Mitochondrial respiration during normothermic liver machine perfusion predicts clinical outcomeResearch in context
Andras T. Meszaros,
Julia Hofmann,
Madita L. Buch,
Benno Cardini,
Theresia Dunzendorfer-Matt,
Florian Nardin,
Michael J. Blumer,
Margot Fodor,
Martin Hermann,
Bettina Zelger,
Giorgi Otarashvili,
Melanie Schartner,
Annemarie Weissenbacher,
Rupert Oberhuber,
Thomas Resch,
Jakob Troppmair,
Dietmar ..fner,
Heinz Zoller,
Herbert Tilg,
Erich Gnaiger,
Theresa Hautz,
Stefan Schneeberger
Affiliations
Andras T. Meszaros
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Julia Hofmann
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Madita L. Buch
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Benno Cardini
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Theresia Dunzendorfer-Matt
Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
Florian Nardin
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria; Department of Anatomy, Histology and Embryology, Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
Michael J. Blumer
Department of Anatomy, Histology and Embryology, Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
Margot Fodor
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Martin Hermann
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Bettina Zelger
Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
Giorgi Otarashvili
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Melanie Schartner
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Annemarie Weissenbacher
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Rupert Oberhuber
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Thomas Resch
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Jakob Troppmair
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Dietmar ..fner
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Heinz Zoller
Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
Herbert Tilg
Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
Erich Gnaiger
Oroboros Instruments, Innsbruck, Austria
Theresa Hautz
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
Stefan Schneeberger
Department of Visceral, Transplant and Thoracic Surgery, organLife... Laboratory and Daniel Swarovski Research Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria; Corresponding author. Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
Summary: Background: Reliable biomarkers for organ quality assessment during normothermic machine perfusion (NMP) are desired. ATP (adenosine triphosphate) production by oxidative phosphorylation plays a crucial role in the bioenergetic homeostasis of the liver. Thus, detailed analysis of the aerobic mitochondrial performance may serve as predictive tool towards the outcome after liver transplantation. Methods: In a prospective clinical trial, 50 livers were subjected to NMP (OrganOx Metra) for up to 24.ßh. Biopsy and perfusate samples were collected at the end of cold storage, at 1.ßh, 6.ßh, end of NMP, and 1.ßh after reperfusion. Mitochondrial function and integrity were characterized by high-resolution respirometry (HRR), AMP, ADP, ATP and glutamate dehydrogenase analysis and correlated with the clinical outcome (L-GrAFT score). Real-time confocal microscopy was performed to assess tissue viability. Structural damage was investigated by histology, immunohistochemistry and transmission electron microscopy. Findings: A considerable variability in tissue viability and mitochondrial respiration between individual livers at the end of cold storage was observed. During NMP, mitochondrial respiration with succinate and tissue viability remained stable. In the multivariate analysis of the 35 transplanted livers (15 were discarded), area under the curve (AUC) of LEAK respiration, cytochrome c control efficiency (mitochondrial outer membrane damage), and efficacy of the mitochondrial ATP production during the first 6.ßh of NMP correlated with L-GrAFT. Interpretations: Bioenergetic competence during NMP plays a pivotal role in addition to tissue injury markers. The AUC for markers of outer mitochondrial membrane damage, ATP synthesis efficiency and dissipative respiration (LEAK) predict the clinical outcome upon liver transplantation. Funding: This study was funded by a Grant from the In Memoriam Dr. Gabriel Salzner Stiftung awarded to SS and the Tiroler Wissenschaftsfond granted to TH.
