Restoration of Bile Duct Injury of Donor Livers During Ex Situ Normothermic Machine Perfusion

Author:

de Jong Iris E.M.123,Bodewes Silke B.12,van Leeuwen Otto B.2,Oosterhuis Dorenda4,Lantinga Veerle A.2,Thorne Adam M.2,Lascaris Bianca2,van den Heuvel Marius C.5,Wells Rebecca G.3,Olinga Peter4,de Meijer Vincent E.2,Porte Robert J.26

Affiliation:

1. Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

2. Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

3. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

4. Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

5. Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

6. Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Division of HPB and Transplant Surgery, Rotterdam, The Netherlands.

Abstract

Background. End-ischemic ex situ normothermic machine perfusion (NMP) enables assessment of donor livers prior to transplantation. The objective of this study was to provide support for bile composition as a marker of biliary viability and to investigate whether bile ducts of high-risk human donor livers already undergo repair during NMP. Methods. Forty-two livers that were initially declined for transplantation were included in our NMP clinical trial. After NMP, livers were either secondary declined (n = 17) or accepted for transplantation (n = 25) based on the chemical composition of bile and perfusate samples. Bile duct biopsies were taken before and after NMP and assessed using an established histological injury severity scoring system and a comprehensive immunohistochemical assessment focusing on peribiliary glands (PBGs), vascular damage, and regeneration. Results. Bile ducts of livers that were transplanted after viability testing during NMP showed better preservation of PBGs, (micro)vasculature, and increased cholangiocyte proliferation, compared with declined livers. Biliary bicarbonate, glucose, and pH were confirmed as accurate biomarkers of bile duct vitality. In addition, we found evidence of PBG-based progenitor cell differentiation toward mature cholangiocytes during NMP. Conclusions. Favorable bile chemistry during NMP correlates well with better-preserved biliary microvasculature and PBGs, with a preserved capacity for biliary regeneration. During NMP, biliary tree progenitor cells start to differentiate toward mature cholangiocytes, facilitating restoration of the ischemically damaged surface epithelium.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Transplantation

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