Transcriptomic Analysis of Kidney Allograft Biopsies May Allow Early Detection of Rejection, Precise Rejection Typing, and Dynamic Treatment Monitoring

Background: The 2022 Banff Meeting Report suggests that biopsy-based transcripts related to antibody-mediated rejection (AMR) could substitute for microvascular inflammation (MVI). In addition, transcriptomic analysis may (1) detect molecular signatures associated with rejection earlier than traditional histopathologic methods, (2) distinguish between different types of rejection more accurately, and (3) provide more quantifiable measures of treatment responses. Studies with follow-up biopsies, however, are needed to test the performance of biopsy-based transcript analysis for these aims. Methods: From 2018 to 2023, we examined 62 kidney transplant recipients and 139 kidney allograft biopsies evaluated by histology and the Molecular Microscope Diagnostic System (MMDx). The 62 biopsy series were analyzed regarding (1) the time of rejection diagnosis, (2) the type of rejection, and (3) the response to treatment. Results: 20, 5, 8, and 29 of the initial biopsies showed histologic AMR/DSA-negative MVI, TCMR, mixed AMR/TCMR, and no AMR/TCMR (including 8 probable AMR cases), respectively. Molecular AMR, TCMR, and mixed AMR/TCMR were detected in 17, 4, and 8 of the initial biopsies, respectively. Follow-up biopsies were obtained at a median of 9 months (IQR 4,18) after the initial biopsy. With the MMDx, AMR was detected sooner in 8 cases (including 3 probable AMR cases by histology), which was verified histologically by the follow-up biopsy. There were 3 cases of histologic TCMR with mixed molecular AMR/TCMR and 2 cases of histologic AMR with mixed molecular AMR/TCMR. Follow-up biopsies verified the presence of mixed AMR/TCMR in all 5 cases by histology. Using transcriptomic analyses, treatment responses were observed in 1 early active AMR and 3 mixed AMR/TCMR cases (by rejection classifier scores) but not by histology. 5 of 20 histologic AMR cases (25%) showed no molecular AMR signature throughout the biopsy series. Conclusion: Biopsy-based transcript diagnostics can help detect rejection sooner and identify rejection types more precisely, which might reduce the need for repeat biopsies and support treatment decisions. Molecular diagnostics may also allow clinicians to measure treatment outcomes more comprehensively through follow-up biopsies. Funding: Private Foundation Support