Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts

Ivan Linares-Cervantes; Juan Echeverri; Stuart Cleland; Johann Moritz Kaths; Roizar Rosales; Toru Goto; Dagmar Kollmann; Matyas Hamar; Peter Urbanellis; Laura Mazilescu; Sujani Ganesh; Oyedele A. Adeyi; Paul Yip; Paulina Goryńska; Barbara Bojko; Krzysztof Goryński; David R. Grant; Nazia Selzner; Marcin Wąsowicz; Markus Selzner

doi:10.1111/ajt.15395

Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts

Ivan Linares-Cervantes, Juan Echeverri, Stuart Cleland, Johann Moritz Kaths, Roizar Rosales, Toru Goto, Dagmar Kollmann, Matyas Hamar, Peter Urbanellis, Laura Mazilescu, Sujani Ganesh, Oyedele A. Adeyi, Paul Yip, Paulina Goryńska, Barbara Bojko, Krzysztof Goryński, David R. Grant, Nazia Selzner, Marcin Wąsowicz, Markus Selzner

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart-beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30′), 70 minutes (DCD70′), and 120 minutes (DCD120′) of warm ischemia were studied. The HBD, DCD30′, and DCD70′-groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120′-group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120′-group (>2 mmol/L) at 4 hours of perfusion (P =.04). The fold-urea increase was significantly lower in the DCD120′-group (≤0.4) compared to the other groups (≥0.65) (P =.01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120′-group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120′-group (≤1) (P <.01). Three hours after transplantation, the DCD120′-group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P =.02). Rocuronium levels were higher at all the time-points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.

Original language	English (US)
Pages (from-to)	2991-3005
Number of pages	15
Journal	American Journal of Transplantation
Volume	19
Issue number	11
DOIs	https://doi.org/10.1111/ajt.15395
State	Published - Nov 1 2019

Bibliographical note

Funding Information:
IL expresses his gratitude to the Mexican National Council of Science and Technology (CONACyT, Mexico City,?Mexico) for its support for the Graduate program at University of Toronto. We thank Uwe Mummenhoff and the Birmingham family for their generous support. The study was supported by the Canadian National Transplant Research Program (CNTRP). This study received support from the 2016 ASTS-Astellas Fellowship in Transplantation Grant.

Funding Information:
IL expresses his gratitude to the Mexican National Council of Science and Technology (CONACyT, Mexico City, Mexico) for its support for the Graduate program at University of Toronto. We thank Uwe Mummenhoff and the Birmingham family for their generous support. The study was supported by the Canadian National Transplant Research Program (CNTRP). This study received support from the 2016 ASTS‐Astellas Fellowship in Transplantation Grant.

Publisher Copyright:
© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

animal models: porcine
basic (laboratory) research/science
ischemia reperfusion injury (IRI)
liver allograft function/dysfunction
liver transplantation/hepatology
organ procurement and allocation
organ transplantation in general
primary nonfunction
translational research/science

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10.1111/ajt.15395

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Linares-Cervantes, I., Echeverri, J., Cleland, S., Kaths, J. M., Rosales, R., Goto, T., Kollmann, D., Hamar, M., Urbanellis, P., Mazilescu, L., Ganesh, S., Adeyi, O. A., Yip, P., Goryńska, P., Bojko, B., Goryński, K., Grant, D. R., Selzner, N., Wąsowicz, M., & Selzner, M. (2019). Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts. American Journal of Transplantation, 19(11), 2991-3005. https://doi.org/10.1111/ajt.15395

Linares-Cervantes, I, Echeverri, J, Cleland, S, Kaths, JM, Rosales, R, Goto, T, Kollmann, D, Hamar, M, Urbanellis, P, Mazilescu, L, Ganesh, S, Adeyi, OA, Yip, P, Goryńska, P, Bojko, B, Goryński, K, Grant, DR, Selzner, N, Wąsowicz, M & Selzner, M 2019, 'Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts', American Journal of Transplantation, vol. 19, no. 11, pp. 2991-3005. https://doi.org/10.1111/ajt.15395

