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      Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation

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          Abstract

          Background

          Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP).

          Methods

          Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion.

          Results

          Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend.

          Conclusion

          Our miniaturized dNEVLP system enables normothermic dual vessel rat liver perfusion. The administration of metamizole effectively ameliorates arterial vasospasm allowing for six hours of dNEVLP, with superior outcome compared to sNEVLP.

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          Most cited references33

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          NAFLD and liver transplantation: Current burden and expected challenges.

          Because of global epidemics of obesity and type 2 diabetes, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing both in Europe and the United States, becoming one of the most frequent causes of chronic liver disease and predictably, one of the leading causes of liver transplantation both for end-stage liver disease and hepatocellular carcinoma. For most transplant teams around the world this will raise many challenges in terms of pre- and post-transplant management. Here we review the multifaceted impact of NAFLD on liver transplantation and will discuss: (1) NAFLD as a frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease, and hepatocellular carcinoma; (2) prevalence of NAFLD as an indication for liver transplantation both in Europe and the United States; (3) the impact of NAFLD on the donor pool; (4) the access of NAFLD patients to liver transplantation and their management on the waiting list in regard to metabolic, renal and vascular comorbidities; (5) the prevalence and consequences of post-transplant metabolic syndrome, recurrent and de novo NAFLD; (6) the alternative management and therapeutic options to improve the long-term outcomes with particular emphasis on the correction and control of metabolic comorbidities.
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            Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial.

            The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury. We present the first patients transplanted using a normothermic machine perfusion (NMP) device that transports and stores an organ in a fully functioning state at 37°C. In this Phase 1 trial, organs were retrieved using standard techniques, attached to the perfusion device at the donor hospital, and transported to the implanting center in a functioning state. NMP livers were matched 1:2 to cold-stored livers. Twenty patients underwent liver transplantation after NMP. Median NMP time was 9.3 (3.5-18.5) h versus median cold ischaemia time of 8.9 (4.2-11.4) h. Thirty-day graft survival was similar (100% NMP vs. 97.5% control, p = 1.00). Median peak aspartate aminotransferase in the first 7 days was significantly lower in the NMP group (417 IU [84-4681]) versus (902 IU [218-8786], p = 0.03). This first report of liver transplantation using NMP-preserved livers demonstrates the safety and feasibility of using this technology from retrieval to transplantation, including transportation. NMP may be valuable in increasing the number of donor livers and improving the function of transplantable organs.
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              Liver transplantation using fatty livers: always feasible?

              Steatotic liver grafts represent the most common type of "extended criteria" organs that have been introduced during the last two decades due to the disparity between liver transplant candidates and the number available organs. A precise definition and reliable and reproducible method for steatosis quantification is currently lacking and the potential influence of the chemical composition of hepatic lipids has not been addressed. In our view, these shortcomings appear to contribute significantly to the inconsistent results of studies reporting on graft steatosis and the outcome of liver transplantation. In this review, various definitions, prevalence and methods of quantification of liver steatosis will be covered. Ischemia/reperfusion injury of the steatotic liver and its consequences on post-transplant outcome will be discussed. Selection criteria for organ allocation and a number of emerging protective strategies are suggested. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: ValidationRole: Visualization
                Role: Data curationRole: Formal analysisRole: Resources
                Role: ConceptualizationRole: Data curation
                Role: MethodologyRole: ResourcesRole: SupervisionRole: Validation
                Role: Data curationRole: Resources
                Role: ConceptualizationRole: Data curationRole: Methodology
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: SupervisionRole: Validation
                Role: Data curationRole: MethodologyRole: Validation
                Role: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 July 2020
                2020
                : 15
                : 7
                : e0235635
                Affiliations
                [1 ] Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
                [2 ] Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
                [3 ] BIH Charité Clinician Scientist Program, Berlin Institute of Health (BIH), Berlin, Germany
                Max Delbruck Centrum fur Molekulare Medizin Berlin Buch, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-5188-8906
                http://orcid.org/0000-0003-1879-4788
                Article
                PONE-D-20-06139
                10.1371/journal.pone.0235635
                7332079
                32614897
                9aa26329-5ff6-41aa-b2cb-bf5c0549cdfb
                © 2020 Claussen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 March 2020
                : 18 June 2020
                Page count
                Figures: 6, Tables: 0, Pages: 16
                Funding
                This work was funded by institutional financial support of the Charité – Universitätsmedizin Berlin, the German Research Foundation (grant number: RA 3044/3-1) and by a Kickbox Seed Grant of the Einstein Center for Regenerative Therapies. Nathanael Raschzok is fellow of the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health.
                Categories
                Research Article
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Digestive System Procedures
                Liver Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Liver Transplantation
                Biology and Life Sciences
                Anatomy
                Liver
                Medicine and Health Sciences
                Anatomy
                Liver
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                Liver
                Biliary System
                Bile Ducts
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                Biliary System
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                Medicine and Health Sciences
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