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

Iris E M de Jong; Silke B Bodewes; Otto B van Leeuwen; Dorenda Oosterhuis; Veerle A Lantinga; Adam M Thorne; Bianca Lascaris; Marius C van den Heuvel; Rebecca G Wells; Peter Olinga; Vincent E de Meijer; Robert J Porte

doi:10.1097/TP.0000000000004531

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

Iris E M de Jong, Silke B Bodewes, Otto B van Leeuwen, Dorenda Oosterhuis, Veerle A Lantinga, Adam M Thorne, Bianca Lascaris, Marius C van den Heuvel, Rebecca G Wells, Peter Olinga, Vincent E de Meijer, Robert J Porte^*

^*Corresponding author voor dit werk

Onderzoeksoutput: Article › Academic › peer review

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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.

Originele taal-2	English
Pagina's (van-tot)	e161-e172
Aantal pagina's	12
Tijdschrift	Transplantation
Volume	107
Nummer van het tijdschrift	6
DOI's	https://doi.org/10.1097/TP.0000000000004531
Status	Published - jun.-2023

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10.1097/TP.0000000000004531Licentie: CC BY-NC-ND

Restoration of Bile Duct Injury of Donor Livers During Ex Situ Normothermic Machine PerfusionFinal publisher's version, 7,27 MBLicentie: CC BY-NC-ND

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de Jong, I. E. M., Bodewes, S. B., van Leeuwen, O. B., Oosterhuis, D., Lantinga, V. A., Thorne, A. M., Lascaris, B., van den Heuvel, M. C., Wells, R. G., Olinga, P., de Meijer, V. E., & Porte, R. J. (2023). Restoration of Bile Duct Injury of Donor Livers During Ex Situ Normothermic Machine Perfusion. Transplantation, 107(6), e161-e172. https://doi.org/10.1097/TP.0000000000004531

@article{c487203c425c4935a1c82374448e1fd7,

title = "Restoration of Bile Duct Injury of Donor Livers During Ex Situ Normothermic Machine Perfusion",

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.",

author = "\{de Jong\}, \{Iris E M\} and Bodewes, \{Silke B\} and \{van Leeuwen\}, \{Otto B\} and Dorenda Oosterhuis and Lantinga, \{Veerle A\} and Thorne, \{Adam M\} and Bianca Lascaris and \{van den Heuvel\}, \{Marius C\} and Wells, \{Rebecca G\} and Peter Olinga and \{de Meijer\}, \{Vincent E\} and Porte, \{Robert J\}",

note = "Funding Information: R.G.W. received personal grants from the Fred and Suzanne Biesecker Center for Pediatric Liver Disease and the National Institutes of Health (NIDDK); these funds supported the use of microscopes. I.E.M.d.J. received the International Travel Scholar Award from the International Liver Transplantation Society and a Fulbright grant for travel to the United States; these funding sources concern only personal funds. Reagents were used from the Molecular Pathology and Imaging Core (MPIC), part of The Center for Molecular Studies in Digestive and Liver Disease at the University of Pennsylvania (grant number: NIH P30DK050306). Funding Information: The authors are thankful to the UPenn Cell and Developmental Biology Microscopy Core and the Center for Molecular Studies in Digestive and Liver Diseases (grant number: NIH P30DK050306) for the use of microscopes and reagents. Publisher Copyright: {\textcopyright} 2023 Lippincott Williams and Wilkins. All rights reserved.",

year = "2023",

month = jun,

doi = "10.1097/TP.0000000000004531",

language = "English",

volume = "107",

pages = "e161--e172",

journal = "Transplantation",

issn = "0041-1337",

publisher = "Lippincott Williams and Wilkins",

number = "6",

}

TY - JOUR

T1 - Restoration of Bile Duct Injury of Donor Livers During Ex Situ Normothermic Machine Perfusion

AU - de Jong, Iris E M

AU - Bodewes, Silke B

AU - van Leeuwen, Otto B

AU - Oosterhuis, Dorenda

AU - Lantinga, Veerle A

AU - Thorne, Adam M

AU - Lascaris, Bianca

AU - van den Heuvel, Marius C

AU - Wells, Rebecca G

AU - Olinga, Peter

AU - de Meijer, Vincent E

AU - Porte, Robert J

N1 - Funding Information: R.G.W. received personal grants from the Fred and Suzanne Biesecker Center for Pediatric Liver Disease and the National Institutes of Health (NIDDK); these funds supported the use of microscopes. I.E.M.d.J. received the International Travel Scholar Award from the International Liver Transplantation Society and a Fulbright grant for travel to the United States; these funding sources concern only personal funds. Reagents were used from the Molecular Pathology and Imaging Core (MPIC), part of The Center for Molecular Studies in Digestive and Liver Disease at the University of Pennsylvania (grant number: NIH P30DK050306). Funding Information: The authors are thankful to the UPenn Cell and Developmental Biology Microscopy Core and the Center for Molecular Studies in Digestive and Liver Diseases (grant number: NIH P30DK050306) for the use of microscopes and reagents. Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.

PY - 2023/6

Y1 - 2023/6

N2 - 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.

AB - 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.

U2 - 10.1097/TP.0000000000004531

DO - 10.1097/TP.0000000000004531

M3 - Article

C2 - 36721302

SN - 0041-1337

VL - 107

SP - e161-e172

JO - Transplantation

JF - Transplantation

IS - 6

ER -

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

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