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Aspord C, Macek Jílková Z, Bonadona A, Gerster T, Lesurtel M, Girard E, Saas P, Decaens T. Hypothermic Oxygenated Machine Perfusion and Static Cold Storage Drive Distinct Immunomodulation During Liver Transplantation: A Pilot Study. Transplantation 2025; 109:658-670. [PMID: 40131763 DOI: 10.1097/tp.0000000000005274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2024]
Abstract
BACKGROUND Organ injury is a major problem in liver transplant. Prolonged liver ischemia may result in ischemia/reperfusion injury (IRI), leading to inadequate activation of innate immunity. Hypothermic oxygenated machine perfusion (HOPE) of the graft emerges as a more physiologic method for liver preservation compared with static cold storage (SCS) by reducing IRI, which improves the quality of the graft. Despite being crucial, the immunological aspects of IRI in liver transplantation remained poorly explored. METHODS We designed a pilot study to assess intrahepatic immune responses to HOPE compared with SCS (6 patients in each group). We explored immunologic and inflammatory pathways using both bulk RNA-sequencing and single-cell multiparametric flow cytometry analyses from liver biopsies performed on the graft before and after transplantation. RESULTS Despite a limited number of patients and heterogeneous effects on IRI, we observed immune changes in liver biopsies before and after organ storage and distinct functional modulations of intrahepatic immune cells from the transplanted liver that underwent SCS versus HOPE. A significant increase of infiltrated monocytes, conventional type 2 dendritic cells (cDC2s), and neutrophils ( P < 0.05) and a trend toward reduced immune cell viability were observed after SCS but not after HOPE. CONCLUSIONS This pilot study did not allow us to conclude on IRI but showed that HOPE perfusion dampens liver infiltration of some innate immune cells. It reveals that the inclusion of additional transplanted patients and analysis of later time points after transplantation are needed to draw a definitive conclusion. However, it can guide future studies evaluating the development of new strategies to prevent IRI.
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Affiliation(s)
- Caroline Aspord
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Etablissement Français du Sang Auvergne-Rhone-Alpes, R&D Laboratory, Grenoble, France
| | - Zuzana Macek Jílková
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, France
| | - Agnes Bonadona
- Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, France
| | - Theophile Gerster
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Etablissement Français du Sang Auvergne-Rhone-Alpes, R&D Laboratory, Grenoble, France
| | - Mickael Lesurtel
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, APHP, University of Paris Cité, Paris, France
| | - Edouard Girard
- Service de Chirurgie Digestive et Générale, Hôpital Michallon, Centre Hospitalier Universitaire Grenoble-Alpes, Boulevard de la Chantourne, La Tronche, France
| | - Philippe Saas
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Etablissement Français du Sang Auvergne-Rhone-Alpes, R&D Laboratory, Grenoble, France
| | - Thomas Decaens
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France
- Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, France
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Egle M, Segiser A, Clavier A, Beer G, Helmer A, Ottersberg R, Graf S, Arnold M, Zulauf F, Lagger D, Bartkevics M, Kadner A, Krummenacher D, Vermathen P, Siepe M, Longnus S. Brief hypothermic oxygenated perfusion provides cardioprotection in a pig model of donation after circulatory death. Eur J Cardiothorac Surg 2025; 67:ezaf061. [PMID: 40053687 PMCID: PMC11919451 DOI: 10.1093/ejcts/ezaf061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 02/04/2025] [Accepted: 03/04/2025] [Indexed: 03/09/2025] Open
Abstract
OBJECTIVES Donation after circulatory death provides excellent patient outcomes in heart transplantation; however, warm ischaemic graft damage remains a concern. We have reported that a brief period of hypothermic oxygenated perfusion prior to normothermic reperfusion improves graft recovery in a rat model. Here, we investigated the cardioprotective benefits and mechanisms of this approach compared to the current clinical standard in a large animal model. METHODS Circulatory death was induced in anaesthetized male Schweizer Edelschwein pigs (55 kg). Hearts underwent 20 min of warm, in-situ ischaemia, followed by a cold coronary flush and explantation. After 15 min backtable preparation, hearts underwent either 15 min cold static storage (control) or 30 min hypothermic oxygenated perfusion. All hearts were perfused ex vivo under normothermic conditions; 3 h in an unloaded mode, followed by 1 h with left ventricular loading to assess cardiac recovery. RESULTS Compared to control conditions (n = 5), hypothermic oxygenated perfusion (n = 5) increased recovery of left ventricular function (cardiac output and maximum relaxation rate, P < 0.001 for both) and decreased cell death marker release (heart-type fatty acid binding protein, P = 0.009 and myoglobin, P < 0.001). In parallel, hypothermic oxygenated perfusion reduced the release of succinate and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine. CONCLUSIONS A brief period of hypothermic oxygenated perfusion, applied as a reperfusion therapy between graft procurement and normothermic machine perfusion, provides cardioprotection in a porcine model of donation after circulatory death. Hypothermic oxygenated perfusion is a promising, easily applicable, cardioprotective reperfusion strategy; this study provides key evidence to support clinical translation.
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Affiliation(s)
- Manuel Egle
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Adrian Segiser
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Alexia Clavier
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Georgia Beer
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Anja Helmer
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Rahel Ottersberg
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Selianne Graf
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Maria Arnold
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Fabio Zulauf
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Deborah Lagger
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Maris Bartkevics
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Alexander Kadner
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Daja Krummenacher
- Magnetic Resonance Methodology Group, Institute of Diagnostic and Interventional Neuroradiology, University of Bern, Bern, Switzerland
| | - Peter Vermathen
- Magnetic Resonance Methodology Group, Institute of Diagnostic and Interventional Neuroradiology, University of Bern, Bern, Switzerland
| | - Matthias Siepe
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Sarah Longnus
- Department of Cardiac Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
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Emerson D, Rabin Y, Kara LB. A simplified computational liver perfusion model, with applications to organ preservation. Sci Rep 2025; 15:2178. [PMID: 39820266 PMCID: PMC11739513 DOI: 10.1038/s41598-025-85170-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 01/01/2025] [Indexed: 01/19/2025] Open
Abstract
Advanced liver preservation strategies could revolutionize liver transplantation by extending preservation time, thereby allowing for broader availability and better matching of transplants. However, developing new cryopreservation protocols requires exploration of a complex design space, further complicated by the scarcity of real human livers to experiment upon. We aim to create computational models of the liver to aid in the development of new cryopreservation protocols. Towards this goal, we present an approach for generating 3D models of the liver vasculature by building upon the space colonization algorithm. Additionally, we introduce the concept of a super lobule which enables a computational abstraction of biological liver lobules. User-tunable parameters allow for vasculatures of varying depth and topology to be generated. In each model, we solve for a common lumped resistance value assigned to the super lobules, allowing the overall physiological blood pressure and flow rate through the liver to be preserved. We demonstrate our approach's ability to maintain consistency between models of varying depth. Finally, we simulate steady state machine perfusion of the generated models and demonstrate how they can be used to quickly test the effect of different boundary conditions when designing organ preservation protocols.
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Affiliation(s)
- Daniel Emerson
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| | - Yoed Rabin
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| | - Levent Burak Kara
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.
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Egle M, Mendez‐Carmona N, Segiser A, Graf S, Siepe M, Longnus S. Hypothermic Oxygenated Perfusion Improves Vascular and Contractile Function by Preserving Endothelial Nitric Oxide Production in Cardiac Grafts Obtained With Donation After Circulatory Death. J Am Heart Assoc 2024; 13:e033503. [PMID: 38606732 PMCID: PMC11262527 DOI: 10.1161/jaha.123.033503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/01/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Cardiac donation after circulatory death is a promising option to increase graft availability. Graft preservation with 30 minutes of hypothermic oxygenated perfusion (HOPE) before normothermic machine perfusion may improve cardiac recovery as compared with cold static storage, the current clinical standard. We investigated the role of preserved nitric oxide synthase activity during HOPE on its beneficial effects. METHODS AND RESULTS Using a rat model of donation after circulatory death, hearts underwent in situ ischemia (21 minutes), were explanted for a cold storage period (30 minutes), and then reperfused under normothermic conditions (60 minutes) with left ventricular loading. Three cold storage conditions were compared: cold static storage, HOPE, and HOPE with Nω-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor). To evaluate potential confounding effects of high coronary flow during early reperfusion in HOPE hearts, bradykinin was administered to normalize coronary flow to HOPE levels in 2 additional groups (cold static storage and HOPE with Nω-nitro-L-arginine methyl ester). Cardiac recovery was significantly improved in HOPE versus cold static storage hearts, as determined by cardiac output, left ventricular work, contraction and relaxation rates, and coronary flow (P<0.05). Furthermore, HOPE attenuated postreperfusion calcium overload. Strikingly, the addition of Nω-nitro-L-arginine methyl ester during HOPE largely abolished its beneficial effects, even when early reperfusion coronary flow was normalized to HOPE levels. CONCLUSIONS HOPE provides superior preservation of ventricular and vascular function compared with the current clinical standard. Importantly, HOPE's beneficial effects require preservation of nitric oxide synthase activity during the cold storage. Therefore, the application of HOPE before normothermic machine perfusion is a promising approach to optimize graft recovery in donation after circulatory death cardiac grafts.
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Affiliation(s)
- Manuel Egle
- Department of Cardiac SurgeryInselspital, Bern University Hospital, University of BernSwitzerland
- Department for BioMedical ResearchUniversity of BernSwitzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of BernSwitzerland
| | - Natalia Mendez‐Carmona
- Department of Cardiac SurgeryInselspital, Bern University Hospital, University of BernSwitzerland
- Department for BioMedical ResearchUniversity of BernSwitzerland
| | - Adrian Segiser
- Department of Cardiac SurgeryInselspital, Bern University Hospital, University of BernSwitzerland
- Department for BioMedical ResearchUniversity of BernSwitzerland
| | - Selianne Graf
- Department of Cardiac SurgeryInselspital, Bern University Hospital, University of BernSwitzerland
- Department for BioMedical ResearchUniversity of BernSwitzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of BernSwitzerland
| | - Matthias Siepe
- Department of Cardiac SurgeryInselspital, Bern University Hospital, University of BernSwitzerland
| | - Sarah Longnus
- Department of Cardiac SurgeryInselspital, Bern University Hospital, University of BernSwitzerland
- Department for BioMedical ResearchUniversity of BernSwitzerland
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Longchamp A, Nakamura T, Uygun K, Markmann JF. Role of Machine Perfusion in Liver Transplantation. Surg Clin North Am 2024; 104:45-65. [PMID: 37953040 DOI: 10.1016/j.suc.2023.07.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
Given the current severe shortage of available livers for transplantation, there is an urgent need to maximize the utilization of donor organs. One of the strategies to increase the number of available livers for transplantation is to improve organ utilization through the use of elderly, overweight, or organs donated after circulatory death. However, the utilization of these "marginal" organs was associated with an increased risk of early allograft dysfunction, primary nonfunction, ischemic biliary complications, or even re-transplantation. Ischemia-reperfusion injury is a key mechanism in the pathogenesis of these complications.
