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1
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Yang S, Hou W, Liu L. Progress in preservation of intestinal grafts by oxygenated hypothermic machine perfusion. Transplant Rev (Orlando) 2024; 38:100802. [PMID: 37891046 DOI: 10.1016/j.trre.2023.100802] [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] [Received: 02/09/2023] [Revised: 07/03/2023] [Accepted: 10/07/2023] [Indexed: 10/29/2023]
Abstract
Intestine transplantation (IT) is a critical treatment strategy for irreversible intestinal failure. Among all abdominal solid organ transplants, the intestine was the most vulnerable to ischemia and reperfusion injury (IRI). The static cold storage (SCS) technique is currently the most commonly used graft preservation method, but its hypoxia condition causes metabolic disorders, resulting in the occurrence of IRI, limiting its application in marginal organs. It is especially important to improve preservation techniques in order to minimize damage to marginal donor organs, which draws more attention to machine perfusion (MP). There has been much debate about whether it is necessary to increase oxygen in these conditions to support low levels of metabolism since the use of machine perfusion to preserve organs. There is evidence that oxygenation helps to restore intracellular ATP levels in the intestine after thermal or cold ischemia damage. The goal of this review is to provide an overview of the role of oxygen in maintaining environmental stability in the gut under hypoxic conditions, as well as to investigate the possibilities and mechanisms of oxygen delivery during preservation in intestine transplantation studies and clinical models.
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Affiliation(s)
- Shuang Yang
- National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Wen Hou
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China.
| | - Lei Liu
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, China; Organ Transplant Department, Tianjin First Central Hospital, Nankai University, Tianjin, China.
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Abstract
The past decade has been the foreground for a radical revolution in the field of preservation in abdominal organ transplantation. Perfusion has increasingly replaced static cold storage as the preferred and even gold standard preservation method for marginal-quality organs. Perfusion is dynamic and offers several advantages in comparison with static cold storage. These include the ability to provide a continuous supply of new metabolic substrates, clear metabolic waste products, and perform some degree of organ viability assessment before actual transplantation in the recipient. At the same time, the ongoing importance of static cold storage cannot be overlooked, in particular when it comes to logistical and technical convenience and cost, not to mention the fact that it continues to work well for the majority of transplant allografts. The present review article provides an overview of the fundamental concepts of organ preservation, providing a brief history of static cold preservation and description of the principles behind and basic components of cold preservation solutions. An evaluation of current evidence supporting the use of different preservation solutions in abdominal organ transplantation is provided. As well, the range of solutions used for machine perfusion of abdominal organs is described, as are variations in their compositions related to changing metabolic needs paralleling the raising of the temperature of the perfusate from hypothermic to normothermic range. Finally, appraisal of new preservation solutions that are on the horizon is provided.
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3
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Muth V, Gassner JMGV, Moosburner S, Lurje G, Michelotto J, Strobl F, Knaub K, Engelmann C, Tacke F, Selzner M, Pratschke J, Sauer IM, Raschzok N. Ex Vivo Liver Machine Perfusion: Comprehensive Review of Common Animal Models. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:10-27. [PMID: 35848526 DOI: 10.1089/ten.teb.2022.0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The most common preservation technique for liver grafts is static cold storage. Due to the organ shortage for liver transplantation (LT), extended criteria donor (ECD) allografts are increasingly used-despite the higher risk of inferior outcome after transplantation. Ex vivo liver machine perfusion (MP) has been developed to improve the outcome of transplantation, especially with ECD grafts, and is currently under evaluation in clinical trials. We performed a literature search on PubMed and ISI Web of Science to assemble an overview of rodent and porcine animal models of ex vivo liver MP for transplantation, which is essential for the present and future development of clinical liver MP. Hypothermic, subnormothermic, and normothermic MP systems have been successfully used for rat and pig LT. In comparison with hypothermic systems, normothermic perfusion often incorporates a dialysis unit. Moreover, it enables metabolic assessment of liver grafts. Allografts experiencing warm ischemic time have a superior survival rate after MP compared with cold storage alone, irrespective of the temperature used for perfusion. Furthermore, ex vivo MP improves the outcome of regular and ECD liver grafts in animal models. Small and large animal models of ex vivo liver MP are available to foster the further development of this new technology. Impact Statement Ex vivo machine perfusion is an important part of current research in the field of liver transplantation. While evidence for improve storage is constantly rising, the development of future applications such as quality assessment and therapeutic interventions necessitates robust animal models. This review is intended to provide an overview of this technology in common large and small animal models and to give an outlook on future applications. Moreover, we describe developmental steps that can be followed by others, and which can help to decrease the number of animals used for experiments based on the replace, reduce, refine concept.