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title = "Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts",

abstract = "Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart-beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30′), 70 minutes (DCD70′), and 120 minutes (DCD120′) of warm ischemia were studied. The HBD, DCD30′, and DCD70′-groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120′-group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120′-group (>2 mmol/L) at 4 hours of perfusion (P =.04). The fold-urea increase was significantly lower in the DCD120′-group (≤0.4) compared to the other groups (≥0.65) (P =.01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120′-group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120′-group (≤1) (P <.01). Three hours after transplantation, the DCD120′-group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P =.02). Rocuronium levels were higher at all the time-points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.",

keywords = "animal models: porcine, basic (laboratory) research/science, ischemia reperfusion injury (IRI), liver allograft function/dysfunction, liver transplantation/hepatology, organ procurement and allocation, organ transplantation in general, primary nonfunction, translational research/science",

author = "Ivan Linares-Cervantes and Juan Echeverri and Stuart Cleland and Kaths, {Johann Moritz} and Roizar Rosales and Toru Goto and Dagmar Kollmann and Matyas Hamar and Peter Urbanellis and Laura Mazilescu and Sujani Ganesh and Adeyi, {Oyedele A.} and Paul Yip and Paulina Gory{\'n}ska and Barbara Bojko and Krzysztof Gory{\'n}ski and Grant, {David R.} and Nazia Selzner and Marcin W{\c a}sowicz and Markus Selzner",

note = "Funding Information: IL expresses his gratitude to the Mexican National Council of Science and Technology (CONACyT, Mexico City,?Mexico) for its support for the Graduate program at University of Toronto. We thank Uwe Mummenhoff and the Birmingham family for their generous support. The study was supported by the Canadian National Transplant Research Program (CNTRP). This study received support from the 2016 ASTS-Astellas Fellowship in Transplantation Grant. Funding Information: IL expresses his gratitude to the Mexican National Council of Science and Technology (CONACyT, Mexico City, Mexico) for its support for the Graduate program at University of Toronto. We thank Uwe Mummenhoff and the Birmingham family for their generous support. The study was supported by the Canadian National Transplant Research Program (CNTRP). This study received support from the 2016 ASTS‐Astellas Fellowship in Transplantation Grant. Publisher Copyright: {\textcopyright} 2019 The American Society of Transplantation and the American Society of Transplant Surgeons Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

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doi = "10.1111/ajt.15395",

language = "English (US)",

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T1 - Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts

AU - Linares-Cervantes, Ivan

AU - Echeverri, Juan

AU - Cleland, Stuart

AU - Kaths, Johann Moritz

AU - Rosales, Roizar

AU - Goto, Toru

AU - Kollmann, Dagmar

AU - Hamar, Matyas

AU - Urbanellis, Peter

AU - Mazilescu, Laura

AU - Ganesh, Sujani

AU - Adeyi, Oyedele A.

AU - Yip, Paul

AU - Goryńska, Paulina

AU - Bojko, Barbara

AU - Goryński, Krzysztof

AU - Grant, David R.

AU - Selzner, Nazia

AU - Wąsowicz, Marcin

AU - Selzner, Markus

N1 - Funding Information: IL expresses his gratitude to the Mexican National Council of Science and Technology (CONACyT, Mexico City,?Mexico) for its support for the Graduate program at University of Toronto. We thank Uwe Mummenhoff and the Birmingham family for their generous support. The study was supported by the Canadian National Transplant Research Program (CNTRP). This study received support from the 2016 ASTS-Astellas Fellowship in Transplantation Grant. Funding Information: IL expresses his gratitude to the Mexican National Council of Science and Technology (CONACyT, Mexico City, Mexico) for its support for the Graduate program at University of Toronto. We thank Uwe Mummenhoff and the Birmingham family for their generous support. The study was supported by the Canadian National Transplant Research Program (CNTRP). This study received support from the 2016 ASTS‐Astellas Fellowship in Transplantation Grant. Publisher Copyright: © 2019 The American Society of Transplantation and the American Society of Transplant Surgeons Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart-beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30′), 70 minutes (DCD70′), and 120 minutes (DCD120′) of warm ischemia were studied. The HBD, DCD30′, and DCD70′-groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120′-group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120′-group (>2 mmol/L) at 4 hours of perfusion (P =.04). The fold-urea increase was significantly lower in the DCD120′-group (≤0.4) compared to the other groups (≥0.65) (P =.01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120′-group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120′-group (≤1) (P <.01). Three hours after transplantation, the DCD120′-group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P =.02). Rocuronium levels were higher at all the time-points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.

AB - Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart-beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30′), 70 minutes (DCD70′), and 120 minutes (DCD120′) of warm ischemia were studied. The HBD, DCD30′, and DCD70′-groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120′-group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120′-group (>2 mmol/L) at 4 hours of perfusion (P =.04). The fold-urea increase was significantly lower in the DCD120′-group (≤0.4) compared to the other groups (≥0.65) (P =.01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120′-group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120′-group (≤1) (P <.01). Three hours after transplantation, the DCD120′-group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P =.02). Rocuronium levels were higher at all the time-points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.

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KW - organ procurement and allocation

KW - organ transplantation in general

KW - primary nonfunction

KW - translational research/science

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Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts

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