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Affiliation(s)
- Alban Longchamp
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Tsukasa Nakamura
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Korkut Uygun
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - James F Markmann
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Minor T, von Horn C, Zlatev H, Saner F, Grawe M, Lüer B, Huessler E, Kuklik N, Paul A. Controlled oxygenated rewarming as novel end-ischemic therapy for cold stored liver grafts. A randomized controlled trial. Clin Transl Sci 2022; 15:2918-2927. [PMID: 36251938 PMCID: PMC9747115 DOI: 10.1111/cts.13409] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/29/2022] [Accepted: 09/03/2022] [Indexed: 01/26/2023] Open
Abstract
Abrupt return to normothermia has been shown a genuine factor contributing to graft dysfunction after transplantation. This study tested the concept to mitigate reperfusion injury of liver grafts by gentle warming-up using ex vivo machine perfusion prior to reperfusion. In a single center randomized controlled study, livers were assigned to conventional static cold storage (SCS) alone or to SCS followed by 90 min of ex vivo machine perfusion including controlled oxygenated rewarming (COR) by gentle and protracted elevation of the perfusate temperature from 10°C to 20°C. Primary outcome mean peak aspartate aminotransferase (AST) was 1371 U/L (SD 2871) after SCS versus 767 U/L (SD 1157) after COR (p = 0.273). Liver function test (LiMAx) on postoperative day 1 yielded 187 μg/kg/h (SD 121) after SCS, but rose to 294 μg/kg/h (SD 106) after COR (p = 0.006). Likewise, hepatic synthesis of coagulation factor V was significantly accelerated in the COR group immediately after transplantation (103% [SD 34] vs. 66% [SD 26]; p = 0.001). Fewer severe complications (Clavien-Dindo grade ≥3b) were reported in the COR group (8) than in the SCS group (15). Rewarming/reperfusion injury of liver grafts can be safely and effectively mitigated by controlling of the rewarming kinetics prior to blood reperfusion using end-ischemic ex vivo machine perfusion after cold storage.
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Affiliation(s)
- Thomas Minor
- Surgical Research DepartmentUniversity Hospital EssenEssenGermany
| | | | - Hristo Zlatev
- Surgical Research DepartmentUniversity Hospital EssenEssenGermany
| | - Fuat Saner
- General Visceral and Transplantation SurgeryUniversity Hospital EssenEssenGermany
| | - Melanie Grawe
- Surgical Research DepartmentUniversity Hospital EssenEssenGermany
| | - Bastian Lüer
- Surgical Research DepartmentUniversity Hospital EssenEssenGermany
| | - Eva‐Maria Huessler
- Institute for Medical Informatics, Biometry and EpidemiologyUniversity Hospital EssenEssenGermany
| | - Nils Kuklik
- Institute for Medical Informatics, Biometry and EpidemiologyUniversity Hospital EssenEssenGermany,Centre for Clinical Trials EssenUniversity Hospital EssenEssenGermany
| | - Andreas Paul
- General Visceral and Transplantation SurgeryUniversity Hospital EssenEssenGermany
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Asong-Fontem N, Panisello-Rosello A, Sebagh M, Gonin M, Rosello-Catafau J, Adam R. The Role of IGL-2 Preservation Solution on Rat Livers during SCS and HOPE. Int J Mol Sci 2022; 23:12615. [PMID: 36293465 PMCID: PMC9604552 DOI: 10.3390/ijms232012615] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/15/2022] [Accepted: 10/18/2022] [Indexed: 11/17/2022] Open
Abstract
The scarcity of livers for transplantation is rising, and new strategies to extend the donor pool are being explored. One solution is to use marginal grafts from extended criteria donors, presenting, for example, liver steatosis. As current preservation solutions (UW, HTK, and IGL-1) were mainly designed for static cold storage (SCS) only, IGL-2, a modified version of IGL-1, was developed to be suitable for SCS and dynamic preservation, such as hypothermic oxygenated perfusion (HOPE). In this study, we investigated the combined effect of IGL-2, SCS, and HOPE and compared it to the most used preservation solution (UW and Belzer MPS). Four experimental groups with six rats each were designed using Zucker rats. All groups underwent 24 h of SCS (in IGL-2 or UW) + 2 h of normothermic machine perfusion (NMP) at 37 °C to mimic transplantation. HOPE (IGL-2 or Belzer MPS) was performed before NMP on half of the rats. The IGL-2 group demonstrated lower transaminases and a significantly low level of glycocalyx proteins, CASP3, and HMGB1 in the perfusates. These data suggest the protective role of IGL-2 for fatty livers in preserving the endothelial glycocalyx, apoptosis, and inflammation.
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Affiliation(s)
- Njikem Asong-Fontem
- Unité Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, 94800 Villejuif, France
| | - Arnau Panisello-Rosello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Catalonia, Spain
| | - Mylène Sebagh
- Centre Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Université Paris-Saclay, 94800 Villejuif, France
| | - Mathilde Gonin
- Unité Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, 94800 Villejuif, France
| | - Joan Rosello-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Catalonia, Spain
| | - René Adam
- Unité Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, 94800 Villejuif, France
- Centre Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Université Paris-Saclay, 94800 Villejuif, France
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The translational approach to liver transplantation. Ann Hepatol 2022; 27:100747. [PMID: 36057435 DOI: 10.1016/j.aohep.2022.100747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/11/2022] [Indexed: 02/04/2023]
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Asong-Fontem N, Panisello-Rosello A, Beghdadi N, Lopez A, Rosello-Catafau J, Adam R. Pre-Ischemic Hypothermic Oxygenated Perfusion Alleviates Protective Molecular Markers of Ischemia-Reperfusion Injury in Rat Liver. Transplant Proc 2022; 54:1954-1969. [PMID: 35961798 DOI: 10.1016/j.transproceed.2022.05.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 04/26/2022] [Accepted: 05/22/2022] [Indexed: 11/16/2022]
Abstract
To expand the pool of organs, hypothermic oxygenated perfusion (HOPE), one of the most promising perfusion protocols, is currently performed after cold storage (CS) at transplant centers (HOPE-END). We investigated a new timing for HOPE, hypothesizing that performing HOPE before CS (HOPE-PRE) could boost mitochondrial protection allowing the graft to better cope with the accumulation of oxidative stress during CS. We analyzed liver injuries at 3 different levels. Histologic analysis demonstrated that, compared to classical CS (CTRL), the HOPE-PRE group showed significantly less ischemic necrosis compared to CTRL vs HOPE-END. From a biochemical standpoint, transaminases were lower after 2 hours of reperfusion in the CTRL vs HOPE-PRE group, which marked decreased liver injury. qPCR analysis on 37 genes involved in ischemia-reperfusion injury revealed protection in HOPE-PRE and HOPE-END compared to CTRL mediated through similar pathways. However, the CTRL vs HOPE-PRE group demonstrated an increased transcriptional level for protective genes compared to the CTRL vs HOPE-END group. This study provides insights on novel biomarkers that could be used in the clinic to better characterize graft quality improving transplantation outcomes.
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Affiliation(s)
- Njikem Asong-Fontem
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France.
| | - Arnau Panisello-Rosello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Catalonia, Spain
| | - Nassiba Beghdadi
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France; Center Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Villejuif, France
| | - Alexandre Lopez
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France
| | - Joan Rosello-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Catalonia, Spain
| | - René Adam
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France; Center Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Villejuif, France
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10
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Panconesi R, Flores Carvalho M, Dondossola D, Muiesan P, Dutkowski P, Schlegel A. Impact of Machine Perfusion on the Immune Response After Liver Transplantation - A Primary Treatment or Just a Delivery Tool. Front Immunol 2022; 13:855263. [PMID: 35874758 PMCID: PMC9304705 DOI: 10.3389/fimmu.2022.855263] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 05/31/2022] [Indexed: 12/12/2022] Open
Abstract
The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion techniques are therefore frequently discussed with an ever-increasing number of experimental and clinical studies. Two main approaches, hypothermic and normothermic perfusion, are the leading strategies to be introduced in clinical practice in many western countries today. Despite this success, the number of studies, which provide robust data on the underlying mechanisms of protection conveyed through this technology remains scarce, particularly in context of different stages of ischemia-reperfusion-injury (IRI). Prior to a successful clinical implementation of machine perfusion, the concept of IRI and potential key molecules, which should be addressed to reduce IRI-associated inflammation, requires a better exploration. During ischemia, Krebs cycle metabolites, including succinate play a crucial role with their direct impact on the production of reactive oxygen species (ROS) at mitochondrial complex I upon reperfusion. Such features are even more pronounced under normothermic conditions and lead to even higher levels of downstream inflammation. The direct consequence appears with an activation of the innate immune system. The number of articles, which focus on the impact of machine perfusion with and without the use of specific perfusate additives to modulate the inflammatory cascade after transplantation is very small. This review describes first, the subcellular processes found in mitochondria, which instigate the IRI cascade together with proinflammatory downstream effects and their link to the innate immune system. Next, the impact of currently established machine perfusion strategies is described with a focus on protective mechanisms known for the different perfusion approaches. Finally, the role of such dynamic preservation techniques to deliver specific agents, which appear currently of interest to modulate this posttransplant inflammation, is discussed together with future aspects in this field.
