Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation.

Schlegel, Andrea, Muller, Xavier, Mueller, Matteo, Stepanova, Anna, Kron, Philipp, de Rougemont, Olivier, Muiesan, Paolo, Clavien, Pierre-Alain, Galkin, Alexander, Meierhofer, David and Dutkowski, Philipp (2020) Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation. EBioMedicine, 60. p. 103014. ISSN 2352-3964.

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Official URL: https://www.thelancet.com/journals/ebiom/article/P...

Abstract

BACKGROUND

Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models.

METHODS

We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation.

FINDINGS

Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function.

INTERPRETATION

Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation.

FUNDING

detailed information can be found in Acknowledgments.

Item Type: Article
Subjects: WO Surgery
Divisions: Planned IP Care > General Surgery
Related URLs:
Depositing User: Mr Philip O'Reilly
Date Deposited: 08 Oct 2020 16:06
Last Modified: 08 Oct 2020 16:06
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3524

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