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1
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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: 0] [Impact Index Per Article: 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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2
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Parente A, Flores Carvalho M, Schlegel A. Endothelial Cells and Mitochondria: Two Key Players in Liver Transplantation. Int J Mol Sci 2023; 24:10091. [PMID: 37373238 PMCID: PMC10298511 DOI: 10.3390/ijms241210091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/30/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Building the inner layer of our blood vessels, the endothelium forms an important line communicating with deeper parenchymal cells in our organs. Previously considered passive, endothelial cells are increasingly recognized as key players in intercellular crosstalk, vascular homeostasis, and blood fluidity. Comparable to other cells, their metabolic function strongly depends on mitochondrial health, and the response to flow changes observed in endothelial cells is linked to their mitochondrial metabolism. Despite the direct impact of new dynamic preservation concepts in organ transplantation, the impact of different perfusion conditions on sinusoidal endothelial cells is not yet explored well enough. This article therefore describes the key role of liver sinusoidal endothelial cells (LSECs) together with their mitochondrial function in the context of liver transplantation. The currently available ex situ machine perfusion strategies are described with their effect on LSEC health. Specific perfusion conditions, including perfusion pressure, duration, and perfusate oxygenation are critically discussed considering the metabolic function and integrity of liver endothelial cells and their mitochondria.
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Affiliation(s)
- Alessandro Parente
- HPB and Transplant Unit, Department of Surgical Science, University of Rome Tor Vergata, 00133 Rome, Italy;
- Division of Hepatobiliary and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Mauricio Flores Carvalho
- Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy;
| | - Andrea Schlegel
- Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy;
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
- Transplantation Center, Digestive Disease and Surgery Institute, Department of Immunity and Inflammation, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
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Banker A, Bhatt N, Rao PS, Agrawal P, Shah M, Nayak M, Mohanka R. A Review of Machine Perfusion Strategies in Liver Transplantation. J Clin Exp Hepatol 2023; 13:335-349. [PMID: 36950485 PMCID: PMC10025749 DOI: 10.1016/j.jceh.2022.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/26/2022] [Accepted: 08/02/2022] [Indexed: 02/17/2023] Open
Abstract
The acceptance of liver transplantation as the standard of care for end-stage liver diseases has led to a critical shortage of donor allografts. To expand the donor organ pool, many countries have liberalized the donor criteria including extended criteria donors and donation after circulatory death. These marginal livers are at a higher risk of injury when they are preserved using the standard static cold storage (SCS) preservation techniques. In recent years, research has focused on optimizing organ preservation techniques to protect these marginal livers. Machine perfusion (MP) of the expanded donor liver has witnessed considerable advancements in the last decade. Research has showed MP strategies to confer significant advantages over the SCS techniques, such as longer preservation times, viability assessment and the potential to recondition high risk allografts prior to implantation. In this review article, we address the topic of MP in liver allograft preservation, with emphasis on current trends in clinical application. We discuss the relevant clinical trials related to the techniques of hypothermic MP, normothermic MP, hypothermic oxygenated MP, and controlled oxygenated rewarming. We also discuss the potential applications of ex vivo therapeutics which may be relevant in the future to further optimize the allograft prior to transplantation.
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Key Words
- ALP, Alkaline phosphatase
- ALT, Alanine transaminase
- ASO, Antisense oligonucleotides
- AST, Aspartate transaminase
- CIT, Cold ischemia times
- COPE, Consortium for Organ Preservation in Europe
- COR, Controlled oxygenated rewarming
- DBD, Donation after brain death
- DCD, Donation after circulatory death
- DHOPE, dual hypothermic oxygenated machine perfusion
- EAD, Early allograft dysfunction
- ECD, Extended criteria donors
- ETC, Electron transport chain
- GGT, Gamma glutamyl transferase
- HCV, Hepatitis C virus
- HMP, Hypothermic machine perfusion
- HOPE, Hypothermic oxygenated machine perfusion
- ICU, Intensive care unit
- IGL, Institute George Lopez-1
- INR, International normalized ratio
- IRI, ischemia reperfusion injury
- LDH, Lactate dehydrogenase
- MELD, Model for end-stage liver disease
- MP, Machine perfusion
- NAS, Non-anastomotic biliary strictures
- NMP, Normothermic machine perfusion
- NO, Nitric oxide
- PNF, Primary nonfunction
- ROS, Reactive oxygen species
- RT-PCR, Reverse transcription polymerase chain reaction
- SNMP, Sub-normothermic machine perfusion
- UW, University of Wisconsin
- WIT, Warm ischemia times
- hypothermic machine perfusion
- hypothermic oxygenated machine perfusion
- machine perfusion
- normothermic machine perfusion
- static cold storage
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Affiliation(s)
- Amay Banker
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Neha Bhatt
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Prashantha S. Rao
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Pravin Agrawal
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Mitul Shah
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Madhavi Nayak
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Ravi Mohanka
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
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Shen C, Cheng H, Zong T, Zhu H. The role of normothermic machine perfusion (NMP) in the preservation of ex-vivo liver before transplantation: A review. Front Bioeng Biotechnol 2023; 11:1072937. [PMID: 36845187 PMCID: PMC9947506 DOI: 10.3389/fbioe.2023.1072937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/31/2023] [Indexed: 02/11/2023] Open
Abstract
The discrepancy between the number of patients awaiting liver transplantation and the number of available donors has become a key issue in the transplant setting. There is a limited access to liver transplantation, as a result, it is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. However, there are still many unknown risks associated with the use of ECD, among which preservation before liver transplantation is important in determining whether patients would experience complications survive after liver transplantation. In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion (NMP) may reduce preservation injury, improve graft viability, and potentially ex vivo assessment of graft viability before transplantation. Data seem to suggest that NMP can enhance the preservation of liver transplantation to some extent and improve the early outcome after transplantation. In this review, we provided an overview of NMP and its application in ex vivo liver preservation and pre-transplantation, and we summarized the data from current clinical trials of normothermic liver perfusion.
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Affiliation(s)
- Chuanyan Shen
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Hongwei Cheng
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Tingting Zong
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
| | - Hongli Zhu
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China,National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, China,Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, China,*Correspondence: Hongli Zhu,
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Łuczykowski K, Warmuzińska N, Kollmann D, Selzner M, Bojko B. Biliary Metabolome Profiling for Evaluation of Liver Metabolism and Biliary Tract Function Related to Organ Preservation Method and Degree of Ischemia in a Porcine Model. Int J Mol Sci 2023; 24:2127. [PMID: 36768452 PMCID: PMC9916698 DOI: 10.3390/ijms24032127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 01/25/2023] Open
Abstract
The development of surgical techniques, immunosuppressive strategies and new organ preservation methods have meant that transplant centers have to face the problem of an insufficient number of organs for transplantation concerning the constantly growing demand. Therefore, using organs from expanded criteria donors and developing new analytical solutions to find parameters or compounds that would allow a more efficient assessment of organ quality before transplantation are options for meeting this challenge. This study proposed bile metabolomic analysis to evaluate liver metabolism and biliary tract function depending on the organ preservation method and degree of warm ischemia time. The analyses were performed on solid-phase microextraction-prepared bile samples from porcine model donors with mild (heart beating donor [HBD]) and moderate warm ischemia (donation after circulatory death [DCD]) grafts subjected to static cold storage (SCS) or normothermic ex vivo liver perfusion (NEVLP) before transplantation. Bile produced in the SCS-preserved livers was characterized by increased levels of metabolites such as chenodeoxycholic acid, arachidonic acid and 5S-hydroxyeicosatetraeonic acid, as well as saturated and monounsaturated lysophosphatidylcholines (LPC). Such changes may be associated with differences in the bile acid synthesis pathways and organ inflammation. Moreover, it has been shown that NEVLP reduced the negative effect of ischemia on organ function. A linear relationship was observed between levels of lipids from the LPC group and the time of organ ischemia. This study identified metabolites worth considering as potential markers of changes occurring in preserved grafts.
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Affiliation(s)
- Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-089 Bydgoszcz, Poland
| | - Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-089 Bydgoszcz, Poland
| | - Dagmar Kollmann
- Department of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Markus Selzner
- Department of Surgery, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-089 Bydgoszcz, Poland
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Danion J, Thuillier R, Allain G, Bruneval P, Tomasi J, Pinsard M, Hauet T, Kerforne T. Evaluation of Liver Quality after Circulatory Death Versus Brain Death: A Comparative Preclinical Pig Model Study. Int J Mol Sci 2020; 21:ijms21239040. [PMID: 33261172 PMCID: PMC7730280 DOI: 10.3390/ijms21239040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/14/2020] [Accepted: 11/21/2020] [Indexed: 02/07/2023] Open
Abstract
The current organ shortage in hepatic transplantation leads to increased use of marginal livers. New organ sources are needed, and deceased after circulatory death (DCD) donors present an interesting possibility. However, many unknown remains on these donors and their pathophysiology regarding ischemia reperfusion injury (IRI). Our hypothesis was that DCD combined with abdominal normothermic regional recirculation (ANOR) is not inferior to deceased after brain death (DBD) donors. We performed a mechanistic comparison between livers from DBD and DCD donors in a highly reproducible pig model, closely mimicking donor conditions encountered in the clinic. DCD donors were conditioned by ANOR. We determined that from the start of storage, pro-lesion pathways such as oxidative stress and cell death were induced in both donor types, but to a higher extent in DBD organs. Furthermore, pro-survival pathways, such as resistance to hypoxia and regeneration showed activation levels closer to healthy livers in DCD-ANOR rather than in DBD organs. These data highlight critical differences between DBD and DCD-ANOR livers, with an apparent superiority of DCD in terms of quality. This confirms our hypothesis and further confirms previously demonstrated benefits of ANOR. This encourages the expended use of DCD organs, particularly with ANOR preconditioning.
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Affiliation(s)
- Jérôme Danion
- Inserm U1082, F-86000 Poitiers, France; (J.D.); (R.T.); (G.A.); (T.K.)
- Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France
- CHU de Poitiers, Service de Chirurgie Générale et Endocrinienne, F-86021 Poitiers, France
| | - Raphael Thuillier
- Inserm U1082, F-86000 Poitiers, France; (J.D.); (R.T.); (G.A.); (T.K.)
- Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France
- CHU Poitiers, Service de Biochimie, F-86021 Poitiers, France
| | - Géraldine Allain
- Inserm U1082, F-86000 Poitiers, France; (J.D.); (R.T.); (G.A.); (T.K.)
- Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France
- CHU Poitiers, Service de Chirurgie Cardiothoracique et Vasculaire, F-86021 Poitiers, France;
| | - Patrick Bruneval
- Hôpital Européen Georges Pompidou, Service D’anatomie Pathologique, F-75015 Paris, France;
- Faculté de Médecine, Université Paris-Descartes, F-75006 Paris, France
| | - Jacques Tomasi
- CHU Poitiers, Service de Chirurgie Cardiothoracique et Vasculaire, F-86021 Poitiers, France;
| | - Michel Pinsard
- CHU Poitiers, Service de Réanimation Chirurgie Cardio-Thoracique et Vasculaire, Coordination des P.M.O., F-86021 Poitiers, France;
| | - Thierry Hauet
- Inserm U1082, F-86000 Poitiers, France; (J.D.); (R.T.); (G.A.); (T.K.)
- Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France
- CHU Poitiers, Service de Biochimie, F-86021 Poitiers, France
- Fédération Hospitalo-Universitaire SUPORT, F-86000 Poitiers, France
- IBiSA Plateforme ‘Plate-Forme MOdélisation Préclinique—Innovation Chirurgicale et Technologique (MOPICT)’, Domaine Expérimental du Magneraud, F-17700 Surgères, France
- Pr. Thierry HAUET, INSERM U1082, CHU de Poitiers, 2 rue de la Miletrie, CEDEX BP 577, 86021 Poitiers, France
- Correspondence: ; Tel.: +33-5-49-44-48-29; Fax: +33-5-49-44-38-34
| | - Thomas Kerforne
- Inserm U1082, F-86000 Poitiers, France; (J.D.); (R.T.); (G.A.); (T.K.)
- Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France
- CHU Poitiers, Service de Réanimation Chirurgie Cardio-Thoracique et Vasculaire, Coordination des P.M.O., F-86021 Poitiers, France;
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7
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Normothermic Ex Vivo Liver Perfusion Prevents Intrahepatic Platelet Sequestration After Liver Transplantation. Transplantation 2020; 104:1177-1186. [PMID: 32091485 DOI: 10.1097/tp.0000000000003194] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The detrimental role of platelets in sinusoidal endothelial cell (SEC) injury during liver transplantation (LT) has been previously addressed after static cold storage (SCS), however, it is currently unknown after normothermic ex vivo liver perfusion (NEVLP). METHODS Pig LT was performed with livers from heart-beating donors or donation after circulatory death (DCD) donors subjected to SCS or NEVLP (n = 5/group). RESULTS All pigs except for 1 (DCD-SCS-group) survived 4 days. The heart-beating donor- and DCD-NEVLP-groups showed significantly lower aspartate transaminase-levels compared with the SCS-groups 3 hours post-LT (P = 0.006), on postoperative day (POD) 2 (P = 0.005), POD3 (P = 0.007), and on POD4 (P = 0.012). Post-LT total platelet count recovered faster in the NEVLP than in the SCS-groups at 12 hours (P = 0.023) and 24 hours (P = 0.0038). Intrahepatic sequestration of platelets was significantly higher in the SCS-groups 3 hours postreperfusion and correlated with severity of SEC injury. In both SCS-groups, levels of tumor growth factor-β were higher 3 hours post-LT, on POD1 and on POD3. Moreover, platelet factor 4 levels and platelet-derived extracellular vesicles were increased in the SCS-groups. Hyaluronic acid levels were significantly higher in the SCS-groups, indicating a higher grade of endothelial cell dysfunction. Platelet inhibition achieved by pretreatment with clopidogrel (n = 3) partly reversed the detrimental effects on SEC injury and therefore provided further evidence of the important role of platelets in ischemia/reperfusion injury and SEC injury. CONCLUSIONS Normothermic perfusion of liver grafts before transplantation effectively reduced platelet aggregation and SEC injury, which translated into an improved posttransplant organ function.
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8
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Buchwald JE, Xu J, Bozorgzadeh A, Martins PN. Therapeutics administered during ex vivo liver machine perfusion: An overview. World J Transplant 2020; 10:1-14. [PMID: 32110510 PMCID: PMC7031625 DOI: 10.5500/wjt.v10.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/26/2019] [Accepted: 12/06/2019] [Indexed: 02/06/2023] Open
Abstract
Although the use of extended criteria donors has increased the pool of available livers for transplant, it has also introduced the need to develop improved methods of protection against ischemia-reperfusion injury (IRI), as these "marginal" organs are particularly vulnerable to IRI during the process of procurement, preservation, surgery, and post-transplantation. In this review, we explore the current basic science research investigating therapeutics administered during ex vivo liver machine perfusion aimed at mitigating the effects of IRI in the liver transplantation process. These various categories of therapeutics are utilized during the perfusion process and include invoking the RNA interference pathway, utilizing defatting cocktails, and administering classes of agents such as vasodilators, anti-inflammatory drugs, human liver stem cell-derived extracellular vesicles, and δ-opioid agonists in order to reduce the damage of IRI. Ex vivo machine perfusion is an attractive alternative to static cold storage due to its ability to continuously perfuse the organ, effectively deliver substrates and oxygen required for cellular metabolism, therapeutically administer pharmacological or cytoprotective agents, and continuously monitor organ viability during perfusion. The use of administered therapeutics during machine liver perfusion has demonstrated promising results in basic science studies. While novel therapeutic approaches to combat IRI are being developed through basic science research, their use in clinical medicine and treatment in patients for liver transplantation has yet to be explored.
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Affiliation(s)
- Julianna E Buchwald
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Jing Xu
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Adel Bozorgzadeh
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Paulo N Martins
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
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9
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Ex Situ Liver Machine Perfusion as an Emerging Graft Protective Strategy in Clinical Liver Transplantation: the Dawn of a New Era. Transplantation 2019; 103:2003-2011. [DOI: 10.1097/tp.0000000000002772] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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10
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Obara H, Morito N, Matsuno N, Yoshikawa R, Nakajo T, Gochi M, Otani M, Shonaka T, Furukawa H, Hirano T, Enosawa S. Initial perfusate purification during subnormothermic machine perfusion for porcine liver donated after cardiac death. J Artif Organs 2019; 23:62-69. [PMID: 31392524 DOI: 10.1007/s10047-019-01123-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 07/29/2019] [Indexed: 01/19/2023]
Abstract
Improvement of machine perfusion (MP) technologies is required to enhance organ quality for donor after cardiac death (DCD) grafts. Installing a dialyzer or a filter into the perfusion circuit to maintain the perfusate condition has some advantages. However, the consequences of purification perfusate during subnormothermic machine perfusion (SNMP) remain unexplained. In this study, the effects of initial purification perfusate with simple method of replacing the first 0.5-L perfusate during SNMP were investigated to consider installation effect of the filter or the dialyzer. Porcine liver grafts, which have 60-min warm ischemia time, were procured to imitate the DCD graft condition. Purified SNMP (PSNMP) results were compared with simple cold storage and conventional SNMP. In PSNMP, initial perfusate of 0.5 L was removed to substitute for purification. After preservation process, the preserved grafts were reperfused with diluted autologous blood for 2 h under normothermic machine perfusion condition to evaluate the liver function using an isolated reperfusion model. The vascular pressures, enzyme release rates and the metabolic indexes during reperfusion were analyzed. The pressures in the hepatic artery after reperfusion 60 min were significantly lower in PSNMP group compared with cold storage (CS) and SNMP groups. In addition, lactate dehydrogenase and alkaline phosphatase were significantly lower after PSNMP than after the CS or SNMP. Also, the metabolic indexes of hyaluronic acid and lactate were significantly decreased by purifying the perfusate in MP preservation than in CS or SNMP. The effectiveness of initial purification perfusate during SNMP was investigated.
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Affiliation(s)
- Hiromichi Obara
- Department of Mechanical Engineering, Tokyo Metropolitan University, 1-1 Minam Osawa, Hachioji, Tokyo, 192-0397, Japan. .,Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, Hokkaido, 078-8510, Japan. .,National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
| | - Noriyuki Morito
- Department of Mechanical Engineering, Tokyo Metropolitan University, 1-1 Minam Osawa, Hachioji, Tokyo, 192-0397, Japan
| | - Naoto Matsuno
- Department of Mechanical Engineering, Tokyo Metropolitan University, 1-1 Minam Osawa, Hachioji, Tokyo, 192-0397, Japan.,Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, Hokkaido, 078-8510, Japan.,National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Ryo Yoshikawa
- Department of Mechanical Engineering, Tokyo Metropolitan University, 1-1 Minam Osawa, Hachioji, Tokyo, 192-0397, Japan
| | - Tetsuya Nakajo
- Veterinary Teaching Hospital, Azabu University, 1-17-71 Fuchinobe, Chuo, Sagamihara, Kanagawa, 252-5201, Japan
| | - Mikako Gochi
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Masahide Otani
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Tatsuya Shonaka
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Hiroyuki Furukawa
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Toshihiko Hirano
- Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Shin Enosawa
- National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
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11
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Bral M, Dajani K, Leon Izquierdo D, Bigam D, Kneteman N, Ceresa CDL, Friend PJ, Shapiro AMJ. A Back-to-Base Experience of Human Normothermic Ex Situ Liver Perfusion: Does the Chill Kill? Liver Transpl 2019; 25:848-858. [PMID: 30938039 DOI: 10.1002/lt.25464] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 03/09/2019] [Indexed: 12/24/2022]
Abstract
Normothermic machine perfusion (NMP) has been shown to protect livers from injury between procurement and transplantation in a randomized controlled trial, where the machine was transported to and from the donor center. The aim of this study was to determine whether an alternative, more practical back-to-base approach after initial static cold storage would compromise beneficial outcomes. Between February 2015 and June 2018, a nonrandomized pilot study was performed at a single site. Outcomes of back-to-base livers (n = 26) were compared with those of grafts procured locally that underwent immediate NMP (n = 17). The primary outcome measure (safety) was defined as 30-day patient and graft survival. A total of 46 liver grafts were perfused with NMP, of which 3 were discarded based on poor ex situ perfusion function. The 30-day patient and graft survival in the back-to-base and local NMP groups were both 100% (primary outcome: safety). Despite significantly prolonged mean cold ischemia time (6 versus 3.2 hours; P = 0.001), the back-to-base livers demonstrated no difference in graft function, incidence of complications, or graft and patient survival. In conclusion, the back-to-base approach was safe, did not compromise the overall benefit of NMP, and offers a practical alternative to portable normothermic ex situ machine transport.