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Affiliation(s)
- Rebecca Panconesi
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della, Scienza di Torino, University of Turin, Turin, Italy
| | - Mauricio Flores Carvalho
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Paolo Muiesan
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | - Andrea Schlegel
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
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Bochimoto H, Ishihara Y, Mohd Zin NK, Iwata H, Kondoh D, Obara H, Matsuno N. Ultrastructural changes in porcine liver sinusoidal endothelial cells of machine perfused liver donated after cardiac death. World J Gastroenterol 2022; 28:2100-2111. [PMID: 35664031 PMCID: PMC9134135 DOI: 10.3748/wjg.v28.i19.2100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/17/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The machine perfusion (MP) preservation including hypothermic MP (HMP) and midthermic MP (MMP) has been considered as a promising strategy to preserve the functions of liver donated after cardiac death. The importance of understanding liver sinusoidal endothelial cells (LSEC) damage in regulating liver injury during MP has been emphasized. However, the ultrastructural changes in the LSEC and sinusoids around them after MP are unclear.
AIM To investigate the ultrastructural changes in the LSEC and sinusoids around them after MP.
METHODS Porcine liver grafts undergo a warm ischemia time of 60 minutes perfused for 4 h with modified University of Wisconsin gluconate solution. Group A grafts were preserved with HMP at 8 °C constantly for 4 h. Group B grafts were preserved with a rewarming solution at 22 °C by MMP for 4 h. Then the ultrastructural changes in the LSEC and sinusoids in Group A and B were comparatively analyzed by using osmium-maceration scanning electron microscopy with complementary transmission electron microscopy methods.
RESULTS An analysis of the LSEC after warm ischemia revealed that mitochondria with condensed-shaped cristae, abnormal vesicles, reduction of ribosomes and the endoplasmic reticulum (ER) surround the mitochondria appeared. The MP subsequent after warm ischemia alleviate the abnormal vesicles and reduction of ribosomes in LSEC, which indicated the reduction of the ER damage. However, MMP could restore the tubular mitochondrial cristae, while after HMP the condensed and narrow mitochondrial cristae remained. In addition, the volume of the sinusoidal space in the liver grafts after MMP were restored, which indicated a lower risk of pressure injury than HMP.
CONCLUSION MMP alleviates the ER damage of LSEC by warm ischemia, additionally restore the metabolism of LSEC via the normalization of mitochondria and prevent the share stress damage of liver grafts.
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Affiliation(s)
- Hiroki Bochimoto
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku 105-8461, Tokyo, Japan
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Yo Ishihara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Nur Khatijah Mohd Zin
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku 105-8461, Tokyo, Japan
| | - Hiroyoshi Iwata
- Department of Surgery, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Daisuke Kondoh
- Laboratory of Veterinary Anatomy, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan
| | - Hiromichi Obara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
- Department of Mechanical Engineering, Tokyo Metropolitan University, Hachioji 192-0397, Tokyo, Japan
| | - Naoto Matsuno
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
- Department of Surgery, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
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Shi JH, Yang DJ, Jin Q, Cheng N, Shi YB, Bai Y, Yu DS, Guo WZ, Ge GB, Zhang SJ. Cytochrome P450 2E1 predicts liver functional recovery from donation after circulatory death using air-ventilated normothermic machine perfusion. Sci Rep 2022; 12:7446. [PMID: 35523980 PMCID: PMC9076671 DOI: 10.1038/s41598-022-11434-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 04/25/2022] [Indexed: 12/05/2022] Open
Abstract
The optimal oxygen concentration is unclear for normothermic machine perfusion (NMP) of livers from donation after circulatory death (DCD). Our purposes were to investigate the effect of air-ventilated NMP on the DCD liver, analyze the underlying mechanism and select the targets to predict liver functional recovery with NMP. NMP was performed using the NMP system with either air ventilation or oxygen ventilation for 2 h in the rat liver following warm ischemia and cold-storage preservation. Proteomics and metabolomics were used to reveal the significant molecular networks. The bioinformation analysis was validated by administering peroxisome proliferator activator receptor-γ (PPARγ) antagonist and agonist via perfusion circuit in the air-ventilated NMP. Results showed that air-ventilated NMP conferred a better functional recovery and a less inflammatory response in the rat DCD liver; integrated proteomics and metabolomics analysis indicated that intrahepatic docosapentaenoic acid downregulation and upregulation of cytochrome P450 2E1 (CYP2E1) expression and activity were associated with DCD liver functional recovery with air-ventilated NMP; PPARγ antagonist worsened liver function under air-oxygenated NMP whereas PPARγ agonist played the opposite role. In conclusion, air-ventilated NMP confers a better liver function from DCD rats through the DAP-PPARγ-CYP2E1 axis; CYP2E1 activity provides a biomarker of liver functional recovery from DCD.
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Affiliation(s)
- Ji-Hua Shi
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation and Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
| | - Dong-Jing Yang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation and Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Qiang Jin
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 200473, China
| | - Nuo Cheng
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation and Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yuan-Bin Shi
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation and Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yang Bai
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation and Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Dong-Sheng Yu
- Division of Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation and Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Guang-Bo Ge
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 200473, China.
| | - Shui-Jun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation and Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
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13
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Hussain B, Kasinath V, Madsen JC, Bromberg J, Tullius SG, Abdi R. Intra-Organ Delivery of Nanotherapeutics for Organ Transplantation. ACS NANO 2021; 15:17124-17136. [PMID: 34714050 PMCID: PMC9050969 DOI: 10.1021/acsnano.1c04707] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Targeted delivery of therapeutics through the use of nanoparticles (NPs) has emerged as a promising method that increases their efficacy and reduces their side effects. NPs can be tailored to localize to selective tissues through conjugation to ligands that bind cell-specific receptors. Although the vast majority of nanodelivery platforms have focused on cancer therapy, efforts have begun to introduce nanotherapeutics to the fields of immunology as well as transplantation. In this review, we provide an overview from a clinician's perspective of current nanotherapeutic strategies to treat solid organ transplants with NPs during the time interval between organ harvest from the donor and placement into the recipient, an innovative technology that can provide major benefits to transplant patients. The use of ex vivo normothermic machine perfusion (NMP), which is associated with preserving the function of the organ following transplantation, also provides an ideal opportunity for a localized, sustained, and controlled delivery of nanotherapeutics to the organ during this critical time period. Here, we summarize previous endeavors to improve transplantation outcomes by treating the organ with NPs prior to placement in the recipient. Investigations in this burgeoning field of research are promising, but more extensive studies are needed to overcome the physiological challenges to achieving effective nanotherapeutic delivery to transplanted organs discussed in this review.
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Affiliation(s)
- Bilal Hussain
- Transplantation Research Center and Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Vivek Kasinath
- Transplantation Research Center and Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Joren C. Madsen
- Department of Surgery and Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Jonathan Bromberg
- Departments of Surgery and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Stefan G. Tullius
- Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Reza Abdi
- Transplantation Research Center and Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
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14
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Cheng N, Shi JH, Jin Y, Shi YB, Liu XD, Zhang HP, Cao SL, Yang H, Guo WZ, Zhang SJ. Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats. Front Surg 2021; 8:665260. [PMID: 34222317 PMCID: PMC8249577 DOI: 10.3389/fsurg.2021.665260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/24/2021] [Indexed: 01/17/2023] Open
Abstract
Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval. Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation. Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05). Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.
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Affiliation(s)
- Nuo Cheng
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Ji-Hua Shi
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yang Jin
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yuan-Bin Shi
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xu-Dong Liu
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Hua-Peng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Sheng-Li Cao
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Han Yang
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shui-Jun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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15
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von Horn C, Wilde B, Rauen U, Paul A, Minor T. Use of the new preservation solution Custodiol-MP for ex vivo reconditioning of kidney grafts. Artif Organs 2021; 45:1117-1123. [PMID: 33683761 DOI: 10.1111/aor.13951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/12/2020] [Accepted: 03/02/2021] [Indexed: 01/02/2023]
Abstract
Organ shortage and the increasing use of extended criteria donor grafts for transplantation drives efforts for more efficient organ preservation strategies from simple cold storage toward dynamic organ reconditioning. The choice of a suitable preservation solution is of high relevance in different organ preservation or reconditioning situations. Custodiol-MP is a new machine perfusion solution giving the opportunity to add colloids according to organ requirements. The present study aimed to compare new Custodiol-MP with clinically established Belzer MPS solution. Porcine kidneys were ischemically predamaged and cold stored for 20 hours. Ex vivo machine reconditioning was performed either with Custodiol-MP (n = 6) or with Belzer MPS solution (n = 6) for 90 minutes with controlled oxygenated rewarming up to 20°C. Kidney function was evaluated using an established ex vivo reperfusion model. In this experimental setting, differences between both types of perfusion solutions could not be observed. Machine perfusion with Custodiol-MP resulted in higher creatinine clearance (7.4 ± 8.6 mL/min vs. 2.8 ± 2.5 mL/min) and less TNC perfusate levels (0.22 ± 0.25 ng/mL vs. 0.09 ± 0.08 ng/mL), although differences did not reach significance. For short-term kidney perfusion Custodiol-MP is safe and applicable. Particularly, the unique feature of flexible colloid supplementation makes the solution attractive in specific experimental and clinical settings.
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Affiliation(s)
- Charlotte von Horn
- Department of Surgical Research, Clinic for General, Visceral and Transplantation Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Benjamin Wilde
- Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, University Duisburg-Essen, Essen, Germany
| | - Ursula Rauen
- Institut für Physiologische Chemie, Universitätsklinikum Essen, University Duisburg-Essen, Essen, Germany
| | - Andreas Paul
- Clinic for General, Visceral and Transplantation Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Thomas Minor
- Department of Surgical Research, Clinic for General, Visceral and Transplantation Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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16
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Tatum R, O'Malley TJ, Bodzin AS, Tchantchaleishvili V. Machine perfusion of donor organs for transplantation. Artif Organs 2021; 45:682-695. [PMID: 33349946 DOI: 10.1111/aor.13894] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/25/2020] [Accepted: 12/17/2020] [Indexed: 12/16/2022]
Abstract
The ever-widening gap between organ supply and demand has resulted in an organ shortage crisis that affects patients all over the world. For decades, static cold storage (SCS) was the gold standard preservation strategy because of its simplicity and cost-effectiveness, but the rising unmet demand for donor organ transplants has prompted investigation into preservation strategies that can expand the available donor pool. Through ex vivo functional assessment of the organ prior to transplant, newer methods to preserve organs such as perfusion-based therapy can potentially expand the available organ pool. This review will explain the physiologic rationale for SCS before exploring the advantages and disadvantages associated with the two broad classes of preservation strategies that have emerged to address the crisis: hypothermic and normothermic machine perfusion. A detailed analysis of how each preservation strategy works will be provided before investigating the current status of clinical data for each preservation strategy for the kidney, liver, pancreas, heart, and lung. For some organs there is robust data to support the use of machine perfusion technologies over SCS, and in others the data are less clear. Nonetheless, machine perfusion technologies represent an exciting frontier in organ preservation research and will remain a crucial component of closing the gap between organ supply and recipient demand.
