). Conclusion: BBT primarily reflects MVI rather than DSA and is particularly informative in probable AMR and MVI-positive biopsies. (c) 2026 The Author(s). Published by Elsevier Inc. on behalf of the International Society of Nephrology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).