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Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Khaled Dajani
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | | - David Bigam
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Norman Kneteman
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Carlo D L Ceresa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.,OrganOx Ltd., Oxford, United Kingdom
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Gorgen A, Prediger C, Prediger JE, Chedid MF, Backes AN, de Araujo A, Grezzana-Filho TJM, Leipnitz I, Chedid AD, Alvares-da-Silva MR, Sapisochin G, Kruel CRP. Serum Factor V Is a Continuous Biomarker of Graft Dysfunction and a Predictor of Graft Loss After Liver Transplantation. Transplantation 2019; 103:944-951. [PMID: 30130328 DOI: 10.1097/tp.0000000000002429] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Factor V has never been compared to a validated early allograft dysfunction (EAD) definition. We aimed to assess factor V as a biomarker of EAD and a predictor of graft loss after liver transplantation (LT). METHODS We retrospectively assessed the serum factor V levels on postoperative day 1 after LT. Patients were divided according to their factor V levels into the ≤36.1 U/mL and > 36.1 U/mL groups. The primary outcome was graft loss within 1, 3, and 6 months. The secondary outcome was EAD, as defined by Olthoff et al. Predictors of outcomes were identified by multivariable logistic regression. RESULTS Two hundred twenty-seven patients were included in the study: 74 with factor V of 36.1 U/mL or less and 153 with factor V >36.1 U/mL. EAD was diagnosed in 41 (55.4%) of 74 patients with factor V of 36.1 U/mL or less and in 20/153 (13.1%) patients with factor V >36.1 U/mL (P < 0.001). According to the multivariable regression model, factor V was a continuous marker of EAD (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.94-0.98 per U/mL). Among the study groups, the 1-, 3-, and 6-month graft survival rates were 82%, 74%, and 74%, respectively, for patients with factor V of 36.1 U/mL or less and 98%, 95%, and 95%, respectively, for patients with factor V >36.1 U/mL (P = 0.001). Factor V was a continuous predictor for 3- and 6-month graft losses (OR, 0.96; 95% CI, 0.94-0.99 and OR, 0.97; 95% CI, 0.94-0.99 per U/mL), whereas EAD was not significant when adjusted for factor V. CONCLUSION Factor V is an early marker for EAD and is a continuous predictor of short-term graft loss after LT.
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Affiliation(s)
- Andre Gorgen
- Postgraduate Program, Surgical Sciences, Medical School, Federal University of Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Multi-Organ Transplant Program, General Surgery Department, University Health Network, Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Carolina Prediger
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - João E Prediger
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Marcio F Chedid
- Postgraduate Program, Surgical Sciences, Medical School, Federal University of Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Ariane N Backes
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Alexandre de Araujo
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Tomaz J M Grezzana-Filho
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Ian Leipnitz
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Aljamir D Chedid
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Mario R Alvares-da-Silva
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, General Surgery Department, University Health Network, Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Cleber R P Kruel
- Postgraduate Program, Surgical Sciences, Medical School, Federal University of Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Liver Transplant Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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The Effects of Short-term Subnormothermic Perfusion After Cold Preservation on Liver Grafts From Donors After Circulatory Death: An Ex Vivo Rat Model. Transplantation 2018; 102:e147-e154. [PMID: 29309377 DOI: 10.1097/tp.0000000000002080] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND We previously reported that short oxygenated warm perfusion before cold storage (CS) had improved the graft viability of rat livers from donors after circulatory death (DCD). In this study, we investigated the effectiveness of short-term oxygenated subnormothermic perfusion for different durations after CS in a rat DCD model. METHODS We used an isolated perfused rat liver system. In study 1: the grafts were retrieved from Wistar rats 30 minutes after cardiac arrest (thoracotomy), preserved in CS for 6 hours, and perfused with oxygenated subnormothermic (20-25°C) Krebs-Henseleit buffer for different durations (0, 15, 30, 60, and 90 minutes groups; n = 5 in each). In study 2: in addition to subnormothermic ex vivo liver perfusion (SELP), after 15-minute incubation at room temperature, the grafts were reperfused under normothermic condition for 60 minutes as a model of liver transplantation (0, 30, 60, and 90 minutes groups; n = 5 in each). RESULTS In study 1, portal flow, bile production and tissue adenosine triphosphate increased with perfusion duration. In study 2, SELP significantly improved portal flow volume (P <0.05), and bile production (P <0.05), decreased liver enzymes (P <0.05) and cytokines (P <0.0001), and increased tissue adenosine triphosphate (P <0.01). Histological examinations showed that additional SELP ameliorated tissue deterioration, preserved the parenchymal structure, and decreased apoptosis (P <0.01). Furthermore, scanning electron microscopy revealed that additional SELP alleviated sinusoidal endothelial cells and hepatic microvasculature. CONCLUSIONS Even 30 minutes of SELP after CS rescued DCD livers from ischemia-reperfusion injury, which may help the viability of the grafts.
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Comparison of BQ123, Epoprostenol, and Verapamil as Vasodilators During Normothermic Ex Vivo Liver Machine Perfusion. Transplantation 2018; 102:601-608. [PMID: 29189484 DOI: 10.1097/tp.0000000000002021] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The optimal vasodilator to avoid hepatic artery vasospasm during normothermic ex vivo liver perfusion (NEVLP) is yet to be determined. We compared safety and efficacy of BQ123 (endothelin1 antagonist), epoprostenol (prostacyclin analogue), and verapamil (calcium channel antagonist). METHODS Livers from porcine heart beating donors were perfused for 3 hours and transplanted into recipient pigs. Four groups were compared: group 1, livers perfused with a dose of 1.25 mg of BQ123 at baseline and at 2 hours of perfusion; group 2, epoprostenol at a continuous infusion of 4 mg/h; group 3, verapamil 2.5 mg at baseline and at 2 hours of perfusion; group 4, no vasodilator used during ex vivo perfusion. Liver injury and function were assessed during perfusion, and daily posttransplantation until postoperative day (POD) 3. All groups were compared with a cold storage group for postoperative graft function. RESULTS Hepatic artery flow during NEVLP was significantly higher in BQ123 compared with verapamil, epoprostenol, and no vasodilator-treated livers. Aspartate aminotransferase levels were significantly lower with BQ123 and verapamil compared with epoprostenol and control group during perfusion. Peak aspartate aminotransferase levels were lower in pigs receiving BQ123 and verapamil perfused grafts compared with epoprostenol and control group. International Normalized Ratio, alkaline phosphatase, and total bilirubin levels were lower in the BQ123 and verapamil groups compared to epoprostenol group. Cold storage group had increased markers of ischemia reperfusion injury and slower graft function recovery compared to machine perfused grafts. CONCLUSION The use of BQ123, epoprostenol, and verapamil during NEVLP is safe. Livers perfused with BQ123 and verapamil have higher hepatic artery flow and reduced hepatocyte injury during perfusion compared with epoprostenol. Hepatic artery flow is significantly reduced in the absence of vasodilators during NEVLP.
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Optimizing Livers for Transplantation Using Machine Perfusion versus Cold Storage in Large Animal Studies and Human Studies: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9180757. [PMID: 30255101 PMCID: PMC6145150 DOI: 10.1155/2018/9180757] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/01/2018] [Accepted: 08/16/2018] [Indexed: 12/25/2022]
Abstract
Background Liver allograft preservation frequently involves static cold storage (CS) and machine perfusion (MP). With its increasing popularity, we investigated whether MP was superior to CS in terms of beneficial outcomes. Methods Human studies and large animal studies that optimized livers for transplantation using MP versus CS were assessed (PubMed/Medline/EMBASE). Meta-analyses were conducted for comparisons. Study quality was assessed according to the Newcastle-Ottawa quality assessment scale and SYRCLE's risk of bias tool. Results Nineteen studies were included. Among the large animal studies, lower levels of lactate dehydrogenase (SMD -3.16, 95% CI -5.14 to -1.18), alanine transferase (SMD -2.46, 95% CI -4.03 to -0.90), and hyaluronic acid (SMD -2.48, 95% CI -4.21 to -0.74) were observed in SNMP-preserved compared to CS-preserved livers. NMP-preserved livers showing lower level of hyaluronic acid (SMD -3.97, 95% CI -5.46 to -2.47) compared to CS-preserved livers. Biliary complications (RR 0.45, 95% CI 0.28 to 0.73) and early graft dysfunction (RR 0.56, 95% CI 0.34 to 0.92) also significantly reduced with HMP preservation in human studies. No evidence of publication bias was found. Conclusions MP preservation could improve short-term outcomes after transplantation compared to CS preservation. Additional randomized controlled trials (RCTs) are needed to develop clinical applications of MP preservation.
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Bral M, Gala-Lopez B, Bigam DL, Freed DH, Shapiro AMJ. Ex situ liver perfusion: Organ preservation into the future. Transplant Rev (Orlando) 2018; 32:132-141. [PMID: 29691119 DOI: 10.1016/j.trre.2018.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 03/27/2018] [Accepted: 03/27/2018] [Indexed: 12/15/2022]
Abstract
In recent years, remarkable progress has occurred in the development of technologies to support ex situ liver perfusion. Building upon extensive preclinical studies in large animal models, pilot and randomized clinical trials have been initiated, and preliminary outcomes suggest more optimal protection of both standard and extended criteria liver grafts. There currently exists an incredible opportunity and need to further refine this technology, determine appropriate viability measures to predict usable liver grafts, and to explore potent protective additive strategies to further optimize the quality of extended criteria organs. These findings will have major bearing in expanding the limited liver donor pool, and may save lives where up to a quarter of listed patients die on wait-lists. Herein we offer a brief overview of the history and current status of ex situ liver perfusion, and discuss future directions that will likely have major impact on the practice of clinical liver transplantation.
