The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study

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Conference Proceeding

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Background: Diagnosing rejection in liver transplant biopsies is challenging given the limitations of histology e.g. low kappa values among pathologists. A Molecular Microscope Diagnostic system (MMDx) analogous to that for kidney and heart transplants could offer improved precision and accuracy. Method: We used microarrays to study gene expression in 235 liver transplant biopsies (73% for indications) from 10 centers (INTERLIVER NCT03193151). Unsupervised archetypal analysis (AA) and principal component analysis (PCA) were used to assign molecular classes based on expression of 417 rejection-associated transcripts (RATs) derived in kidney transplants. Results: We found four major clusters in our population: R1normal, R2TCMR, R3early injury, and R4late, differing in time post-transplant e.g. median R3injury 99 vs. R4late 3117 days. The molecular phenotypes were distinct: R2TCMR biopsies expressed IFNG-induced TCMR-related transcripts (e.g. CXCL11); R3injury displayed increased injury transcripts (e.g. hypoxia inducible factor EGLN1); and R4late biopsies showed associations with atrophy-fibrosis (e.g. immunoglobulin transcripts) and injury transcripts. Moving average plots indicated that TCMR and acute injury phenotypes decrease over time, while scores representing normalness' and atrophy-fibrosis slowly increase. No MMDx antibodymediated rejection (ABMR) phenotype analogous to that in kidney and heart transplants was identified, indicating that liver ABMR is at best uncommon. We examined the relationship of MMDx findings to histology and biochemical findings. TCMR-related transcripts were increased in biopsies with rejection histology lesions (p-value 0.027). Comparison of biopsies called TCMR by MMDx showed moderate agreement (33/56 cases), but with extensive disagreement similar to that in heart transplants (AUCs for R2TCMR prediction of histologic TCMR=0.7). Liver biochemistry scores were abnormal in groups R2-R4. Conclusion: MMDx phenotypes correlated with histologic rejection (R2TCMR), and groups R2-R4 were biochemically abnormal. No distinct antibody-mediated rejection phenotype was detected. Molecular unsupervised phenotyping of liver transplants shows promise for improving the accuracy and precision of rejection diagnoses and guiding patient management.

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