Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival

Zeynep Demir; Marc Raynaud; Olivier Aubert; Dominique Debray; Mylène Sebagh; Jean-Paul Duong Van Huyen; Arnaud Del Bello; Nicolas Congy Jolivet; Valérie Paradis; François Durand; Sophie Muratot; Cécile Lozach; Christophe Chardot; Claire Francoz; Nassim Kamar; Sabine Sarnacki; Audrey Coilly; Didier Samuel; Eric Vibert; Cyrille Féray; Carmen Lefaucheur; Alexandre Loupy

doi:10.1016/j.ajt.2023.12.007

Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival

Am J Transplant. 2023 Dec 12:S1600-6135(23)00907-3. doi: 10.1016/j.ajt.2023.12.007. Online ahead of print.

Authors

Zeynep Demir¹, Marc Raynaud¹, Olivier Aubert², Dominique Debray³, Mylène Sebagh⁴, Jean-Paul Duong Van Huyen⁵, Arnaud Del Bello⁶, Nicolas Congy Jolivet⁷, Valérie Paradis⁸, François Durand⁹, Sophie Muratot¹, Cécile Lozach¹⁰, Christophe Chardot¹¹, Claire Francoz⁹, Nassim Kamar⁶, Sabine Sarnacki¹¹, Audrey Coilly¹², Didier Samuel¹², Eric Vibert¹², Cyrille Féray¹², Carmen Lefaucheur¹³, Alexandre Loupy¹⁴

Affiliations

¹ Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France.
² Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Kidney Transplantation Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
³ Pediatric Hepatology and Liver Transplantation Unit, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
⁴ Pathology Department Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Villejuif, France.
⁵ Pathology Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
⁶ Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.
⁷ Department of Immunology, Hôpital de Rangueil, CHU de Toulouse, Molecular Immunogenetics Laboratory, EA 3034, IFR150 (INSERM), Toulouse, France.
⁸ Pathology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France.
⁹ Hepatology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France.
¹⁰ Department of Pediatric Radiology, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
¹¹ Department of Pediatric Surgery, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
¹² Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France.
¹³ Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
¹⁴ Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Kidney Transplantation Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. Electronic address: alexandre.loupy@inserm.fr.

PMID: 38097016
DOI: 10.1016/j.ajt.2023.12.007

Abstract

The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

Keywords: donor-specific anti-HLA antibody; liver allograft injury; liver biological markers; liver transplantation; outcome.