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Affiliation(s)
- Robert Tatum
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Thomas J O'Malley
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam S Bodzin
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
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17
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Haque O, Yuan Q, Uygun K, Markmann JF. Evolving utilization of donation after circulatory death livers in liver transplantation: The day of DCD has come. Clin Transplant 2021; 35:e14211. [PMID: 33368701 PMCID: PMC7969458 DOI: 10.1111/ctr.14211] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/29/2020] [Accepted: 12/21/2020] [Indexed: 12/15/2022]
Abstract
Compared to donation after brain death (DBD), livers procured for transplantation from donation after circulatory death (DCD) donors experience more ischemia-reperfusion injury and higher rates of ischemic cholangiopathy due to the period of warm ischemic time (WIT) following withdrawal of life support. As a result, utilization of DCD livers for liver transplant (LT) has generally been limited to short WITs and younger aged donor grafts, causing many recovered DCD organs to be discarded without consideration for transplant. This study assesses how DCD liver utilization and outcomes have changed over time, using OPTN data from adult, first-time, deceased donor, whole-organ LTs between January 1995 and December 2019. Results show that increased clinical experience with DCD LT has translated into increased use of livers from DCD donors, shorter ischemic times, shorter lengths of hospitalization after transplant, and lower rates of retransplantation. The data also reveal that over the past decade, the rate of increase in DCD LTs conducted in the United States has outpaced that of DBD. Together, these trends signal an opportunity for the field of liver transplantation to mitigate the organ shortage by capitalizing on DCD liver allografts that are currently not being utilized.
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Affiliation(s)
- Omar Haque
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard, Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Qing Yuan
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- 8th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Korkut Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard, Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - James F Markmann
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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18
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Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies. Int J Mol Sci 2021; 22:ijms22041864. [PMID: 33668478 PMCID: PMC7918617 DOI: 10.3390/ijms22041864] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular–pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
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19
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Bonaccorsi-Riani E, Brüggenwirth IMA, Buchwald JE, Iesari S, Martins PN. Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials. Semin Liver Dis 2020; 40:264-281. [PMID: 32557478 DOI: 10.1055/s-0040-1713118] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.
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Affiliation(s)
- E Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.,Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium
| | - I M A Brüggenwirth
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J E Buchwald
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
| | - S Iesari
- Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - P N Martins
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
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20
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21
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Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts? Int J Mol Sci 2020; 21:ijms21093132. [PMID: 32365506 PMCID: PMC7246795 DOI: 10.3390/ijms21093132] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/18/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.
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22
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Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial. Sci Rep 2020; 10:6063. [PMID: 32269237 PMCID: PMC7142134 DOI: 10.1038/s41598-020-62979-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 03/04/2020] [Indexed: 02/08/2023] Open
Abstract
With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of liver (LT) and kidney transplantation (KT) from Extended Criteria Donors (ECD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (SCS-L and SCS-K). HOPE and SCS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in SCS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary non-function was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in KT and in LT.
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Minor T, von Horn C, Gallinat A, Kaths M, Kribben A, Treckmann J, Paul A. First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation. Am J Transplant 2020; 20:1192-1195. [PMID: 31599063 DOI: 10.1111/ajt.15647] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/08/2019] [Accepted: 09/25/2019] [Indexed: 01/25/2023]
Abstract
Cold preservation sensitizes organ grafts to exacerbation of tissue injury upon reperfusion. This reperfusion injury is not fully explained by the mere re-introduction of oxygen but rather is pertinent to the immediate rise in metabolic turnover associated with the abrupt restoration of normothermia. Here we report the first clinical case of gradual resumption of graft temperature upon ex vivo machine perfusion from hypothermia up to normothermic conditions using cell-free buffer as a perfusate. A kidney graft from an extended criteria donor was put on the machine after 12.5 hours of cold storage. During ex vivo perfusion, perfusion pressure and temperature were gradually elevated from 30 mm Hg and 8°C to 75 mm Hg and 35°C, respectively. Perfusate consisted of diluted Steen solution, oxygenated with 100% oxygen. Final flow rates at 35°C were 850 mL/min. The kidney was transplanted without complications and showed good immediate function. Serum creatinine fell from preoperative 720 µmol/L to 506 µmol/L during the first 24 hours after transplantation. Clearance after 1 week was 43.1 mL/min. Controlled oxygenated rewarming prior to transplantation can be performed up to normothermia without blood components or artificial oxygen carriers and may represent a promising tool to mitigate cold-induced reperfusion injury or to evaluate graft performance.
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Affiliation(s)
- Thomas Minor
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Charlotte von Horn
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Anja Gallinat
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Moritz Kaths
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Andreas Kribben
- Department of Nephrology, University Hospital Essen, Essen, Germany
| | - Jürgen Treckmann
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Andreas Paul
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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Ravaioli M, Maroni L, Angeletti A, Fallani G, De Pace V, Germinario G, Odaldi F, Corradetti V, Caraceni P, Baldassarre M, Vasuri F, D'Errico A, Sangiorgi G, Siniscalchi A, Morelli MC, Rossetto A, Ranieri VM, Cescon M, Del Gaudio M, Zanfi C, Bertuzzo V, Comai G, La Manna G. Hypothermic Oxygenated Perfusion Versus Static Cold Storage for Expanded Criteria Donors in Liver and Kidney Transplantation: Protocol for a Single-Center Randomized Controlled Trial. JMIR Res Protoc 2020; 9:e13922. [PMID: 32191209 PMCID: PMC7118551 DOI: 10.2196/13922] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 12/23/2019] [Accepted: 01/07/2020] [Indexed: 12/24/2022] Open
Abstract
Background Extended criteria donors (ECD) are widely utilized due to organ shortage, but they may increase the risk of graft dysfunction and poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, allowing a redirect from anaerobic metabolism to aerobic metabolism under hypothermic conditions and protecting grafts from oxidative species–related damage. These mechanisms may improve graft function and survival. Objective With this study, we will evaluate the benefit of end-ischemic HOPE on ECD grafts for livers and kidneys as compared to static cold storage (SCS). The aim of the study is to demonstrate the ability of HOPE to improve graft function and postoperative outcomes of ECD kidney and liver recipients. Methods This is an open-label, single-center randomized clinical trial with the aim of comparing HOPE with SCS in ECD kidney and liver transplantation. In the study protocol, which has been approved by the ethics committee, 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to the HOPE group undergo machine perfusion with cold Belzer solution (4-10°C) and continuous oxygenation (partial pressure of oxygen of 500-600 mm Hg). In the control group, livers and kidneys undergoing SCS are steeped in Celsior solution and stored on ice. Using the same perfusion machine for both liver and kidney grafts, organs are perfused from the start of the back-table procedure until implantation, without increasing the cold ischemia time. For each group, we will evaluate clinical outcomes, graft function tests, histologic findings, perfusate, and the number of allocated organs. Publication of the results is expected to begin in 2021. Results Dynamic preservation methods for organs from high-risk donors should improve graft dysfunction after transplantation. To date, we have recruited 108 participants. The study is ongoing, and recruitment of participants will continue until January 2020. Conclusions The proposed preservation method should improve ECD graft function and consequently the postoperative patient outcomes. Trial Registration ClinicalTrials.gov NCT03837197; https://clinicaltrials.gov/ct2/show/NCT03837197 ; Archived by WebCite® at http://www.webcitation.org/76fSutT3R International Registered Report Identifier (IRRID) DERR1-10.2196/13922
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Affiliation(s)
- Matteo Ravaioli
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Lorenzo Maroni
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Andrea Angeletti
- Department of Experimental Diagnostic and Specialty Medicine, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Guido Fallani
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Vanessa De Pace
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Giuliana Germinario
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Federica Odaldi
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Valeria Corradetti
- Department of Experimental Diagnostic and Specialty Medicine, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Maurizio Baldassarre
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Francesco Vasuri
- Pathology Division, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Antonia D'Errico
- Pathology Division, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | | | - Antonio Siniscalchi
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Maria Cristina Morelli
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Anna Rossetto
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Vito Marco Ranieri
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Matteo Cescon
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Massimo Del Gaudio
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Chiara Zanfi
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Valentina Bertuzzo
- Department of Medical and Surgical Sciences, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Giorgia Comai
- Department of Experimental Diagnostic and Specialty Medicine, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Gaetano La Manna
- Department of Experimental Diagnostic and Specialty Medicine, University of Bologna Sant'Orsola-Malpighi Hospital, Bologna, Italy
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Roselló-Catafau J. New trends in transient hyperthermia and liver preservation. Transpl Int 2020; 33:270-271. [PMID: 31756012 DOI: 10.1111/tri.13561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 11/19/2019] [Indexed: 12/23/2022]
Affiliation(s)
- Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona, Barcelona, Catalonia, Spain
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Twenty-Four-Hour Ex Vivo Perfusion with Acellular Solution Enables Successful Replantation of Porcine Forelimbs. Plast Reconstr Surg 2020; 144:608e-618e. [PMID: 31568296 DOI: 10.1097/prs.0000000000006084] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND A critical barrier to successful limb replantation and allotransplantation is the maximum allowable limb ischemia time of 4 to 6 hours. The current gold standard is to preserve amputated limbs on an ice slurry. Experimental machine perfusion has yielded promising results as an alternative. In particular, hypothermic acellular perfusion has enabled preservation of amputated limbs for up to 12 hours thus far. METHODS Amputated forelimbs of Yorkshire pigs were preserved on static cold storage at 4°C for 4 hours (static cold storage group) or perfused at 8°C for 24 hours (perfusion group) with oxygenated modified STEEN Solution perfusate before replantation. Animals were followed up for 7 days after replantation. RESULTS Eight animals underwent replantation (cold storage group, n = 4; perfusion group, n = 4). Seventy-five and 100 percent of animals in the static cold storage and perfusion groups survived for 7 days, respectively. Glycogen and adenosine triphosphate remained stable throughout perfusion. Heart and respiratory rate after replantation were increased in the static cold storage group. There was increased damage in muscle biopsy specimens obtained from animals in the static cold storage group after 7 days when compared with those from animals in the perfusion group. CONCLUSIONS Hypothermic acellular ex vivo perfusion of limbs for up to 24 hours enables tissue preservation comparable to that obtained with conventional static cold storage for 4 hours and may reduce muscle damage and systemic reactions on limb replantation. Translation to human limbs may help improve limb replantation and allotransplantation outcomes.
