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      Observations on the ex situ perfusion of livers for transplantation

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          Abstract

          Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH < 7.4) from those that did not (pH > 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25‐50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid‐base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.

          Abstract

          The authors describe a series of ex situ normothermic liver perfusions in which they examine biochemical markers of hepatocyte and cholangiocyte biochemistry in an effort to predict posttransplant viability.

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          Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors.

          Translational studies in liver transplantation often require an endpoint of graft function or dysfunction beyond graft loss. Prior definitions of early allograft dysfunction (EAD) vary, and none have been validated in a large multicenter population in the Model for End-Stage Liver Disease (MELD) era. We examined an updated definition of EAD to validate previously used criteria, and correlated this definition with graft and patient outcome. We performed a cohort study of 300 deceased donor liver transplants at 3 U.S. programs. EAD was defined as the presence of one or more of the following previously defined postoperative laboratory analyses reflective of liver injury and function: bilirubin >or=10mg/dL on day 7, international normalized ratio >or=1.6 on day 7, and alanine or aspartate aminotransferases >2000 IU/L within the first 7 days. To assess predictive validity, the EAD definition was tested for association with graft and patient survival. Risk factors for EAD were assessed using multivariable logistic regression. Overall incidence of EAD was 23.2%. Most grafts met the definition with increased bilirubin at day 7 or high levels of aminotransferases. Of recipients meeting the EAD definition, 18.8% died, as opposed to 1.8% of recipients without EAD (relative risk = 10.7 [95% confidence interval: 3.6, 31.9] P < 0.0001). More recipients with EAD lost their grafts (26.1%) than recipients with no EAD (3.5%) (relative risk = 7.4 [95% confidence interval: 3.4, 16.3] P < 0.0001). Donor age and MELD score were significant EAD risk factors in a multivariate model. In summary a simple definition of EAD using objective posttransplant criteria identified a 23% incidence, and was highly associated with graft loss and patient mortality, validating previously published criteria. This definition can be used as an endpoint in translational studies aiming to identify mechanistic pathways leading to a subgroup of liver grafts with clinical expression of suboptimal function. (c) 2010 AASLD.
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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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              First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis.

              Exposure of donor liver grafts to prolonged periods of warm ischemia before procurement causes injuries including intrahepatic cholangiopathy, which may lead to graft loss. Due to unavoidable prolonged ischemic time before procurement in donation after cardiac death (DCD) donation in 1 participating center, each liver graft of this center was pretreated with the new machine perfusion "Hypothermic Oxygenated PErfusion" (HOPE) in an attempt to improve graft quality before implantation.
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                Author and article information

                Contributors
                cjew2@cam.ac.uk
                Journal
                Am J Transplant
                Am. J. Transplant
                10.1111/(ISSN)1600-6143
                AJT
                American Journal of Transplantation
                John Wiley and Sons Inc. (Hoboken )
                1600-6135
                1600-6143
                14 March 2018
                August 2018
                : 18
                : 8 ( doiID: 10.1111/ajt.2018.18.issue-8 )
                : 2005-2020
                Affiliations
                [ 1 ] Department of Surgery University of Cambridge Addenbrooke's Hospital Cambridge UK
                [ 2 ] NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge Cambridge UK
                [ 3 ] NIHR Cambridge Biomedical Research Centre Cambridge UK
                [ 4 ] Department of Medicine Cambridge University Hospitals NHS Foundation Trust Cambridge UK
                [ 5 ] Department of Radiology Cambridge University Hospitals NHS Foundation Trust Cambridge UK
                [ 6 ] Department of Pathology Cambridge University Hospitals NHS Foundation Trust Cambridge UK
                [ 7 ] Department of Microbiology and Immunology Laboratory of Abdominal Transplantation Katholieke Universiteit Leuven Leuven Belgium
                [ 8 ] Department of Abdominal Transplant Surgery University Hospitals Leuven Leuven Belgium
                Author notes
                [*] [* ] Correspondence

                Chris Watson

                Email: cjew2@ 123456cam.ac.uk

                Author information
                http://orcid.org/0000-0002-0590-4901
                http://orcid.org/0000-0003-4592-2810
                Article
                AJT14687
                10.1111/ajt.14687
                6099221
                29419931
                7ebcbea9-3f81-48b4-9ab5-8ce60a6b5e0e
                © 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 September 2017
                : 26 January 2018
                : 31 January 2018
                Page count
                Figures: 11, Tables: 3, Pages: 16, Words: 10622
                Funding
                Funded by: Addenbrooke's Charitable Trust, Cambridge University Hospitals
                Funded by: National Institute for Health Research
                Categories
                Original Article
                ORIGINAL ARTICLES
                Clinical Science
                Custom metadata
                2.0
                ajt14687
                August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:20.08.2018

                Transplantation
                clinical research/practice,liver allograft function/dysfunction,liver transplantation/hepatology,metabolism/metabolite,organ perfusion and preservation

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