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Affiliation(s)
- Vanessa Muth
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Joseph M G V Gassner
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Moosburner
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Julian Michelotto
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Felix Strobl
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Kristina Knaub
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Markus Selzner
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, Canada
| | - Johann Pratschke
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Igor M Sauer
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nathanael Raschzok
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
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4
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Hou W, Yang S, Lu J, Shi Y, Chen J, Chen D, Wang F, Liu L. Hypothermic machine perfusion alleviates ischemia-reperfusion injury of intestinal transplantation in pigs. Front Immunol 2023; 14:1117292. [PMID: 36926337 PMCID: PMC10011072 DOI: 10.3389/fimmu.2023.1117292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/16/2023] [Indexed: 03/08/2023] Open
Abstract
Background Intestinal transplantation (IT) has become an important procedure for the treatment of irreversible intestinal failure. However, IT is extremely vulnerable to ischemia-reperfusion injury (IRI). Due to the limitations of static cold storage (SCS), hypothermic machine perfusion (HMP) is rapidly gaining popularity. In this study, the intestinal HMP system is established and HMP is compared with SCS. Methods An intestinal HMP system was built. Ten miniature pigs were randomly divided into the HMP and SCS groups, and their intestines were perfused using the HMP device and SCS, respectively, followed by orthotopic auto-transplantation. Analysis was done on the grafts between the two groups. Results Operation success rates of the surgery were 100% in both groups. The 7-day survival rate was 100% in the HMP group, which was significantly higher than that of the SCS group (20%, P< 0.05). The pathological results showed that fewer injuries of grafts were in the HMP group. Endotoxin (ET), IL-1, IL-6, IFN-γ and TNF-α levels in the HMP group were significantly lower than in the SCS group (P<0.05), whereas IL-10 levels were significantly higher (P<0.05).The intestinal expression levels of ZO-1 and Occludin were higher in the HMP group compared to the SCS group, whereas Toll-like receptor 4 (TLR4), nuclear factor kappa B (NFκB), and caspase-3 were lower. Conclusions In this study, we established a stable intestinal HMP system and demonstrated that HMP could significantly alleviate intestinal IRI and improve the outcome after IT.
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Affiliation(s)
- Wen Hou
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Shuang Yang
- National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China
| | - Jiansen Lu
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Yuan Shi
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Jing Chen
- Organ Transplant Department, Tianjin First Central Hospital, Tianjin, China
| | - Decheng Chen
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Fei Wang
- School of Medicine, Nankai University, Tianjin, China
| | - Lei Liu
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China.,Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, Tianjin, China.,Organ Transplant Department, Tianjin First Central Hospital, Tianjin, China
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5
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Panconesi R, Flores Carvalho M, Dondossola D, Muiesan P, Dutkowski P, Schlegel A. Impact of Machine Perfusion on the Immune Response After Liver Transplantation - A Primary Treatment or Just a Delivery Tool. Front Immunol 2022; 13:855263. [PMID: 35874758 PMCID: PMC9304705 DOI: 10.3389/fimmu.2022.855263] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 05/31/2022] [Indexed: 12/12/2022] Open
Abstract
The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion techniques are therefore frequently discussed with an ever-increasing number of experimental and clinical studies. Two main approaches, hypothermic and normothermic perfusion, are the leading strategies to be introduced in clinical practice in many western countries today. Despite this success, the number of studies, which provide robust data on the underlying mechanisms of protection conveyed through this technology remains scarce, particularly in context of different stages of ischemia-reperfusion-injury (IRI). Prior to a successful clinical implementation of machine perfusion, the concept of IRI and potential key molecules, which should be addressed to reduce IRI-associated inflammation, requires a better exploration. During ischemia, Krebs cycle metabolites, including succinate play a crucial role with their direct impact on the production of reactive oxygen species (ROS) at mitochondrial complex I upon reperfusion. Such features are even more pronounced under normothermic conditions and lead to even higher levels of downstream inflammation. The direct consequence appears with an activation of the innate immune system. The number of articles, which focus on the impact of machine perfusion with and without the use of specific perfusate additives to modulate the inflammatory cascade after transplantation is very small. This review describes first, the subcellular processes found in mitochondria, which instigate the IRI cascade together with proinflammatory downstream effects and their link to the innate immune system. Next, the impact of currently established machine perfusion strategies is described with a focus on protective mechanisms known for the different perfusion approaches. Finally, the role of such dynamic preservation techniques to deliver specific agents, which appear currently of interest to modulate this posttransplant inflammation, is discussed together with future aspects in this field.