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Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - Boris Gala-Lopez
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - David L Bigam
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - Darren H Freed
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - A M James Shapiro
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
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17
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Normothermic Ex Vivo Machine Perfusion for Liver Grafts Recovered from Donors after Circulatory Death: A Systematic Review and Meta-Analysis. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2018; 2018:6867986. [PMID: 29849531 PMCID: PMC5937385 DOI: 10.1155/2018/6867986] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 03/15/2018] [Indexed: 12/20/2022]
Abstract
As a result of donation after circulatory death liver grafts' poor tolerance to cold storage, there has been increasing research interest in normothermic machine perfusion. This study aims to systematically review the current literature comparing normothermic perfusion to cold storage in donation after circulatory death liver grafts and complete a meta-analysis of published large animal and human studies. A total of nine porcine studies comparing cold storage to normothermic machine perfusion for donation after circulatory death grafts were included for analysis. There was a significant reduction in AST (mean difference −2291 U/L, CI (−3019, −1563); P ≤ 0.00001) and ALT (mean difference −175 U/L, CI (−266, −85); P = 0.0001), for normothermic perfusion relative to static cold storage, with moderate (I2 = 61%) and high (I2 = 96%) heterogeneity, respectively. Total bile production was also significantly higher (mean difference = 174 ml, CI (155, 193); P ≤ 0.00001). Further research focusing on standardization, performance of this technology following periods of cold storage, economic implications, and clinical trial data focused on donation after circulatory death grafts will be helpful to advance this technology toward routine clinical utilization for these grafts.
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Yoshikawa R, Obara H, Matsuno N, Morito N, Gouchi M, Otani M, Shonaka T, Takahashi H, Enosawa S, Hirano T, Furukawa H. Ex Vivo Reperfusion Model to Evaluate Utility of Machine Preservation for Porcine Liver Donated After Cardiac Death. Transplant Proc 2018; 50:2826-2829. [PMID: 30401405 DOI: 10.1016/j.transproceed.2018.04.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/22/2018] [Accepted: 04/06/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Machine perfusion (MP) techniques are expected to prove useful for preserving the organ viability and recovering organ function for organ transplantation. Furthermore, an accurate assessment of organ viability using MP is important for expanding the donor criteria. In this study, an ex vivo reperfusion model (ERM) simulating transplantation using diluted autologous blood under normothermic conditions was evaluated for its utility of MP under subnormothermic conditions for livers donated after cardiac death (DCD). METHODS The liver preservation methods for DCD porcine livers were evaluated using the ERM. This investigation was performed using a novel perfusion system developed by our research group. Porcine livers were procured with a warm ischemia time (WIT) of 60 minutes. The organs were then preserved using subnormothemic machine perfusion (SNMP) or static cold storage (CS) for 4 hours. We also compared these tissues with SNMP livers procured under a WIT of 0 minutes. After the preservation, the livers were reperfused for 2 hours using the ERM with diluted autologous blood oxygenated by a membrane oxygenator under NMP conditions. Reperfusion was evaluated based on perfusion flow dynamics and outflow of deviating enzymes. RESULTS In the early stages of reperfusion, pressure in the blood vessels increased sharply in the CS group. Furthermore, the amount of aspartate aminotransferase accumulation was lower in the SNMP group than in the other groups. These results suggest ischemia-reperfusion injury is suppressed in SNMP conditions. CONCLUSION An ERM has use in evaluating the utility of MP for the DCD liver.
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Affiliation(s)
- R Yoshikawa
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan
| | - H Obara
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan; National Center for Child Health and Development, Tokyo, Japan
| | - N Matsuno
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan; National Center for Child Health and Development, Tokyo, Japan; Department of Surgery, Asahikawa Medical University, Hokkaido, Japan.
| | - N Morito
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan
| | - M Gouchi
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - M Otani
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - T Shonaka
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - H Takahashi
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - S Enosawa
- National Center for Child Health and Development, Tokyo, Japan
| | - T Hirano
- Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - H Furukawa
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
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Obara H, Morito N, Matsuno N, Yoshikawa R, Gouchi M, Otani M, Shonaka T, Takahashi H, Enosawa S, Hirano T, Furukawa H. Optimum Perfusate Volume of Purified Subnormothermic Machine Perfusion for Porcine Liver Donated After Cardiac Death. Transplant Proc 2018; 50:2830-2833. [PMID: 30401406 DOI: 10.1016/j.transproceed.2018.03.055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 03/02/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Subnormothermic machine perfusion (SNMP) shows some advantages for the preservation of grafts donated after cardiac death (DCD) and improvements in machine perfusion (MP) technology are important to enhance organ preservation outcomes for liver transplantation. In this study, we focused on purified subnormothermic machine perfusion (PSNMP) and volumes of perfusate removed to substitute for purification and replaced by modified University of Wisconsin-gluconate after the start of perfusion and investigated, in particular, the optimum perfusate purification volume. Several purification volumes under SNMP were compared. In addition, the perfusate purification during MP was indicated as a potential technique to enhance the organ quality of DCD grafts and extended-criteria donors. METHODS The PSNMP at several volumes (0.5 L, 1.5 L, and 3 L) were compared with regular SNMP without any purification treatment (untreated control). In the PSNMP group, all perfusate was removed to substitute for purification of the perfusate by modified University of Wisconsin-gluconate solution after the start of perfusion. After removing the perfusate, new perfusate with the same components was perfused to preserve the porcine livers obtained under warm ischemia for 60 minutes using SNMP at 22°C porcine liver for 4 hours. RESULTS The concentrations of aspartate aminotransferase and lactate dehydrogenase in the untreated group were significantly higher during perfusion compared to those of the intervention group. There are no significant differences among the volume conditions of the purification groups. CONCLUSIONS The optimal volume of perfusate purification was confirmed with a simple experimental comparison between untreated and PSNMP conditions.
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Affiliation(s)
- H Obara
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan; National Center for Child Health and Development, Tokyo, Japan.
| | - N Morito
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan
| | - N Matsuno
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan; National Center for Child Health and Development, Tokyo, Japan; Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - R Yoshikawa
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan
| | - M Gouchi
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - M Otani
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - T Shonaka
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - H Takahashi
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - S Enosawa
- National Center for Child Health and Development, Tokyo, Japan
| | - T Hirano
- Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - H Furukawa
- Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
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Bochimoto H, Matsuno N, Ishihara Y, Shonaka T, Koga D, Hira Y, Nishikawa Y, Furukawa H, Watanabe T. The ultrastructural characteristics of porcine hepatocytes donated after cardiac death and preserved with warm machine perfusion preservation. PLoS One 2017; 12:e0186352. [PMID: 29023512 PMCID: PMC5638504 DOI: 10.1371/journal.pone.0186352] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 10/01/2017] [Indexed: 12/15/2022] Open
Abstract
The effects of warm machine perfusion preservation of liver grafts donated after cardiac death on the intracellular three-dimensional ultrastructure of the organelles in hepatocytes remain unclear. Here we analyzed comparatively the ultrastructure of the endomembrane systems in porcine hepatocytes under warm ischemia and successive hypothermic and midthermic machine perfusion preservation, a type of the warm machine perfusion. Porcine liver grafts which had a warm ischemia time of 60 minutes were perfused for 4 hours with modified University of Wisconsin gluconate solution. Group A grafts were preserved with hypothermic machine perfusion preservation at 8°C constantly for 4 hours. Group B grafts were preserved with rewarming up to 22°C by warm machine perfusion preservation for 4 hours. An analysis of hepatocytes after 60 minutes of warm ischemia by scanning electron microscope revealed the appearance of abnormal vacuoles and invagination of mitochondria. In the hepatocytes preserved by subsequent hypothermic machine perfusion preservation, strongly swollen mitochondria were observed. In contrast, the warm machine perfusion preservation could preserve the functional appearance of mitochondria in hepatocytes. Furthermore, abundant vacuoles and membranous structures sequestrating cellular organelles like autophagic vacuoles were frequently observed in hepatocytes after warm machine perfusion preservation. In conclusion, the ultrastructure of the endomembrane systems in the hepatocytes of liver grafts changed in accordance with the temperature conditions of machine perfusion preservation. In addition, temperature condition of the machine perfusion preservation may also affect the condition of the hepatic graft attributed to autophagy systems, and consequently alleviate the damage of the hepatocytes.
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Affiliation(s)
- Hiroki Bochimoto
- Health Care Administration Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Naoto Matsuno
- Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
- * E-mail:
| | - Yo Ishihara
- Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Tatsuya Shonaka
- Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Daisuke Koga
- Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Yoshiki Hira
- Area of Functional Anatomy, Department of Nursing, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Yuji Nishikawa
- Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Hiroyuki Furukawa
- Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Tsuyoshi Watanabe
- Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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de Vries Y, von Meijenfeldt FA, Porte RJ. Post-transplant cholangiopathy: Classification, pathogenesis, and preventive strategies. Biochim Biophys Acta Mol Basis Dis 2017. [PMID: 28645651 DOI: 10.1016/j.bbadis.2017.06.013] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Biliary complications are the most frequent cause of morbidity, re-transplantation, and even mortality after liver transplantation. In general, biliary leakage and anastomotic and non-anastomotic biliary strictures (NAS) can be recognized. There is no consensus on the exact definition of NAS and different names and criteria have been used in literature. We propose to use the term post-transplant cholangiopathy for the spectrum of abnormalities of large donor bile ducts, that includes NAS, but also intraductal casts and intrahepatic biloma formation, in the presence of a patent hepatic artery. Combinations of these manifestations of cholangiopathy are not infrequently found in the same liver and ischemia-reperfusion injury is generally considered the common underlying mechanism. Other factors that contribute to post-transplant cholangiopathy are biliary injury due to bile salt toxicity and immune-mediated injury. This review provides an overview of the various types of post-transplant cholangiopathy, the presumed pathogenesis, clinical implications, and preventive strategies.
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Affiliation(s)
- Yvonne de Vries
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Fien A von Meijenfeldt
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands.
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Bral M, Gala-Lopez B, Bigam D, Kneteman N, Malcolm A, Livingstone S, Andres A, Emamaullee J, Russell L, Coussios C, West LJ, Friend PJ, Shapiro AMJ. Preliminary Single-Center Canadian Experience of Human Normothermic Ex Vivo Liver Perfusion: Results of a Clinical Trial. Am J Transplant 2017; 17:1071-1080. [PMID: 27639262 DOI: 10.1111/ajt.14049] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 08/28/2016] [Accepted: 08/30/2016] [Indexed: 01/25/2023]
Abstract
After extensive experimentation, outcomes of a first clinical normothermic machine perfusion (NMP) liver trial in the United Kingdom demonstrated feasibility and clear safety, with improved liver function compared with standard static cold storage (SCS). We present a preliminary single-center North American experience using identical NMP technology. Ten donor liver grafts were procured, four (40%) from donation after circulatory death (DCD), of which nine were transplanted. One liver did not proceed because of a technical failure with portal cannulation and was discarded. Transplanted NMP grafts were matched 1:3 with transplanted SCS livers. Median NMP was 11.5 h (range 3.3-22.5 h) with one DCD liver perfused for 22.5 h. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (primary outcome) was not statistically different between groups on an intent-to-treat basis (p = 0.25). Intensive care and hospital stays were significantly more prolonged in the NMP group. This preliminary experience demonstrates feasibility as well as potential technical risks of NMP in a North American setting and highlights a need for larger, randomized studies.
