#3429 Biopsy-based transcriptomics allow earlier detection of rejection, gradual phenotyping and monitoring of anti-rejection treatment interventions in kidney transplant recipients: lessons from follow-up biopsies

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Abstract Background and Aims Transcriptomics in biopsy-based diagnosis of kidney allograft rejection has the potential to detect rejection earlier than histopathology, offer continuous rejection phenotyping, and quantify disease activity and injury degrees to reflect anti-rejection treatment responses. Method From 2018 to 2024, we investigated 85 biopsy series (each consisting of a baseline and corresponding follow-up biopsy) assessed by histopathology (Banff classification 2022) and the Molecular Microscope Diagnostic System (MMDx). Results Baseline biopsies showed histological rejection in 47/85 (55%) cases, with concordant molecular rejection in 81%. Follow-up biopsies, obtained after a median of 8 months (IQR 4, 17), identified histological rejection in 13/38 (34%) cases without full histological rejection at baseline. These baseline cases had significantly higher rejection classifier (median 0.17 vs. 0.03, P = 0.01) and all antibody-mediated rejection (AMR) archetype scores (median 0.23 vs. 0.09, P = 0.007) than those without histological rejection at follow-up (n = 25). A gradual rejection phenotyping along the AMR and T cell-mediated rejection (TCMR) classifier activity identified molecular patterns of resolution and progression at follow-up. Cases with mixed molecular AMR/TCMR showed resolution of the AMR classifier activity only, if predominant TCMR archetype clusters were present at baseline. Treatment responses in anti-rejection interventions for molecular TCMR (pulsed steroids with/without T cell-depletion) were measurable through TCMR classifier scores, while interventions for molecular AMR showed significant reductions in AMR classifiers (P = 0.036) beyond histological changes. Conclusion Biopsy-based transcriptomics differentiate early rejection signs along histologically ambiguous baseline biopsies, aid in gradual AMR/TCMR phenotyping, and provide a tool for monitoring treatment effects after conventional anti-rejection therapies.

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