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

Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1 " (N = 129), T cell-mediated rejection (TCMR) "R2 " (N = 37), early injury "R3 " (N = 61), and fibrosis "R4 " (N = 8). Groups differed in median time posttransplant, for example, R3 99 days vs R4 3117 days. R2 biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3 displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4 biopsies showed immunoglobulin transcripts and injury-related transcripts. R2 correlated with histologic rejection although with many discrepancies, and R4 with fibrosis. R2 , R3 , and R4 correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2 scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.