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Affiliation(s)
- M Bral
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, Canada
| | - B Gala-Lopez
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, Canada
| | - D Bigam
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - N Kneteman
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, Canada
| | - A Malcolm
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, Canada
| | - S Livingstone
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - A Andres
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - J Emamaullee
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | | - C Coussios
- Institute of Biomedical Engineering, University of Oxford, Oxford, UK
| | - L J West
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, Canada
| | - P J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - A M J Shapiro
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, Canada
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25
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Goldaracena N, Spetzler VN, Echeverri J, Kaths JM, Cherepanov V, Persson R, Hodges MR, Janssen HLA, Selzner N, Grant DR, Feld JJ, Selzner M. Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation-A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion. Am J Transplant 2017; 17:970-978. [PMID: 27805315 DOI: 10.1111/ajt.14100] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 10/12/2016] [Accepted: 10/16/2016] [Indexed: 01/25/2023]
Abstract
Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation.
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Affiliation(s)
- N Goldaracena
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - V N Spetzler
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - J Echeverri
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - J M Kaths
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - V Cherepanov
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada
| | - R Persson
- Roche Innovation Center, Copenhagen, Denmark
| | | | - H L A Janssen
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada
| | - N Selzner
- Multi Organ Transplant Program-Department of Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - D R Grant
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - J J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada
| | - M Selzner
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
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26
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Abstract
The demand of donor livers for transplantation exceeds the supply. In an attempt to maximize the number of potentially usable donor livers, several centers are exploring the role of machine perfusion. This review provides an update on machine perfusion strategies and basic concepts, based on current clinical issues, and discuss challenges, including currently used biomarkers for assessing the quality and viability of perfused organs. The potential benefits of machine perfusion on immunogenicity and the consequences on post-operative immunosuppression management are discussed.
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27
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Toniutto P, Zanetto A, Ferrarese A, Burra P. Current challenges and future directions for liver transplantation. Liver Int 2017; 37:317-327. [PMID: 27634369 DOI: 10.1111/liv.13255] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 09/08/2016] [Indexed: 12/14/2022]
Abstract
Liver transplantation is an effective and widely used therapy for several patients with acute and chronic liver diseases. The discrepancy between the number of patients on the waiting list and available donors remains the key issue and is responsible for the high rate of waiting list mortality. The recent news is that the majority of patients with hepatitis C virus related liver disease will be cured by new antivirals therefore we should expect soon a reduction in the need of liver transplantation for these recipients. This review aims to highlight, in two different sections, the main open issues of liver transplantation concerning the current and future strategies to the best use of limited number of organs. The first section cover the strategies to increase the donor pool, discussing the use of older donors, split grafts, living donation and donation after cardiac death and mechanical perfusion systems to improve the preservation of organs before liver transplantation. Challenges in immunosuppressive therapy and operational tolerance induction will be evaluated as potential tools to increase the survival in liver transplant recipients and to reducing the need of re-transplantation. The second section is devoted to the evaluation of possible new indications to liver transplantation, where the availability of organs by implementing the strategies mentioned in the first section and the reduction in the number of waiting transplants for HCV disease is realized. Among these new potential indications for transplantation, the expansion of the Milan criteria for hepatocellular cancer is certainly the most open to question.
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Affiliation(s)
- Pierluigi Toniutto
- Department of Clinical Sciences Experimental and Clinical, Medical Liver Transplant Section, University of Udine, Udine, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padova, Italy
| | - Alberto Ferrarese
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padova, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padova, Italy
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28
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Selzner M, Goldaracena N, Echeverri J, Kaths JM, Linares I, Selzner N, Serrick C, Marquez M, Sapisochin G, Renner EL, Bhat M, McGilvray ID, Lilly L, Greig PD, Tsien C, Cattral MS, Ghanekar A, Grant DR. Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results. Liver Transpl 2016; 22:1501-1508. [PMID: 27339754 DOI: 10.1002/lt.24499] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 05/08/2016] [Accepted: 05/23/2016] [Indexed: 12/12/2022]
Abstract
The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non-US Food and Drug Administration-approved, bovine-derived, gelatin-based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin-based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340-580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56-1.74 mmol/L) and produced bile (61 mL; 14-146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP-preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1-3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1-1.56] versus 1.1 [1-1.3]; P = 0.5) and bilirubin (1.5; 1-7.7 mg/dL versus 2.78; 0.4-15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0-8 versus 0-23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8-17 versus 7-89 days; P = 0.23). Major complications (Dindo-Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration-approved Steen solution will avoid a potential regulatory barrier in North America. Liver Transplantation 22 1501-1508 2016 AASLD.
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Affiliation(s)
- Markus Selzner
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | | | - Juan Echeverri
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Johan M Kaths
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Ivan Linares
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Nazia Selzner
- Departments of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
| | - Cyril Serrick
- Perfusion Services, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Max Marquez
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Gonzalo Sapisochin
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Eberhard L Renner
- Departments of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Departments of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
| | - Ian D McGilvray
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Leslie Lilly
- Departments of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
| | - Paul D Greig
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Cynthia Tsien
- Departments of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
| | - Mark S Cattral
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Anand Ghanekar
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - David R Grant
- Departments of Surgery, Toronto General Hospital, Toronto, Ontario, Canada.
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29
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Goldaracena N, Echeverri J, Spetzler VN, Kaths JM, Barbas AS, Louis KS, Adeyi OA, Grant DR, Selzner N, Selzner M. Anti-inflammatory signaling during ex vivo liver perfusion improves the preservation of pig liver grafts before transplantation. Liver Transpl 2016; 22:1573-1583. [PMID: 27556578 DOI: 10.1002/lt.24603] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 06/12/2016] [Accepted: 07/21/2016] [Indexed: 12/13/2022]
Abstract
Normothermic ex vivo liver perfusion (NEVLP) improves graft preservation by avoiding cold ischemia injury. We investigated whether the protective effects of NEVLP can be further improved by applying strategies targeted on reducing the activation of proinflammatory cytokines during perfusion. Livers retrieved under heart-beating conditions were perfused for 4 hours. Following the preservation period, a pig liver transplantation was performed. In group 1 (n = 5), anti-inflammatory strategies (alprostadil, n-acetylcysteine, carbon monoxide, sevoflurane, and subnormothermic temperature [33°C]) were applied. This was compared with a perfused control group (group 2) where livers (n = 5) were perfused at 37°C without anti-inflammatory agents, similar to the setup used in current European clinical trials, and to a control group preserved with static cold storage (group 3). During 3-day follow-up, markers of reperfusion injury, bile duct injury, and liver function were examined. Aspartate aminotransferase (AST) levels during perfusion were significantly lower in the study versus control group at 1 hour (52 ± 6 versus 162 ± 86 U/L; P = 0.01), 2 hours (43 ± 5 versus 191 ± 111 U/L; P = 0.008), and 3 hours (24 ± 16 versus 218 ± 121 U/L; P = 0.009). During perfusion, group 1 versus group 2 had reduced interleukin (IL) 6, tumor necrosis factor α, and galactosidase levels and increased IL10 levels. After transplantation, group 1 had lower AST peak levels compared with group 2 and group 3 (1400 ± 653 versus 2097 ± 1071 versus 1747 ± 842 U/L; P = 0.47) without reaching significance. Bilirubin levels were significantly lower in group 1 versus group 2 at day 1 (3.6 ± 1.5 versus 6.60 ± 1.5 μmol/L; P = 0.02) and 3 (2 ± 1.1 versus 9.7 ± 7.6 μmol/L; P = 0.01). A trend toward decreased hyaluronic acid, as a marker of improved endothelial cell function, was observed at 1, 3, and 5 hours after reperfusion in group 1 versus group 2. Only 1 early death occurred in each group (80% survival). In conclusion, addition of anti-inflammatory strategies further improves warm perfused preservation. Liver Transplantation 22 1573-1583 2016 AASLD.
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Affiliation(s)
- Nicolas Goldaracena
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Juan Echeverri
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.,Programa de Doctorat en Cirurgia i Ciències Morfològiques, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Vinzent N Spetzler
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Johan M Kaths
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Andrew S Barbas
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Kristine S Louis
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Oyedele A Adeyi
- Department of Pathology, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David R Grant
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Nazia Selzner
- Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Markus Selzner
- Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
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30
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Abstract
BACKGROUND The high demand for livers for transplantation has led to organs of limited quality being accepted to expand the donor pool. This is associated with inferior outcomes due to more pronounced preservation injury. Accordingly, recent research has aimed to develop preservation modalities for improved preservation as well as strategies for liver viability assessment and liver reconditioning. METHODS The PubMed database was searched using the terms 'perfusion', 'liver', 'preservation', and 'reconditioning' in various combinations, and the according literature was reviewed. RESULTS Several perfusion techniques have been developed in recent years with the potential for liver reconditioning. Preclinical and first emerging clinical data suggest feasibility, safety, and superiority over the current gold standard of cold storage. CONCLUSION This review outlines current advances in the field of liver preservation with an emphasis on liver reconditioning methods.