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Hypothermic Oxygenated Machine Perfusion Alleviates Donation After Circulatory Death Liver Injury Through Regulating P-selectin-dependent and -independent Pathways in Mice. Transplantation 2019; 103:918-928. [PMID: 31033856 DOI: 10.1097/tp.0000000000002621] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hypothermic oxygenated machine perfusion (HOPE) has been shown to improve the quality of liver donation after circulatory death (DCD) compared to cold storage (CS). However, the mechanism by which HOPE works is unclear. In this study, a mouse liver HOPE system was developed to characterize the role of P-selectin in the protective effect of HOPE on DCD livers. METHODS A warm ischemia model of the liver and an isolated perfused liver system were established to determine a suitable flow rate for HOPE. Perfusate and tissue samples from wild-type and P-selectin knockout (KO) mice were used to determine liver function, apoptosis and necrosis rates, deoxyribonucleic acid injury and oxidative stress levels, leukocyte and endothelial cell activation, and inflammatory reactions. RESULTS A mouse liver HOPE system was successfully established. HOPE at flow rates between 0.1 and 0.5 mL/min · g were shown to have a protective effect on the DCD liver. P-selectin KO improved the quality of the DCD liver in the CS group, and reduction of P-selectin expression in the wild-type HOPE group had similar protective effects. Moreover, there was a reduction in the degree of oxidative stress and deoxyribonucleic acid injury in the P-selectin KO HOPE group compared with the P-selectin KO CS group. CONCLUSIONS We established a mouse HOPE system and determined its suitable flow. We also proved that P-selectin deficiency alleviated DCD liver injury. HOPE protected the DCD liver through regulating P-selectin-dependent and -independent pathways.
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Horn C, Minor T. Transient hyperthermia during oxygenated rewarming of isolated rat livers. Transpl Int 2019; 33:272-278. [DOI: 10.1111/tri.13542] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 09/02/2019] [Accepted: 10/15/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Charlotte Horn
- Surgical Research Department General, Visceral and Transplantation Surgery University Hospital Essen Essen Germany
| | - Thomas Minor
- Surgical Research Department General, Visceral and Transplantation Surgery University Hospital Essen Essen Germany
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Kanazawa H, Obara H, Yoshikawa R, Meng L, Hirano T, Okada Y, Nishikawa Y, Matsuno N. Impact of Machine Perfusion on Sinusoid Microcirculation of Liver Graft Donated After Cardiac Death. J Surg Res 2019; 245:410-419. [PMID: 31437648 DOI: 10.1016/j.jss.2019.07.058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 07/02/2019] [Accepted: 07/18/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND The present study examined the impact of oxygenated machine perfusion on preservation of liver grafts donated after cardiac death by measuring sinusoidal endothelial injury and microcirculatory disturbances. MATERIALS AND METHODS Fifteen porcine livers were retrieved 60 min after warm ischemia and allocated into three groups as follows: (1) CS group: static cold storage, (2) HMP group: oxygenated hypothermic perfusion preservation, (3) SNMP group: oxygenated subnormothermic perfusion preservation. The liver grafts donated after cardiac death were preserved for 4 h in different treatment conditions mentioned previously, then subject to ex vivo reperfusion for 2 h using diluted allogeneic blood. The hemodynamic parameters, liver function tests, tissue adenosine triphosphate (ATP) levels, and immunohistochemical findings were investigated. RESULTS The number of sinusoidal epithelial cells and trabecular structures were maintained after 4 h of preservation in the CS, HMP, and SNMP group. Liver tissue ATP levels after 4 h of preservation in the HMP and SNMP groups were significantly higher compared with that in the CS group. The sinusoidal epithelial cells were significantly exfoliated to a more severe extent in the CS group than in the HMP and SNMP groups. Intrasinusoidal platelet aggregation occurred more frequently in the CS group than in the HMP and SNMP groups. CONCLUSIONS The results indicated that oxygenated machine perfusion preservation was important to prevent the depletion of tissue ATP and maintain sinusoidal homeostasis regardless of the perfusate temperature. Our findings suggest oxygenated machine perfusion preservation as an effective alternative to static cold storage.
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Affiliation(s)
- Hiroyuki Kanazawa
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa city, Hokkaido, Japan.
| | - Hiromichi Obara
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan
| | - Ryo Yoshikawa
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan
| | - Lingtong Meng
- Department of Pathology, Asahikawa Medical University, Asahikawa city, Hokkaido, Japan
| | - Toshihiko Hirano
- Department of Clinical Pharmacology, Tokyo Universiaty of Pharmacy and Life Sciences, Tokyo, Japan
| | - Yoko Okada
- Department of Pathology, Asahikawa Medical University, Asahikawa city, Hokkaido, Japan
| | - Yuji Nishikawa
- Department of Pathology, Asahikawa Medical University, Asahikawa city, Hokkaido, Japan
| | - Naoto Matsuno
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa city, Hokkaido, Japan
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Hendriks KDW, Brüggenwirth IMA, Maassen H, Gerding A, Bakker B, Porte RJ, Henning RH, Leuvenink HGD. Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation. J Transl Med 2019; 17:265. [PMID: 31409351 PMCID: PMC6693148 DOI: 10.1186/s12967-019-2013-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/03/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation. However, the exact effect of hypothermic kidney preservation on mitochondrial function remains unclear. METHODS We evaluated mitochondrial function [i.e. oxygen consumption and production of reactive oxygen species (ROS)] in different models (porcine kidney perfusion, isolated kidney mitochondria, and HEK293 cells) at temperatures ranging 7-37 °C. RESULTS Lowering temperature in perfused kidneys and isolated mitochondria resulted in a rapid decrease in oxygen consumption (65% at 27 °C versus 20% at 7 °C compared to normothermic). Decreased oxygen consumption at lower temperatures was accompanied by a reduction in mitochondrial ROS production, albeit markedly less pronounced and amounting only 50% of normothermic values at 7 °C. Consequently, malondialdehyde (a marker of ROS-induced lipid peroxidation) accumulated in cold stored kidneys. Similarly, low temperature incubation of kidney cells increased lipid peroxidation, which is due to a loss of ROS scavenging in the cold. CONCLUSIONS Lowering of temperature highly affects mitochondrial function, resulting in a progressive discrepancy between the lowering of mitochondrial respiration and their production of ROS, explaining the deleterious effects of hypothermia in transplantation procedures. These results highlight the necessity to develop novel strategies to decrease the formation of ROS during hypothermic organ preservation.
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Affiliation(s)
- Koen D W Hendriks
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713JZ, Groningen, The Netherlands. .,Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands.
| | - Isabel M A Brüggenwirth
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hanno Maassen
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Albert Gerding
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Barbara Bakker
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Robert H Henning
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713JZ, Groningen, The Netherlands
| | - Henri G D Leuvenink
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
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Zeng X, Wang S, Li S, Yang Y, Fang Z, Huang H, Wang Y, Fan X, Ye Q. Hypothermic oxygenated machine perfusion alleviates liver injury in donation after circulatory death through activating autophagy in mice. Artif Organs 2019; 43:E320-E332. [PMID: 31237688 DOI: 10.1111/aor.13525] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/12/2019] [Accepted: 06/13/2019] [Indexed: 12/13/2022]
Abstract
Hypothermic oxygenated machine perfusion (HOPE) is a safe and reliable method that could alleviate liver injury in donation after circulatory death (DCD). This study focuses on the role of autophagy in HOPE's protective effect on DCD liver injury. A 30-minute warm ischemic liver model was established in mice. After 4 hours of cold storage (CS), 1 hour of hypothermic machine perfusion (HMP) with 100% O2 or 100% N2 was employed. During 2 hours of reperfusion, liver tissue and perfusate were collected to evaluate liver function, oxidative stress level, apoptosis, and necrosis. Western blotting was used to explore the level of autophagy. When the liver experienced warm ischemic injury, LC3B-II expression was significantly enhanced. Compared with the CS, HOPE induced lower release of AST and ALT, as well as lower oxidative stress levels, apoptosis, and necrosis cell numbers, and led to higher tissue ATP content. Meanwhile, expression of autophagy-related proteins, such as ULK1, Atg5, and LC3B-II, increased. When oxygen was completely replaced by nitrogen, the washout effect of HMP did not activate autophagy and did not relieve DCD liver injury. When the autophagy inhibitor 3-methyladenine was used in HOPE, the protective effect of HOPE was attenuated. In conclusion, DCD liver injury activated autophagy compared with healthy liver, while HOPE alleviated DCD liver injury by increasing autophagy levels further in this mouse model. However, HMP with 100% of N2 had no beneficial effect on DCD liver injury or on autophagy levels compared with CS. The research on autophagy may provide a new strategy for alleviating DCD liver injury in clinical practice.
