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

Katelynn Madill-Thomsen; Marwan Abouljoud; Chandra Bhati; Michał Ciszek; Magdalena Durlik; Sandy Feng; Bartosz Foroncewicz; Iman Francis; Michał Grąt; Krzysztof Jurczyk; Goran Klintmalm; Maciej Krasnodębski; Geoff McCaughan; Rosa Miquel; Aldo Montano-Loza; Dilip Moonka; Krzysztof Mucha; Marek Myślak; Leszek Pączek; Agnieszka Perkowska-Ptasińska; Grzegorz Piecha; Trevor Reichman; Alberto Sanchez-Fueyo; Olga Tronina; Marta Wawrzynowicz-Syczewska; Andrzej Więcek; Krzysztof Zieniewicz; Philip F Halloran

doi:10.1111/ajt.15828

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

Am J Transplant. 2020 Aug;20(8):2156-2172. doi: 10.1111/ajt.15828. Epub 2020 Apr 9.

Authors

Katelynn Madill-Thomsen¹, Marwan Abouljoud², Chandra Bhati³, Michał Ciszek⁴, Magdalena Durlik⁵, Sandy Feng⁶, Bartosz Foroncewicz⁴, Iman Francis², Michał Grąt⁷, Krzysztof Jurczyk⁸, Goran Klintmalm⁹, Maciej Krasnodębski⁷, Geoff McCaughan¹⁰, Rosa Miquel¹¹, Aldo Montano-Loza¹², Dilip Moonka², Krzysztof Mucha⁴, Marek Myślak¹³, Leszek Pączek⁴, Agnieszka Perkowska-Ptasińska⁵, Grzegorz Piecha¹⁴, Trevor Reichman³, Alberto Sanchez-Fueyo¹¹, Olga Tronina⁵, Marta Wawrzynowicz-Syczewska⁸, Andrzej Więcek¹⁴, Krzysztof Zieniewicz⁷, Philip F Halloran^{1

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Affiliations

¹ Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada.
² Henry Ford Hospital, Detroit, Michigan, USA.
³ Virginia Commonwealth University, Richmond, Virginia, USA.
⁴ Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁵ Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁶ University of California San Francisco, San Francisco, California, USA.
⁷ Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
⁸ Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland.
⁹ Baylor University Medical Center, Dallas, Texas, USA.
¹⁰ Centenary Research Institute, Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, The University of Sydney, Sydney, NSW, Australia.
¹¹ King's College London, London, UK.
¹² University of Alberta, Edmonton, Alberta, Canada.
¹³ Department of Clinical Interventions, Department of Nephrology and Kidney, Transplantation, SPWSZ Hospital, Pomeranian Medical University, Szczecin, Poland.
¹⁴ Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland.

PMID: 32090446
DOI: 10.1111/ajt.15828

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.

Keywords: basic (laboratory) research/science; biopsy; liver transplantation/hepatology; microarray/gene array; molecular biology: mRNA/mRNA expression; rejection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biopsy
Graft Rejection / etiology
Graft Rejection / genetics
Heart Transplantation*
Kidney Transplantation*
Liver Transplantation* / adverse effects