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Affiliation(s)
- Dieter P Hoyer
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Thomas Minor
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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31
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Subnormothermic Perfusion in the Isolated Rat Liver Preserves the Antioxidant Glutathione and Enhances the Function of the Ubiquitin Proteasome System. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:9324692. [PMID: 27800122 PMCID: PMC5075307 DOI: 10.1155/2016/9324692] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/09/2016] [Accepted: 09/15/2016] [Indexed: 12/18/2022]
Abstract
The reduction of oxidative stress is suggested to be one of the main mechanisms to explain the benefits of subnormothermic perfusion against ischemic liver damage. In this study we investigated the early cellular mechanisms induced in isolated rat livers after 15 min perfusion at temperatures ranging from normothermia (37°C) to subnormothermia (26°C and 22°C). Subnormothermic perfusion was found to maintain hepatic viability. Perfusion at 22°C raised reduced glutathione levels and the activity of glutathione reductase; however, lipid and protein oxidation still occurred as determined by malondialdehyde, 4-hydroxynonenal-protein adducts, and advanced oxidation protein products. In livers perfused at 22°C the lysosomal and ubiquitin proteasome system (UPS) were both activated. The 26S chymotrypsin-like (β5) proteasome activity was significantly increased in the 26°C (46%) and 22°C (42%) groups. The increased proteasome activity may be due to increased Rpt6 Ser120 phosphorylation, which is known to enhance 26S proteasome activity. Together, our results indicate that the early events produced by subnormothermic perfusion in the liver can induce oxidative stress concomitantly with antioxidant glutathione preservation and enhanced function of the lysosomal and UPS systems. Thus, a brief hypothermia could trigger antioxidant mechanisms and may be functioning as a preconditioning stimulus.
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32
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Eren EA, Latchana N, Beal E, Hayes D, Whitson B, Black SM. Donations After Circulatory Death in Liver Transplant. EXP CLIN TRANSPLANT 2016; 14:463-470. [PMID: 27733105 PMCID: PMC5461820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
The supply of liver grafts for treatment of end-stage liver disease continues to fall short of ongoing demands. Currently, most liver transplants originate from donations after brain death. Enhanced utilization of the present resources is prudent to address the needs of the population. Donation after circulatory or cardiac death is a mechanism whereby the availability of organs can be expanded. Donations after circulatory death pose unique challenges given their exposure to warm ischemia. Technical principles of donations after circulatory death procurement and pertinent studies investigating patient outcomes, graft outcomes, and complications are highlighted in this review. We also review associated risk factors to suggest potential avenues to achieve improved outcomes and reduced complications. Future considerations and alternative techniques of organ preservation are discussed, which may suggest novel strategies to enhance preservation and donor expansion through the use of marginal donors. Ultimately, without effective measures to bolster organ supply, donations after circulatory death should remain a consideration; however, an understanding of inherent risks and limitations is necessary.
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Affiliation(s)
- Emre A. Eren
- Department of Surgery, Division of Transplantation, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Nicholas Latchana
- Department of Surgery, Division of Transplantation, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Eliza Beal
- Department of Surgery, Division of Transplantation, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Don Hayes
- Departments of Pediatrics and Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- Section of Pulmonary Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Bryan Whitson
- Department of Surgery, Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sylvester M. Black
- Department of Surgery, Division of Transplantation, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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33
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Karangwa SA, Dutkowski P, Fontes P, Friend PJ, Guarrera JV, Markmann JF, Mergental H, Minor T, Quintini C, Selzner M, Uygun K, Watson CJ, Porte RJ. Machine Perfusion of Donor Livers for Transplantation: A Proposal for Standardized Nomenclature and Reporting Guidelines. Am J Transplant 2016; 16:2932-2942. [PMID: 27129409 PMCID: PMC5132023 DOI: 10.1111/ajt.13843] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/28/2016] [Accepted: 04/19/2016] [Indexed: 02/06/2023]
Abstract
With increasing demand for donor organs for transplantation, machine perfusion (MP) promises to be a beneficial alternative preservation method for donor livers, particularly those considered to be of suboptimal quality, also known as extended criteria donor livers. Over the last decade, numerous studies researching MP of donor livers have been published and incredible advances have been made in both experimental and clinical research in this area. With numerous research groups working on MP, various techniques are being explored, often applying different nomenclature. The objective of this review is to catalog the differences observed in the nomenclature used in the current literature to denote various MP techniques and the manner in which methodology is reported. From this analysis, we propose a standardization of nomenclature on liver MP to maximize consistency and to enable reliable comparison and meta-analyses of studies. In addition, we propose a standardized set of guidelines for reporting the methodology of future studies on liver MP that will facilitate comparison as well as clinical implementation of liver MP procedures.
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Affiliation(s)
- S. A. Karangwa
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
- Surgical Research LaboratoryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - P. Dutkowski
- Department of Surgery & TransplantationUniversity Hospital ZurichZurichSwitzerland
| | - P. Fontes
- Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical CenterPittsburghPA
- McGowan Institute of Regenerative MedicineUniversity of PittsburghPittsburghPA
| | - P. J. Friend
- Nuffield Department of SurgeryOxford Transplant CentreUniversity of OxfordChurchill HospitalOxfordUK
| | - J. V. Guarrera
- Department of SurgeryCenter for Liver Disease and TransplantationColumbia University Medical CenterNew YorkNY
| | | | - H. Mergental
- Liver UnitUniversity Hospital BirminghamBirminghamUK
| | - T. Minor
- Department of Surgical ResearchClinic for General Visceral and Transplantation SurgeryUniversity Hospital EssenEssenGermany
| | - C. Quintini
- Department of SurgeryTransplant CenterDigestive Disease InstituteCleveland Clinic FoundationClevelandOH
| | - M. Selzner
- Department of SurgeryMulti Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - K. Uygun
- Department of SurgeryCenter for Engineering in MedicineMassachusetts General HospitalHarvard Medical SchoolBostonMA
| | - C. J. Watson
- University of Cambridge Department of Surgery and the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation University of CambridgeAddenbrooke's HospitalCambridgeUK
| | - R. J. Porte
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
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34
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Jochmans I, Akhtar MZ, Nasralla D, Kocabayoglu P, Boffa C, Kaisar M, Brat A, O'Callaghan J, Pengel LHM, Knight S, Ploeg RJ. Past, Present, and Future of Dynamic Kidney and Liver Preservation and Resuscitation. Am J Transplant 2016; 16:2545-55. [PMID: 26946212 DOI: 10.1111/ajt.13778] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 02/03/2016] [Accepted: 02/23/2016] [Indexed: 01/25/2023]
Abstract
The increased demand for organs has led to the increased usage of "higher risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, preimplantation) and temperatures (hypo-, sub, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes ongoing research and emerging clinical trials.
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Affiliation(s)
- I Jochmans
- Abdominal Transplant Surgery, KU Leuven, University Hospitals Leuven, Leuven, Belgium
| | - M Z Akhtar
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - D Nasralla
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - P Kocabayoglu
- Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany
| | - C Boffa
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - M Kaisar
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - A Brat
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - J O'Callaghan
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - L H M Pengel
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - S Knight
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - R J Ploeg
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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35
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Goldaracena N, Sapisochin G, Spetzler V, Echeverri J, Kaths M, Cattral MS, Greig PD, Lilly L, McGilvray ID, Levy GA, Ghanekar A, Renner EL, Grant DR, Selzner M, Selzner N. Live Donor Liver Transplantation With Older (≥50 Years) Versus Younger (<50 Years) Donors: Does Age Matter? Ann Surg 2016; 263:979-85. [PMID: 26106842 DOI: 10.1097/sla.0000000000001337] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To compare the outcome of adult live donor liver transplantation (LDLT) with grafts from older versus younger donors. INTRODUCTION Using older donor grafts for adult LDLT may help expand the donor pool. However, the risks of LDLT with older donors remain controversial, and many centers are reluctant to use live donors aged 45 years or older for adult LDLT. METHODS Outcomes of patients receiving a LDLT graft from donors aged 50 years or older (n = 91) were compared with those receiving a live donor graft from donors younger than 50 years (n = 378). RESULTS Incidences of biliary (LDLT <50: 24% vs LDLT ≥50: 23%; P = 0.89) and major complications (LDLT <50: 24% vs LDLT ≥50: 24%; P = 1) were similar between both groups of recipients. No difference was observed in 30-day recipient mortality (LDLT <50: 3% vs LDLT ≥50: 0%; P = 0.13). The 1- (90% vs 90%), 5- (82% vs 73%), and 10- (71% vs 58%) year graft survival was statistically similar between both groups (P = 0.075). Likewise, patient survival after 1- (92% vs 96%), 5- (83% vs 79%), and 10- (76% vs 69%) years was also similar (P = 0.686). Overall, donors rate of major complications (Dindo-Clavien ≥3b) within 30 days was low (n = 2.3%) and not different in older versus younger donors (P = 1). Donor median hospital stay in both groups was identical [LDLT <50: 6 (4-17) vs LDLT ≥50: 6 (4-14) days; P = 0.65]. No donor death occurred and all donors had full recovery and returned to baseline activity. CONCLUSIONS Right lobe LDLT with donors aged 50 years or older results in acceptable recipient outcome without increased donor morbidity or mortality. Potential live donors should not be declined on the basis of age alone.
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Affiliation(s)
- Nicolas Goldaracena
- *Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada †Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
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Banan B, Watson R, Xu M, Lin Y, Chapman W. Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers. Liver Transpl 2016; 22:979-93. [PMID: 27027254 DOI: 10.1002/lt.24451] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 03/08/2016] [Accepted: 03/21/2016] [Indexed: 12/23/2022]
Abstract
Donor organ shortages have led to an increased interest in finding new approaches to recover organs from extended criteria donors (ECD). Normothermic extracorporeal liver perfusion (NELP) has been proposed as a superior preservation method to reduce ischemia/reperfusion injury (IRI), precondition suboptimal grafts, and treat ECD livers so that they can be successfully used for transplantation. The aim of this study was to investigate the beneficial effects of a modified NELP circuit on discarded human livers. Seven human livers that were rejected for transplantation were placed on a modified NELP circuit for 8 hours. Perfusate samples and needle core biopsies were obtained at hourly intervals. A defatting solution that contained exendin-4 (50 nM) and L-carnitine (10 mM) was added to the perfusate for 2 steatotic livers. NELP provided normal temperature, electrolytes, and pH and glucose levels in the perfusate along with physiological vascular flows and pressures. Functional, biochemical, and microscopic evaluation revealed no additional injuries to the grafts during NELP with an improved oxygen extraction ratio (>0.5) and stabilized markers of hepatic injury. All livers synthesized adequate amounts of bile and coagulation factors. We also demonstrated a mild reduction (10%) of macroglobular steatosis with the use of the defatting solution. Histology demonstrated normal parenchymal architecture and a minimal to complete lack of IRI at the end of NELP. In conclusion, a modified NELP circuit preserved hepatocyte architecture, recovered synthetic functions, and hepatobiliary parameters of ECD livers without additional injuries to the grafts. This approach has the potential to increase the donor pool for clinical transplantation. Liver Transplantation 22 979-993 2016 AASLD.
