The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study
Katelynn S. Madill-Thomsen, Marwan Abouljoud, Chandra Bhati, Michał Ciszek, Magdalena Durlik, Sandy Feng, Bartosz Foroncewicz, Iman Francis, Michał Grąt, Krzysztof Jurczyk, Göran B. Klintmalm, Maciej Krasnodębski, Geoffrey W. McCaughan, Rosa Miquel, Aldo J. Montaño‐Loza, Dilip Moonka, Krzysztof Mucha, Marek Myślak, Leszek Pączek, Agnieszka Perkowska‐Ptasińska, Grzegorz Piecha, Trevor Reichman, Alberto Sánchez‐Fueyo, Olga Tronina, Marta Wawrzynowicz‐Syczewska, Andrzej Więcek, Krzysztof Zieniewicz, Philip F. Halloran
Abstract
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 normal " (N = 129), T cell–mediated rejection (TCMR) "R2 TCMR " (N = 37), early injury "R3 injury " (N = 61), and fibrosis "R4 late " (N = 8). Groups differed in median time posttransplant, for example, R3 injury 99 days vs R4 late 3117 days. R2 TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3 injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4 late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2 TCMR correlated with histologic rejection although with many discrepancies, and R4 late with fibrosis. R2 TCMR , R3 injury , and R4 late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2 TCMR 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.