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Affiliation(s)
- Xianpeng Zeng
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Shengjie Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Shiyi Li
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Yunying Yang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Zehong Fang
- The Third General Surgery Department of Jiangxi Provincial People's Hospital, Organ Transplant Department of Jiangxi Provincial People's Hospital, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Honglei Huang
- Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Xiaoli Fan
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China.,Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The 3rd Xiangya Hospital of Central South University, Changsha, China
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Patrono D, Surra A, Catalano G, Rizza G, Berchialla P, Martini S, Tandoi F, Lupo F, Mirabella S, Stratta C, Salizzoni M, Romagnoli R. Hypothermic Oxygenated Machine Perfusion of Liver Grafts from Brain-Dead Donors. Sci Rep 2019; 9:9337. [PMID: 31249370 PMCID: PMC6597580 DOI: 10.1038/s41598-019-45843-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 06/06/2019] [Indexed: 02/08/2023] Open
Abstract
Hypothermic oxygenated machine perfusion (HOPE) was introduced in liver transplantation (LT) to mitigate ischemia-reperfusion injury. Available clinical data mainly concern LT with donors after circulatory-determined death, whereas data on brain-dead donors (DBD) are scarce. To assess the impact of end-ischemic HOPE in DBD LT, data on primary adult LTs performed between March 2016 and June 2018 were analyzed. HOPE was used in selected cases of donor age >80 years, apparent severe graft steatosis, or ischemia time ≥10 hours. Outcomes of HOPE-treated cases were compared with those after static cold storage. Propensity score matching (1:2) and Bayesian model averaging were used to overcome selection bias. During the study period, 25 (8.5%) out of 294 grafts were treated with HOPE. After matching, HOPE was associated with a lower severe post-reperfusion syndrome (PRS) rate (4% versus 20%, p = 0.13) and stage 2–3 acute kidney injury (AKI) (16% versus 42%, p = 0.046). Furthermore, Bayesian model averaging showed lower transaminases peak and a lower early allograft dysfunction (EAD) rate after HOPE. A steeper decline in arterial graft resistance throughout perfusion was associated with lower EAD rate. HOPE determines a significant reduction of ischemia reperfusion injury in DBD LT.
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Affiliation(s)
- Damiano Patrono
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Astrid Surra
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Giorgia Catalano
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Giorgia Rizza
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Paola Berchialla
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Silvia Martini
- Gastrohepatology Unit, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
| | - Francesco Tandoi
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Francesco Lupo
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Stefano Mirabella
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Chiara Stratta
- Anesthesia Department 2, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
| | - Mauro Salizzoni
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Renato Romagnoli
- General Surgery 2U - Liver Transplant Unit, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
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Boteon YL, Laing RW, Schlegel A, Wallace L, Smith A, Attard J, Bhogal RH, Neil DAH, Hübscher S, Perera MTPR, Mirza DF, Afford SC, Mergental H. Combined Hypothermic and Normothermic Machine Perfusion Improves Functional Recovery of Extended Criteria Donor Livers. Liver Transpl 2018; 24:1699-1715. [PMID: 30058119 PMCID: PMC6588092 DOI: 10.1002/lt.25315] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/03/2018] [Indexed: 12/23/2022]
Abstract
Hypothermic oxygenated perfusion (HOPE) and normothermic perfusion are seen as distinct techniques of ex situ machine perfusion of the liver. We aimed to demonstrate the feasibility of combining both techniques and whether it would improve functional parameters of donor livers into transplant standards. Ten discarded human donor livers had either 6 hours of normothermic perfusion (n = 5) or 2 hours of HOPE followed by 4 hours of normothermic perfusion (n = 5). Liver function was assessed according to our viability criteria; markers of tissue injury and hepatic metabolic activity were compared between groups. Donor characteristics were comparable. During the hypothermic perfusion phase, livers down-regulated mitochondrial respiration (oxygen uptake, P = 0.04; partial pressure of carbon dioxide perfusate, P = 0.04) and increased adenosine triphosphate levels 1.8-fold. Following normothermic perfusion, those organs achieved lower tissue expression of markers of oxidative injury (4-hydroxynonenal, P = 0.008; CD14 expression, P = 0.008) and inflammation (CD11b, P = 0.02; vascular cell adhesion molecule 1, P = 0.05) compared with livers that had normothermic perfusion alone. All livers in the combined group achieved viability criteria, whereas 40% (2/5) in the normothermic group failed (P = 0.22). In conclusion, this study suggests that a combined protocol of hypothermic oxygenated and normothermic perfusions might attenuate oxidative stress, tissue inflammation, and improve metabolic recovery of the highest-risk donor livers compared with normothermic perfusion alone.
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Affiliation(s)
- Yuri L. Boteon
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Richard W. Laing
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | | | - Lorraine Wallace
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | | | | | - Ricky H. Bhogal
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Desley A. H. Neil
- Department of PathologyQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
| | - Stefan Hübscher
- Department of PathologyQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
| | | | - Darius F. Mirza
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Simon C. Afford
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Hynek Mergental
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
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Jia JJ, Li JH, Xie HY, Zhou L, Zheng SS. Implementing an innovated liver ex-situ machine perfusion technology: The 2018 Joint International Congress of ILTS, ELITA and LICAGE. Hepatobiliary Pancreat Dis Int 2018; 17:283-285. [PMID: 30097405 DOI: 10.1016/j.hbpd.2018.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 07/20/2018] [Indexed: 02/05/2023]
Affiliation(s)
- Jun-Jun Jia
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian-Hui Li
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hai-Yang Xie
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin Zhou
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Preliminary Experience With Hypothermic Oxygenated Machine Perfusion in an Italian Liver Transplant Center. Transplant Proc 2018; 51:111-116. [PMID: 30736971 DOI: 10.1016/j.transproceed.2018.04.070] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/13/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Machine perfusion is increasingly utilized in liver transplantation to face the detrimental consequences of the use of extended-criteria donors. Hypothermic oxygenated machine perfusion (HOPE) appears to be more protective relative to static cold storage. Conversely, normothermic machine perfusion (NMP) allows a better graft evaluation. We describe a pilot prospective study on machine perfusion in selected grafts. METHODS HOPE was executed for all the grafts procured from donors after cardiac death (DCDs) and for livers from donors after brain death (DBDs) requiring prolonged preservation time. NMP was used when a more precise evaluation was needed. Both HOPE and NMP were performed through the portal vein and hepatic artery. RESULTS From July 2016 to November 2017, we performed 7 HOPE procedures: 5 for DCD and 2 for DBD grafts. Two livers presented with macrovesicular steatosis >30% (1 DCD and 1 DBD). HOPE lasted 240 minutes (180-320 min) with a total ischemia time of 575 minutes (410-810 min). Six grafts were successfully transplanted. One DCD graft required additional evaluation using NMP. The graft was then discarded due to extensive hepatocellular necrosis. In the post-transplant course, acute and chronic renal failure were the main complications affecting 3 and 2 recipients, respectively. In our series, steatosis was the main risk factor for kidney injury. Patient and graft survival rate was 100% and no ischemic cholangiopathies were observed after 270 days (106-582 days). CONCLUSIONS Our study confirms HOPE safety and efficacy for DCD and DBD grafts. These data are particularly significant for DCD management in the Italian setting where the mandatory 20-minute hands-off interval before death declaration further prolongs warm ischemia time.
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He W, Ye S, Zeng C, Xue S, Hu X, Zhang X, Gao S, Xiong Y, He X, Vivalda S, Li L, Wang Y, Ye Q. Hypothermic oxygenated perfusion (HOPE) attenuates ischemia/reperfusion injury in the liver through inhibition of the TXNIP/NLRP3 inflammasome pathway in a rat model of donation after cardiac death. FASEB J 2018; 32:fj201800028RR. [PMID: 29870680 DOI: 10.1096/fj.201800028rr] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hypothermic oxygenated perfusion (HOPE) is a relatively new dynamic preservation procedure that has not been widely implemented in liver transplantation despite its advantages. Improved graft protection is one such advantage offered by HOPE and has been attributed to multiple mechanisms, one of which may be the modulation of the thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The TXNIP/NLRP3 inflammasome pathway plays a critical role in sterile inflammation under oxidative stress as a result of ischemia/reperfusion injury (IRI). In the current study, we aimed to investigate the graft protection offered by HOPE and its impact on the TXNIP/NLRP3 inflammasome pathway. To simulate conditions of donation after cardiac death (DCD) liver transplantation, rat livers were exposed to 30 min of warm ischemia after cardiac arrest. Livers were then preserved under cold storage (CS) or with HOPE for 3 h. Livers were then subjected to 1 h of isolated reperfusion. Liver injuries were assessed on the isolated perfusion rat liver model system before and after reperfusion. Compared with the CS group, the HOPE group had a significant reduction in liver injury and improvement in liver function. Our findings also revealed that reperfusion injury induced liver damage and activated the TXNIP/NLRP3 inflammasome pathway in DCD rat livers. Pretreatment of DCD rat livers with HOPE inhibited the TXNIP/NLRP3 inflammasome pathway and attenuated liver IRI. Attenuation of oxidative stress as a result of HOPE led to the down-regulation of the TXNIP/NLRP3 inflammasome pathway and thus offered superior protection compared with the traditional CS method of organ preservation.-He, W., Ye, S., Zeng, C., Xue, S., Hu, X., Zhang, X., Gao, S., Xiong, Y., He, X., Vivalda, S., Li, L., Wang, Y., Ye, Q. Hypothermic oxygenated perfusion (HOPE) attenuates ischemia/reperfusion injury in the liver through inhibition of the TXNIP/NLRP3 inflammasome pathway in a rat model of donation after cardiac death.
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Affiliation(s)
- Weiyang He
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Shaojun Ye
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Cheng Zeng
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Shuai Xue
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Xiaoyan Hu
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Xingjian Zhang
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Siqi Gao
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yan Xiong
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Xueyu He
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Soatina Vivalda
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Ling Li
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yanfeng Wang
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Qifa Ye
- Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital, Wuhan University, Wuhan, China
- Transplantation Medicine Engineering and Technology Research Center, National Health Commission, The 3rd Xiangya Hospital of Central South University, Changsha, China
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van Rijn R, van Leeuwen OB, Matton APM, Burlage LC, Wiersema‐Buist J, van den Heuvel MC, de Kleine RHJ, de Boer MT, Gouw ASH, Porte RJ. Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers. Liver Transpl 2018; 24:655-664. [PMID: 29369470 PMCID: PMC5947530 DOI: 10.1002/lt.25023] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/18/2017] [Accepted: 01/07/2018] [Indexed: 12/27/2022]
Abstract
Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE-preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655-664 2018 AASLD.