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Affiliation(s)
- Babak Banan
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Rao Watson
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.,Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Min Xu
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Yiing Lin
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
| | - William Chapman
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
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37
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Normothermic and subnormothermic ex-vivo liver perfusion in liver transplantation. Curr Opin Organ Transplant 2016; 21:315-21. [DOI: 10.1097/mot.0000000000000305] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Demetris AJ, Bellamy COC, Gandhi CR, Prost S, Nakanuma Y, Stolz DB. Functional Immune Anatomy of the Liver-As an Allograft. Am J Transplant 2016; 16:1653-80. [PMID: 26848550 DOI: 10.1111/ajt.13749] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/26/2016] [Accepted: 01/28/2016] [Indexed: 01/25/2023]
Abstract
The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.
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Affiliation(s)
- A J Demetris
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C O C Bellamy
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - C R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Department of Surgery, University of Cincinnati, Cincinnati, OH
| | - S Prost
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - Y Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - D B Stolz
- Center for Biologic Imaging, Cell Biology, University of Pittsburgh, Pittsburgh, PA
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39
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Barbas AS, Goldaracena N, Dib MJ, Selzner M. Ex-vivo liver perfusion for organ preservation: Recent advances in the field. Transplant Rev (Orlando) 2016; 30:154-60. [PMID: 27158081 DOI: 10.1016/j.trre.2016.03.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 02/15/2016] [Accepted: 03/01/2016] [Indexed: 01/13/2023]
Abstract
Liver transplantation is the optimal treatment for end-stage liver disease but is limited by the severe shortage of donor organs. This shortage has prompted increased utilization of marginal grafts from DCD and extended criteria donors, which poorly tolerate cold storage in comparison to standard criteria grafts. Ex-vivo liver perfusion (EVLP) technology has emerged as a potential alternative to cold storage for organ preservation, but there is no consensus regarding the optimal temperature or conditions for EVLP. Herein, we review recent advances in both pre-clinical and clinical studies, organized by perfusion temperature (hypothermic, subnormothermic, normothermic).
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Affiliation(s)
- A S Barbas
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada.
| | - N Goldaracena
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
| | - M J Dib
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
| | - M Selzner
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
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40
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Ghinolfi D, De Simone P, Lai Q, Pezzati D, Coletti L, Balzano E, Arenga G, Carrai P, Grande G, Pollina L, Campani D, Biancofiore G, Filipponi F. Risk analysis of ischemic-type biliary lesions after liver transplant using octogenarian donors. Liver Transpl 2016; 22:588-598. [PMID: 26784011 DOI: 10.1002/lt.24401] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 11/23/2015] [Accepted: 12/31/2015] [Indexed: 12/22/2022]
Abstract
The use of octogenarian donors to increase the donor pool in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk of ischemic-type biliary lesions (ITBL). The aim of this study was to investigate retrospectively the role of a number of different pre-LT risk factors for ITBL in a selected population of recipients of octogenarian donor grafts. Between January 2003 and December 2013, 123 patients underwent transplantation at our institution with deceased donor grafts from donors of age ≥80 years. Patients were divided into 2 groups based on the presence of ITBL in the posttransplant course. Exclusion criteria were retransplantations, presence of vascular complications, and no availability of procurement liver biopsy. A total of 88 primary LTs were included, 73 (83.0%) with no posttransplant ITBLs and 15 (17.0%) with ITBLs. The median follow-up after LT was 2.1 years (range, 0.7-5.4 years). At multivariate analysis, donor hemodynamic instability (hazard ratio [HR], 7.6; P = 0.005), donor diabetes mellitus (HR, 9.5; P = 0.009), and donor age-Model for End-Stage Liver Disease (HR, 1.0; P = 0.04) were risk factors for ITBL. Transplantation of liver grafts from donors of age ≥80 years is associated with a higher risk for ITBL. However, favorable results can be achieved with accurate donor selection. Donor hemodynamic instability, a donor history of diabetes mellitus, and allocation to higher Model for End-Stage Liver Disease score recipient all increase the risk of ITBL and are associated with worse graft survival when octogenarian donors are used. Liver Transplantation 22 588-598 2016 AASLD.
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Affiliation(s)
- Davide Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Paolo De Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Quirino Lai
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Daniele Pezzati
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Laura Coletti
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Emanuele Balzano
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Giuseppe Arenga
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Paola Carrai
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Gennaro Grande
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Luca Pollina
- Department of Pathology, University of Pisa Medical School Hospital, Pisa, Italy
| | - Daniela Campani
- Department of Pathology, University of Pisa Medical School Hospital, Pisa, Italy
| | - Gianni Biancofiore
- Post-transplant Intensive Care Unit, University of Pisa Medical School Hospital, Pisa, Italy
| | - Franco Filipponi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
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Nassar A, Liu Q, Farias K, Buccini L, Baldwin W, Bennett A, Mangino M, Irefin S, Cywinski J, Okamoto T, Diago Uso T, Iuppa G, Soliman B, Miller C, Quintini C. Impact of Temperature on Porcine Liver Machine Perfusion From Donors After Cardiac Death. Artif Organs 2016; 40:999-1008. [PMID: 27086771 DOI: 10.1111/aor.12699] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Revised: 12/22/2015] [Accepted: 12/28/2015] [Indexed: 12/11/2022]
Abstract
Normothermic machine perfusion (NMP) has been introduced as a promising technology to preserve and possibly repair marginal liver grafts. The aim of this study was to compare the effect of temperature on the preservation of donation after cardiac death (DCD) liver grafts in an ex vivo perfusion model after NMP (38.5°C) and subnormothermic machine perfusion (SNMP, 21°C) with a control group preserved by cold storage (CS, 4°C). Fifteen porcine livers with 60 min of warm ischemia were preserved for 10 h by NMP, SNMP or CS (n = 5/group). After the preservation phase all livers were reperfused for 24 h in an isolated perfusion system with whole blood at 38.5°C to simulate transplantation. At the end of transplant simulation, the NMP group showed significantly lower hepatocellular enzyme level (AST: 277 ± 69 U/L; ALT: 22 ± 2 U/L; P < 0.03) compared to both SNMP (AST: 3243 ± 1048 U/L; ALT: 127 ± 70 U/L) and CS (AST: 3150 ± 1546 U/L; ALT: 185 ± 97 U/L). There was no significant difference between SNMP and CS. Bile production was significantly higher in the NMP group (219 ± 43 mL; P < 0.01) compared to both SNMP (49 ± 84 mL) and CS (12 ± 16 mL) with no significant difference between the latter two groups. Histologically, the NMP livers showed preserved cellular architecture compared to the SNMP and CS groups. NMP was able to recover DCD livers showing superior hepatocellular integrity, biliary function, and microcirculation compared to SNMP and CS. SNMP showed some significant benefit over CS, yet has not shown any advantage over NMP.
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Affiliation(s)
- Ahmed Nassar
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Qiang Liu
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Kevin Farias
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Laura Buccini
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - William Baldwin
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Ana Bennett
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Martin Mangino
- Department of Surgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Samuel Irefin
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Jacek Cywinski
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Toshihiro Okamoto
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Teresa Diago Uso
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Giuseppe Iuppa
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Basem Soliman
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Charles Miller
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Cristiano Quintini
- Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH, USA.
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Spetzler VN, Goldaracena N, Echiverri J, Kaths JM, Louis KS, Adeyi OA, Yip PM, Grant DR, Selzner N, Selzner M. Subnormothermic ex vivo liver perfusion is a safe alternative to cold static storage for preserving standard criteria grafts. Liver Transpl 2016; 22:111-9. [PMID: 26390093 DOI: 10.1002/lt.24340] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Revised: 08/01/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023]
Abstract
We developed a novel technique of subnormothermic ex vivo liver perfusion (SNEVLP) for the storage of liver grafts before transplantation. To test the safety of SNEVLP for the nonextended criteria grafts (standard grafts), we compared it to a control group with minimal cold static storage (CS) time. Heart-beating pig liver retrieval was performed. Grafts were either stored in cold unmodified University of Wisconsin solution (CS-1), in cold University of Wisconsin solution with ex vivo perfusion additives (CS-2), or preserved with a sequence of 3 hours CS and 3 hours SNEVLP (33°C), followed by orthotopic liver transplantation. Liver function tests and histology were investigated. Aspartate aminotransferase (AST) levels during SNEVLP remained stable (54.3 ± 12.6 U/L at 1 hour to 47.0 ± 31.9 U/L at 3 hours). Posttransplantation, SNEVLP versus CS-1 livers had decreased AST levels (peak at day 1, 1081.9 ± 788.5 versus 1546.7 ± 509.3 U/L; P = 0.14; at day 2, 316.7 ± 188.1 versus 948.2 ± 740.9 U/L; P = 0.04) and alkaline phosphatase levels (peak at day 1, 150.4 ± 19.3 versus 203.7 ± 33.6 U/L; P = 0.003). Bilirubin levels were constantly within the physiological range in the SNEVLP group, whereas the CS-1 group presented a large standard deviation, including pathologically increased values. Hyaluronic acid as a marker of endothelial cell (EC) function was markedly improved by SNEVLP during the early posttransplant phase (5 hours posttransplant, 1172.75 ± 598.5 versus 5540.5 ± 2755.4 ng/mL). Peak international normalized ratio was similar between SNEVLP and CS-1 groups after transplantation. Immunohistochemistry for cleaved caspase 3 demonstrated more apoptotic sinusoidal cells in the CS-1 group when compared to SNEVLP grafts 2 hours after reperfusion (19.4 ± 19.5 versus 133.2 ± 48.8 cells/high-power field; P = 0.002). Adding normothermic CS-2 had no impact on liver injury or function after transplantation when compared to CS-1. In conclusion, SNEVLP is safe to use for standard donor grafts and is associated with improved EC and bile duct injury even in grafts with minimal CS time.
