Kidney Metabolism During Normothermic Machine Perfusion Differs Substantially From In Vivo Conditions
Transplantation, vol. 110, pp. e405–e415
Abstract
BACKGROUND: Normothermic machine perfusion (NMP) is being explored as a promising method to assess pretransplant viability and potentially enhance the functional performance of deceased-donor kidneys. To realize NMPs full potential, however, understanding ex vivo kidney metabolism and its differences from our clinical in vivo reference frame is essential. Here, a multiomics approach including metabolomics, transcriptomics, and proteomics analyses was used to explore metabolic differences between ex vivo and in vivo kidneys and assess the additional impact of warm ischemia on ex vivo kidney metabolism. METHODS: Paired kidneys from laboratory pigs (n = 30) sustained either minimal or 75 min of warm ischemia. All kidneys underwent 6 h of oxygenated hypothermic machine perfusion followed by 6 h of NMP. Cortical tissue samples were collected in vivo, after cold preservation, and after NMP for metabolomics, transcriptomics, and proteomics analyses. RESULTS: Metabolomics analysis revealed increased branched-chain amino acid metabolism and decreased uracil- and cytidine-containing pyrimidine metabolism after NMP compared with in vivo. Subsequent analyses demonstrated enhanced glycolysis, decreased gluconeogenesis, impaired tricarboxylic acid cycle activity, and nicotinamide adenine dinucleotide depletion. Multiomics analysis showed associations between metabolic alterations and increased immune response and cell death processes during NMP. CONCLUSIONS: Together, our findings indicate substantial differences between in vivo and ex vivo kidney metabolism and reveal a link between metabolic alterations and potentially detrimental cellular processes.
Authors 22
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Baran Ogurlu corresponding
University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Leiden University Medical Center · Amsterdam UMC Location University of Amsterdam
Affiliation as printed
Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Affiliation as printed
Department of Urology, Aarhus University Hospital, Aarhus, Denmark
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Mount Sinai Hospital · University Medical Center Groningen · University of Groningen · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Recanati/Miller Transplantation Institute, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, NY
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Affiliation as printed
Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Affiliation as printed
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Affiliation as printed
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Affiliation as printed
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Aarhus University · Aarhus University Hospital · Steno Diabetes Center Aarhus
Affiliation as printed
Department of Biomedicine, Aarhus University, Aarhus, Denmark
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Aarhus University · Aarhus University Hospital · Steno Diabetes Center Aarhus
Affiliation as printed
Department of Biomedicine, Aarhus University, Aarhus, Denmark
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Aarhus University · Aarhus University Hospital
Affiliation as printed
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Laboratory of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Queen Mary University of London · Berlin Institute of Health at Charité - Universitätsmedizin Berlin
Affiliation as printed
Health Data Modelling, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Berlin, Germany
Precision Healthcare University Research Institute, Queen Mary University of London, London, United Kingdom
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Aarhus University · Aarhus University Hospital
Affiliation as printed
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Urology, Aarhus University Hospital, Aarhus, Denmark
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Surgery—Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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