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Affiliation(s)
- Rianne van Rijn
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Otto B. van Leeuwen
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Alix P. M. Matton
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Laura C. Burlage
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Janneke Wiersema‐Buist
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Marius C. van den Heuvel
- Department of Pathology, University Medical Center GroningenUniversity of Groningenthe Netherlands
| | - Ruben H. J. de Kleine
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
| | - Marieke T. de Boer
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
| | - Annette S. H. Gouw
- Department of Pathology, University Medical Center GroningenUniversity of Groningenthe Netherlands
| | - Robert J. Porte
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
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Boteon YL, Afford SC, Mergental H. Pushing the Limits: Machine Preservation of the Liver as a Tool to Recondition High-Risk Grafts. CURRENT TRANSPLANTATION REPORTS 2018; 5:113-120. [PMID: 29774176 PMCID: PMC5945712 DOI: 10.1007/s40472-018-0188-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF THE REVIEW Machine perfusion (MP) is a novel technology recently introduced in liver transplantation, redefining the current practice of organ preservation and pushing the limits of high-risk liver utilisation. This review highlights the key benefits of machine perfusion over conventional static cold storage (SCS), demonstrated in human liver research and clinical transplants. RECENT FINDINGS The first clinical trials have demonstrated both safety and feasibility of MP. The most recent transplant series and result from a randomised trial suggest the technology is superior to SCS. The key benefits include extended period of organ preservation, decreased incidence of early allograft dysfunction and reduction of biliary complications. Normothermic liver perfusion allows viability testing to guide transplantability of the highest-risk organs. This technology also provides opportunities for therapeutic interventions to improve liver function and quality in organs that are currently declined for clinical use. SUMMARY Machine perfusion is likely to transform the liver preservation pathway and to improve utilisation of high-risk grafts.
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Affiliation(s)
- Yuri L. Boteon
- Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH UK
- National Institute for Health Research, Birmingham Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Simon C. Afford
- National Institute for Health Research, Birmingham Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH UK
- National Institute for Health Research, Birmingham Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Schlegel A, Kalisvaart M, Scalera I, Laing RW, Mergental H, Mirza DF, Perera T, Isaac J, Dutkowski P, Muiesan P. The UK DCD Risk Score: A new proposal to define futility in donation-after-circulatory-death liver transplantation. J Hepatol 2018; 68:456-464. [PMID: 29155020 DOI: 10.1016/j.jhep.2017.10.034] [Citation(s) in RCA: 186] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 10/17/2017] [Accepted: 10/25/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Primary non-function and ischaemic cholangiopathy are the most feared complications following donation-after-circulatory-death (DCD) liver transplantation. The aim of this study was to design a new score on risk assessment in liver-transplantation DCD based on donor-and-recipient parameters. METHODS Using the UK national DCD database, a risk analysis was performed in adult recipients of DCD liver grafts in the UK between 2000 and 2015 (n = 1,153). A new risk score was calculated (UK DCD Risk Score) on the basis of a regression analysis. This is validated using the United Network for Organ Sharing database (n = 1,617) and our own DCD liver-transplant database (n = 315). Finally, the new score was compared with two other available prediction systems: the DCD risk scores from the University of California, Los Angeles and King's College Hospital, London. RESULTS The following seven strongest predictors of DCD graft survival were identified: functional donor warm ischaemia, cold ischaemia, recipient model for end-stage liver disease, recipient age, donor age, previous orthotopic liver transplantation, and donor body mass index. A combination of these risk factors (UK DCD risk model) stratified the best recipients in terms of graft survival in the entire UK DCD database, as well as in the United Network for Organ Sharing and in our own DCD population. Importantly, the UK DCD Risk Score significantly predicted graft loss caused by primary non-function or ischaemic cholangiopathy in the futile group (>10 score points). The new prediction model demonstrated a better C statistic of 0.79 compared to the two other available systems (0.71 and 0.64, respectively). CONCLUSIONS The UK DCD Risk Score is a reliable tool to detect high-risk and futile combinations of donor-and-recipient factors in DCD liver transplantation. It is simple to use and offers a great potential for making better decisions on which DCD graft should be rejected or may benefit from functional assessment and further optimization by machine perfusion. LAY SUMMARY In this study, we provide a new prediction model for graft loss in donation-after-circulatory-death (DCD) liver transplantation. Based on UK national data, the new UK DCD Risk Score involves the following seven clinically relevant risk factors: donor age, donor body mass index, functional donor warm ischaemia, cold storage, recipient age, recipient laboratory model for end-stage liver disease, and retransplantation. Three risk classes were defined: low risk (0-5 points), high risk (6-10 points), and futile (>10 points). This new model stratified best in terms of graft survival compared to other available models. Futile combinations (>10 points) achieved an only very limited 1- and 5-year graft survival of 37% and less than 20%, respectively. In contrast, an excellent graft survival has been shown in low-risk combinations (≤5 points). The new model is easy to calculate at the time of liver acceptance. It may help to decide which risk combination will benefit from additional graft treatment, or which DCD liver should be declined for a certain recipient.
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Affiliation(s)
- Andrea Schlegel
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - Marit Kalisvaart
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - Irene Scalera
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - Richard W Laing
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - Hynek Mergental
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - Darius F Mirza
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - Thamara Perera
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - John Isaac
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Zurich, Switzerland
| | - Paolo Muiesan
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK.
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Schlegel A, Muller X, Dutkowski P. Hypothermic Machine Preservation of the Liver: State of the Art. CURRENT TRANSPLANTATION REPORTS 2018; 5:93-102. [PMID: 29564206 PMCID: PMC5843682 DOI: 10.1007/s40472-018-0183-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW In this review, we highlight which livers may benefit from additional treatment before implantation and describe the concept of hypothermic machine liver perfusion. Furthermore, we explain why cold oxygenated perfusion concepts could potentially lead to a breakthrough in this challenging field of transplantation. Accordingly, we summarize recent clinical applications of different hypothermic perfusion approaches. RECENT FINDINGS The impact of end-ischemic, hypothermic liver perfusion in liver transplantation is currently assessed by two multicenter, randomized controlled trials. Recently, new applications of hypothermic perfusion showed promising results and recipients were protected from severe intrahepatic biliary complications, despite the use of very extended criteria grafts including donation after circulatory death livers. SUMMARY Hypothermic machine liver perfusion is beneficial for high-risk livers and protects recipients from most feared complications. Importantly, such easy approach is currently implemented in several European centers and new markers obtained from perfusate may improve the prediction of liver function in the future.
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Affiliation(s)
- Andrea Schlegel
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
- NIHR Liver Biomedical Research Unit, University Hospitals Birmingham, Birmingham, UK
| | - Xavier Muller
- Department of Surgery & Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery & Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland
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The Crosstalk between ROS and Autophagy in the Field of Transplantation Medicine. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:7120962. [PMID: 29410735 PMCID: PMC5749284 DOI: 10.1155/2017/7120962] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 09/21/2017] [Accepted: 10/08/2017] [Indexed: 12/17/2022]
Abstract
Many factors during the transplantation process influence posttransplant graft function and survival, including donor type and age, graft preservation methods (cold storage, machine perfusion), and ischemia-reperfusion injury. Successively, they will lead to cellular and molecular alterations that determine cell and ultimately organ fate. Oxidative stress and autophagy are implicated in posttransplant outcome since they are both affected by the stress responses triggered in each step (donor, preservation, and recipient) of the transplantation process. Furthermore, oxidative stress influences autophagy and vice versa. Interestingly, both processes have positive as well as negative effects on graft outcome, suggesting they are tightly linked during the transplantation process. In this review, we discuss the importance, regulation and crosstalk of oxidative signals, and autophagy in the field of transplantation medicine.
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Krezdorn N, Tasigiorgos S, Wo L, Turk M, Lopdrup R, Kiwanuka H, Win TS, Bueno E, Pomahac B. Tissue conservation for transplantation. Innov Surg Sci 2017; 2:171-187. [PMID: 31579751 PMCID: PMC6754021 DOI: 10.1515/iss-2017-0010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023] Open
Abstract
Pathophysiological changes that occur during ischemia and subsequent reperfusion cause damage to tissues procured for transplantation and also affect long-term allograft function and survival. The proper preservation of organs before transplantation is a must to limit these injuries as much as possible. For decades, static cold storage has been the gold standard for organ preservation, with mechanical perfusion developing as a promising alternative only recently. The current literature points to the need of developing dedicated preservation protocols for every organ, which in combination with other interventions such as ischemic preconditioning and therapeutic additives offer the possibility of improving organ preservation and extending it to multiple times its current duration. This review strives to present an overview of the current body of knowledge with regard to the preservation of organs and tissues destined for transplantation.
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Affiliation(s)
- Nicco Krezdorn
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Hannover Medical School, Hannover, Germany
| | - Sotirios Tasigiorgos
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Luccie Wo
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Marvee Turk
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Rachel Lopdrup
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Harriet Kiwanuka
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Thet-Su Win
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Ericka Bueno
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Bohdan Pomahac
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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Role of temperature in reconditioning and evaluation of cold preserved kidney and liver grafts. Curr Opin Organ Transplant 2017; 22:267-273. [PMID: 28266940 PMCID: PMC5617555 DOI: 10.1097/mot.0000000000000402] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of review Organ shortage in transplantation medicine forces surgical research toward the development of more efficient approaches in organ preservation to enable the application of ‘less than optimal’ grafts. This review summarizes current techniques aiming to recondition cold-stored organ grafts prior to transplantation to reduce reperfusion-induced tissue injury and improve postimplantation graft function. Recent findings End-ischemic reconditioning has classically been attempted by cold oxygenated perfusion. By contrast, evaluation of graft performance prior to transplantation might be facilitated by perfusion at higher temperatures, ideally at normothermia. A drastic temperature shift from cold preservation to warm perfusion, however, has been incriminated to trigger a so-called rewarming injury associated with mitochondrial alterations. A controlled gradual warming up during machine perfusion could enhance the restitution of cellular homeostasis and improve functional outcome upon warm reperfusion. Summary Machine perfusion after conventional cold storage is beneficial for ulterior function after transplantation. Cold grafts should be initially perfused at low temperatures allowing for restitution of cellular homeostasis under protective hypothermic limitation of metabolic turnover. Delayed slow rewarming of the organ might further mitigate rewarming injury upon reperfusion and also increases the predictive power of evaluative measures, taken during pretransplant perfusion.
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Abstract
PURPOSE OF THE REVIEW The purpose of the review is to report recent human application of hypothermic machine liver perfusion, and to discuss potential protective mechanisms. RECENT FINDINGS Human application of hypothermic machine liver perfusion is still very limited. Currently, three transplant centers apply this novel treatment in donation after cardiac death (DCD) or donation after brain death (DBD) liver grafts. In all cases, endischemic perfusion was performed after initial cold storage for organ transport. Perfusion conditions differ slightly in terms of oxygenation (pO2 15-60 kPa), perfusion route (dual vs. portal), perfusion time (2-4 h), and perfusate. SUMMARY The current data support the hypothesis that applying endischemic hypothermic machine liver perfusion protects extended criteria DBD and DCD livers from initial reperfusion injury, with better graft function and less biliary complications. Hypothermic machine perfusion may therefore offer revitalization of liver grafts before implantation by a simple and practical perfusion technique with a high impact on enlarging the donor pool. Multicentric phase III randomized control trials in DBD and DCD liver transplantation have been initiated to further test this strategy, which may establish machine liver perfusion in the clinical setting.