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Affiliation(s)
- Vinzent N Spetzler
- Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Nicolas Goldaracena
- Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Juan Echiverri
- Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - J Moritz Kaths
- Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Kristine S Louis
- Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Oyedele A Adeyi
- Departments of Pathology, University of Toronto, Toronto, Ontario, Canada
| | - Paul M Yip
- Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - David R Grant
- Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - Nazia Selzner
- Departments of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Markus Selzner
- Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada
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Xie F, Zhang SH, Cheng J, Wang HW, Fei X, Jiao ZY, Tang J, Luo YK. Evaluation of hepatic vascular endothelial injury during liver storage by molecular detection and targeted contrast-enhanced ultrasound imaging. IUBMB Life 2015; 68:51-7. [PMID: 26662566 DOI: 10.1002/iub.1459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 11/16/2015] [Indexed: 11/12/2022]
Abstract
We hypothesized that lack of the high-energy phosphates during liver storage may potentially cause persistent injury to the vascular endothelium. Biopsies were obtained from livers obtained from beating heart human donors, stored either in the standard storage solution, that is, University of Wisconsin solution (UWS) or Celsior, and examined for various markers related to progressive endothelial injury. The expression of P2Y1 receptor, the major signal transduction machinery for adenosine triphosphate/adenosine diphosphate, decreased in hepatic vascular endothelial cells over time. Despite unaltered endothelial nitric oxide synthase (eNOS) levels, serine1177-phosphorylated eNOS, the active form of eNOS, progressively decreased with time. The production of nitric oxide enzyme decreased with time when liver tissues were examined in vitro. This also coincided with decreased interaction of eNOS with actin nucleating proteins like myristoylated alanine-rich C kinase substrate and Rac1, which plays a role in modulating the cytoskeleton and helps position eNOS in a favorable cytosolic position for active enzymatic activity. Conversely, the interaction of eNOS with caveolin1 was significantly increased 6 H after ex vivo storage. Finally, we demonstrated by targeted contrast-enhanced ultrasound that membrane-bound vascular cell adhesion molecule-1 in the hepatic vascular endothelial cell increased after 6 H of ex vivo storage. Overall, the results of this study provide evidence of a progressive hepatic vascular endothelial injury during the ex vivo storage. This may be a causative factor for ischemic cholangiopathy and delayed graft function post liver transplantation. © 2015 IUBMB Life, 68(1):51-57, 2015.
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Affiliation(s)
- Fang Xie
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China.,Department of Ultrasound, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Shu-Hua Zhang
- Department of Ultrasound, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Jia Cheng
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Hong-Wei Wang
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Xiang Fei
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Zi-Yu Jiao
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Jie Tang
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Yu-Kun Luo
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China
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44
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Utilization of Machine Perfusion and Nanotechnology for Liver Transplantation. CURRENT TRANSPLANTATION REPORTS 2015. [DOI: 10.1007/s40472-015-0076-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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45
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Westerkamp AC, Mahboub P, Meyer SL, Hottenrott M, Ottens PJ, Wiersema-Buist J, Gouw ASH, Lisman T, Leuvenink HGD, Porte RJ. End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature. Liver Transpl 2015; 21:1300-11. [PMID: 26097213 DOI: 10.1002/lt.24200] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/06/2015] [Accepted: 06/08/2015] [Indexed: 12/20/2022]
Abstract
A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation.
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Affiliation(s)
- Andrie C Westerkamp
- Surgical Research Laboratory.,Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
| | | | - Sophie L Meyer
- Surgical Research Laboratory.,Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
| | | | | | | | - Annette S H Gouw
- Departments of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ton Lisman
- Surgical Research Laboratory.,Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
| | | | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
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46
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Abstract
PURPOSE OF REVIEW To summarize the history of organ preservation and place into this context the current trends in preservation. RECENT FINDINGS Multiple large retrospective studies have analyzed cold preservation solutions in an attempt to determine superiority with largely negative results. Experimental and some clinical studies have examined machine perfusion of procured grafts, in both hypothermic and normothermic contexts with variable, but promising, results. Lastly, there are experimental efforts to evaluate mesenchymal stem cell therapy on rehabilitation of marginal donor organs. SUMMARY New trends in organ preservation may soon translate into more efficient use of the limited donor pool.
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47
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Donation after circulatory death: the current state and technical approaches to organ procurement. Curr Opin Organ Transplant 2015; 20:127-32. [PMID: 25719900 DOI: 10.1097/mot.0000000000000179] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW In this review, we discuss the current state of donation after circulatory death (DCD). We define the DCD donor and describe the current protocols in management of the DCD patient. We then discuss current techniques in organ procurement of the lung and abdominal organs. RECENT FINDINGS Although donation after brain death is preferable to DCD, recent data have demonstrated acceptable early outcomes in both thoracic and abdominal organ transplant. In spite of advancements in surgical techniques and organ preservation, much has yet to be learned to minimize warm ischemia time and reperfusion injury in the DCD population. SUMMARY In light of the continually growing disparity between organ supply and demand, DCD has regained traction as a means to increase the donor pool.
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48
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Orman ES, Mayorga ME, Wheeler SB, Townsley RM, Toro-Diaz HH, Hayashi PH, Barritt SA. Declining liver graft quality threatens the future of liver transplantation in the United States. Liver Transpl 2015; 21:1040-50. [PMID: 25939487 PMCID: PMC4566853 DOI: 10.1002/lt.24160] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 03/31/2015] [Accepted: 04/22/2015] [Indexed: 12/31/2022]
Abstract
National liver transplantation (LT) volume has declined since 2006, in part because of worsening donor organ quality. Trends that degrade organ quality are expected to continue over the next 2 decades. We used the United Network for Organ Sharing (UNOS) database to inform a 20-year discrete event simulation estimating LT volume from 2010 to 2030. Data to inform the model were obtained from deceased organ donors between 2000 and 2009. If donor liver utilization practices remain constant, utilization will fall from 78% to 44% by 2030, resulting in 2230 fewer LTs. If transplant centers increase their risk tolerance for marginal grafts, utilization would decrease to 48%. The institution of "opt-out" organ donation policies to increase the donor pool would still result in 1380 to 1866 fewer transplants. Ex vivo perfusion techniques that increase the use of marginal donor livers may stabilize LT volume. Otherwise, the number of LTs in the United States will decrease substantially over the next 15 years. In conclusion, the transplant community will need to accept inferior grafts and potentially worse posttransplant outcomes and/or develop new strategies for increasing organ donation and utilization in order to maintain the number of LTs at the current level.
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Affiliation(s)
- Eric S. Orman
- Department of Medicine, University of North Carolina, Chapel Hill, NC,Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Maria E. Mayorga
- Department of Industrial and Systems Engineering, North Carolina State University, Raleigh, NC
| | - Stephanie B. Wheeler
- Department of Health Policy and Management, University of North Carolina, Chapel Hill, NC
| | - Rachel M. Townsley
- Department of Industrial and Systems Engineering, North Carolina State University, Raleigh, NC
| | | | - Paul H. Hayashi
- Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - Sidney A. Barritt
- Department of Medicine, University of North Carolina, Chapel Hill, NC
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49
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Kaths JM, Spetzler VN, Goldaracena N, Echeverri J, Louis KS, Foltys DB, Strempel M, Yip P, John R, Mucsi I, Ghanekar A, Bagli D, Robinson L, Selzner M. Normothermic Ex Vivo Kidney Perfusion for the Preservation of Kidney Grafts prior to Transplantation. J Vis Exp 2015:e52909. [PMID: 26275014 PMCID: PMC4544894 DOI: 10.3791/52909] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Kidney transplantation has become a well-established treatment option for patients with end-stage renal failure. The persisting organ shortage remains a serious problem. Therefore, the acceptance criteria for organ donors have been extended leading to the usage of marginal kidney grafts. These marginal organs tolerate cold storage poorly resulting in increased preservation injury and higher rates of delayed graft function. To overcome the limitations of cold storage, extensive research is focused on alternative normothermic preservation methods. Ex vivo normothermic organ perfusion is an innovative preservation technique. The first experimental and clinical trials for ex vivo lung, liver, and kidney perfusions demonstrated favorable outcomes. In addition to the reduction of cold ischemic injury, the method of normothermic kidney storage offers the opportunity for organ assessment and repair. This manuscript provides information about kidney retrieval, organ preservation techniques, and isolated ex vivo normothermic kidney perfusion (NEVKP) in a porcine model. Surgical techniques, set up for the perfusion solution and the circuit, potential assessment options, and representative results are demonstrated.
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Affiliation(s)
- J Moritz Kaths
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital; Division of Nephrology, The Hospital for Sick Children, Toronto;
| | - Vinzent N Spetzler
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital
| | - Nicolas Goldaracena
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital
| | - Juan Echeverri
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital
| | - Kristine S Louis
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital
| | - Daniel B Foltys
- Department of General, Visceral & Transplant Surgery, University Medical Center Mainz
| | - Mari Strempel
- Department of Abdominal, Vascular & Transplant Surgery, Merheim Medical Center Cologne
| | - Paul Yip
- Laboratory Medicine & Pathobiology, Toronto General Hospital
| | - Rohan John
- Laboratory Medicine & Pathobiology, Toronto General Hospital
| | - Istvan Mucsi
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital
| | - Anand Ghanekar
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital
| | - Darius Bagli
- Departments of Surgery (Urology) & Physiology, The Hospital for Sick Children, Toronto; Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto
| | - Lisa Robinson
- Division of Nephrology, The Hospital for Sick Children, Toronto
| | - Markus Selzner
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital
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50
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Weeder PD, van Rijn R, Porte RJ. Machine perfusion in liver transplantation as a tool to prevent non-anastomotic biliary strictures: Rationale, current evidence and future directions. J Hepatol 2015; 63:265-75. [PMID: 25770660 DOI: 10.1016/j.jhep.2015.03.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 02/25/2015] [Accepted: 03/02/2015] [Indexed: 02/08/2023]
Abstract
The high incidence of non-anastomotic biliary strictures (NAS) after transplantation of livers from extended criteria donors is currently a major barrier to widespread use of these organs. This review provides an update on the most recent advances in the understanding of the etiology of NAS. These new insights give reason to believe that machine perfusion can reduce the incidence of NAS after transplantation by providing more protective effects on the biliary tree during preservation of the donor liver. An overview is presented regarding the different endpoints that have been used for assessment of biliary injury and function before and after transplantation, emphasizing on methods used during machine perfusion. The wide spectrum of different approaches to machine perfusion is discussed, including the many different combinations of techniques, temperatures and perfusates at varying time points. In addition, the current understanding of the effect of machine perfusion in relation to biliary injury is reviewed. Finally, we explore directions for future research such as the application of (pharmacological) strategies during machine perfusion to further improve preservation. We stress the great potential of machine perfusion to possibly expand the donor pool by reducing the incidence of NAS in extended criteria organs.
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Affiliation(s)
- Pepijn D Weeder
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rianne van Rijn
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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