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Patrono D, Lavezzo B, Molinaro L, Rizza G, Catalano G, Gonella F, Salizzoni M, Romagnoli R. Hypothermic Oxygenated Machine Perfusion for Liver Transplantation: An Initial Experience. EXP CLIN TRANSPLANT 2017; 16:172-176. [PMID: 29108514 DOI: 10.6002/ect.2016.0347] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Due to widespread exploitation of extended criteria donors, machine perfusion is emerging as an alternative to static cold storage for organ preservation. Hypothermic oxygenated machine perfusion has been associated with improved outcomes after liver transplant, both in laboratory and clinical settings. Here, we present our initial experience with hypothermic oxygenated machine perfusion, evaluating incidence of postreperfusion syndrome, early allograft dysfunction, and long-term biliary complications. MATERIALS AND METHODS End-ischemic dual (hepatic artery and portal vein) hypothermic oxygenated machine perfusion was carried out for 150 to 200 minutes before organ implantation in 4 liver transplants considered at increased risk due to donor, recipient, or matching issues. RESULTS No device malfunction occurred. Theatre logistics were minimally affected. Incidences of post-reperfusion syndrome and early allograft dysfunction were 25% and 50%. At 6-month follow-up, all patients were alive with normal hepatic function and no evidence of ischemic cholangiopathy. CONCLUSIONS In our experience, hypothermic oxygenated machine perfusion appeared safe and logistically simple. Further studies are needed to assess the real value of this technique and to identify which subset of patients would benefit from its implementation.
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Affiliation(s)
- Damiano Patrono
- From the Department of General Surgery, Liver Transplant Center, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
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Czigany Z, Schöning W, Ulmer TF, Bednarsch J, Amygdalos I, Cramer T, Rogiers X, Popescu I, Botea F, Froněk J, Kroy D, Koch A, Tacke F, Trautwein C, Tolba RH, Hein M, Koek GH, Dejong CHC, Neumann UP, Lurje G. Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): a prospective multicentre randomised controlled trial (HOPE ECD-DBD). BMJ Open 2017; 7:e017558. [PMID: 29018070 PMCID: PMC5652559 DOI: 10.1136/bmjopen-2017-017558] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. In an attempt to improve the availability of donor allografts and reduce waiting list mortality, graft acceptance criteria were extended increasingly over the decades. The use of extended criteria donor (ECD) allografts is associated with a higher incidence of primary graft non-function and/or delayed graft function. As such, several strategies have been developed aiming at reconditioning poor quality ECD liver allografts. Hypothermic oxygenated machine perfusion (HOPE) has been successfully tested in preclinical experiments and in few clinical series of donation after cardiac death OLT. METHODS AND ANALYSIS HOPE ECD-DBD is an investigator-initiated, open-label, phase-II, prospective multicentre randomised controlled trial on the effects of HOPE on ECD allografts in donation after brain death (DBD) OLT. Human whole organ liver grafts will be submitted to 1-2 hours of HOPE (n=23) via the portal vein before implantation and are going to be compared with a control group (n=23) of patients transplanted after conventional cold storage. Primary (peak and Δ peak alanine aminotransferase within 7 days) and secondary (aspartate aminotransferase, bilirubin and international normalised ratio, postoperative complications, early allograft dysfunction, duration of hospital and intensive care unit stay, 1-year patient and graft survival) endpoints will be analysed within a 12-month follow-up. Extent of ischaemia-reperfusion (I/R) injury will be assessed using liver tissue, perfusate, bile and serum samples taken during the perioperative phase of OLT. ETHICS AND DISSEMINATION The study was approved by the institutional review board of the RWTH Aachen University, Aachen, Germany (EK 049/17). The current paper represent the pre-results phase. First results are expected in 2018. TRIAL REGISTRATION NUMBER NCT03124641.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Wenzel Schöning
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Thorsten Cramer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Xavier Rogiers
- Department of Solid Organ Transplantation, Ghent University Hospital and Medical School, Ghent, Belgium
| | - Irinel Popescu
- Department of General Surgery and Liver transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Florin Botea
- Department of General Surgery and Liver transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Jiří Froněk
- Department of Transplantation Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Daniela Kroy
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Alexander Koch
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Rene H Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Marc Hein
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ger H Koek
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Cornelis H C Dejong
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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von Horn C, Baba HA, Hannaert P, Hauet T, Leuvenink H, Paul A, Minor T. Controlled oxygenated rewarming up to normothermia for pretransplant reconditioning of liver grafts. Clin Transplant 2017; 31. [PMID: 28871615 DOI: 10.1111/ctr.13101] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2017] [Indexed: 12/15/2022]
Abstract
Controlled oxygenated rewarming (COR) up to 20°C during ex vivo machine perfusion limits reperfusion-induced tissue injury upon graft implantation. Rewarming up to normothermia might add further benefits and provide better prediction of post-transplantation organ function. The effect of 90 minutes of oxygenated machine perfusion with Aqix RS-I after cold storage combined with gentle rewarming up to 20°C (COR20) or 35°C (COR35) was studied in rat livers and compared with cold storage alone (CS, n = 6, resp). Postpreservation recovery was evaluated upon warm reperfusion using an established in vitro system. COR generally resulted in significantly improved energetic recovery, increased bile flow, less activities alanine aminotransferase (ALT) release, and improved histopathology upon reperfusion as compared to only cold-stored livers, without significant differences between COR20 and COR35. Parameters obtained during COR, especially during COR35, also allowed for prediction of hepatic recovery upon reperfusion. For instance, ulterior bile production upon reperfusion was found closely correlated to bile flow observed already during COR35 (R2 = 0.91). COR significantly improved liver quality after static cold storage. Elevation of machine perfusion temperature up to 35°C may prove promising to refine ex vivo evaluation of the graft prior to transplantation.
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Affiliation(s)
- Charlotte von Horn
- Department for Surgical Research, General Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University Hospital Essen, Essen, Germany
| | - Patrik Hannaert
- RTOMIT, INSERM, Université de Médecine et de Pharmacie de Poitiers, Poitiers, France
| | - Thierry Hauet
- RTOMIT, INSERM, Université de Médecine et de Pharmacie de Poitiers, Poitiers, France
| | - Henri Leuvenink
- Department of Surgery, University Medical Center Groningen, The Netherlands
| | - Andreas Paul
- Department for Surgical Research, General Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Thomas Minor
- Department for Surgical Research, General Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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An Oxygenated and Transportable Machine Perfusion System Fully Rescues Liver Grafts Exposed to Lethal Ischemic Damage in a Pig Model of DCD Liver Transplantation. Transplantation 2017; 101:e205-e213. [PMID: 28403128 DOI: 10.1097/tp.0000000000001764] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Control of warm ischemia (WI) lesions that occur with donation after circulatory death (DCD) would significantly increase the donor pool for liver transplantation. We aimed to determine whether a novel, oxygenated and hypothermic machine perfusion device (HMP Airdrive system) improves the quality of livers derived from DCDs using a large animal model. METHODS Cardiac arrest was induced in female large white pigs by intravenous injection of potassium chloride. After 60 minutes of WI, livers were flushed in situ with histidine-tryptophan-ketoglutarate and subsequently preserved either by simple cold storage (WI-SCS group) or HMP (WI-HMP group) using Belzer-MPS solution. Liver grafts procured from heart-beating donors and preserved by SCS served as controls. After 4 hours of preservation, all livers were transplanted. RESULTS All recipients in WI-SCS group died within 6 hours after transplantation. In contrast, the HMP device fully protected the liver against lethal ischemia/reperfusion injury, allowing 100% survival rate. A postreperfusion syndrome was observed in all animals of the WI-SCS group but none of the control or WI-HMP groups. After reperfusion, HMP-preserved livers functioned better and showed less hepatocellular and endothelial cell injury, in agreement with better-preserved liver histology relative to WI-SCS group. In addition to improved energy metabolism, this protective effect was associated with an attenuation of inflammatory response, oxidative load, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. CONCLUSIONS This study demonstrates for the first time the efficacy of the HMP Airdrive system to protect liver grafts from lethal ischemic damage before transplantation in a clinically relevant DCD model.
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Short, Cool, and Well Oxygenated - HOPE for Kidney Transplantation in a Rodent Model. Ann Surg 2017; 264:815-822. [PMID: 27584571 DOI: 10.1097/sla.0000000000001766] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVES The aim of this study was to investigate novel and easily applicable preservation perfusion techniques in kidney grafts obtained from donors after circulatory death (DCD). BACKGROUND A novel perfusion approach, hypothermic oxygenated perfusion (HOPE), used for DCD liver grafts, is based on cold perfusion for 1 hour by an oxygenated solution before implantation. Here, we aimed to test HOPE in a rodent model of kidney grafts associated with substantial warm ischemia. METHODS Rat kidneys were exposed to 30 minutes in situ warm ischemia, without application of heparin. Kidneys were removed and cold stored for 4 and 18 hours, mimicking DCD organ procurement and conventional preservation. In additional experiments, kidneys were normothermically perfused with oxygenated blood for 1 hour after cold storage. In a third group, kidneys were perfused by HOPE for 1 hour after cold storage. In each group, orthotopic kidney transplantation was performed after recipient nephrectomy. RESULTS HOPE-treated DCD kidneys showed dramatically better function after transplantation, than cold-stored grafts in terms of nuclear injury, macrophage activation, endothelium activation, tubulus damage, and graft function. A short period of warm oxygenated perfusion before implantation improved graft quality as compared with cold storage, but was significantly less effective in all endpoints compared with HOPE. The effect of HOPE was dependent on perfusate oxygenation in the cold. CONCLUSIONS HOPE of DCD kidneys was superior to other clinically used preservation approaches, consistent to earlier results in livers. On the basis of this, we assume a strong and generalized effect on solid organ viability by HOPE before transplantation. These results justify a clinical trial.
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