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Affiliation(s)
- Rebecca Panconesi
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della, Scienza di Torino, University of Turin, Turin, Italy
| | - Mauricio Flores Carvalho
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Paolo Muiesan
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | - Andrea Schlegel
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
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6
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Kvietkauskas M, Leber B, Strupas K, Stiegler P, Schemmer P. Machine Perfusion of Extended Criteria Donor Organs: Immunological Aspects. Front Immunol 2020; 11:192. [PMID: 32180769 PMCID: PMC7057848 DOI: 10.3389/fimmu.2020.00192] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 01/24/2020] [Indexed: 12/20/2022] Open
Abstract
Due to higher vulnerability and immunogenicity of extended criteria donor (ECD) organs used for organ transplantation (Tx), the discovery of new treatment strategies, involving tissue allorecognition pathways, is important. The implementation of machine perfusion (MP) led to improved estimation of the organ quality and introduced the possibility to achieve graft reconditioning prior to Tx. A significant number of experimental and clinical trials demonstrated increasing support for MP as a promising method of ECD organ preservation compared to classical static cold storage. MP reduced ischemia-reperfusion injury resulting in the protection from inadequate activation of innate immunity. However, there are no general agreements on MP protocols, and clinical application is limited. The objective of this comprehensive review is to summarize literature on immunological effects of MP of ECD organs based on experimental studies and clinical trials.
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Affiliation(s)
- Mindaugas Kvietkauskas
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Bettina Leber
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
| | | | - Philipp Stiegler
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
| | - Peter Schemmer
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
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7
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Kim J, Zimmerman M, Hong J. Emerging Innovations in Liver Preservation and Resuscitation. Transplant Proc 2018; 50:2308-2316. [DOI: 10.1016/j.transproceed.2018.03.080] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 03/02/2018] [Indexed: 12/18/2022]
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9
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Ghinolfi D, Rreka E, Pezzati D, Filipponi F, De Simone P. Perfusion machines and hepatocellular carcinoma: a good match between a marginal organ and an advanced disease? Transl Gastroenterol Hepatol 2017; 2:87. [PMID: 29264425 DOI: 10.21037/tgh.2017.10.01] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 09/27/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the second leading cause of cancer-related deaths and the leading cause of death in patients with cirrhosis. Liver transplantation (LT) represents the ideal treatment for selected patients as it removes both the tumor and the underlying cirrhotic liver with 5-year survival rates higher than 70%. Unfortunately, due to tumor characteristics, patient co-morbidities or shortage of organs available for transplant, only 20% of patients can undergo curative treatment. Ex situ machine perfusion (MP) is a technology recently introduced that might potentially improve organ preservation, allow graft assessment and increase the pool of available organs. The purpose of this review is to provide an update on the current role of ex situ liver MP in liver transplantation for HCC patients.
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Affiliation(s)
- Davide Ghinolfi
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Erion Rreka
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Daniele Pezzati
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Franco Filipponi
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Paolo De Simone
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
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10
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Kron P, Schlegel A, Mancina L, Clavien PA, Dutkowski P. Hypothermic oxygenated perfusion (HOPE) for fatty liver grafts in rats and humans. J Hepatol 2017; 68:S0168-8278(17)32268-7. [PMID: 28870676 DOI: 10.1016/j.jhep.2017.08.028] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 08/16/2017] [Accepted: 08/18/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS Pretreatment of marginal organs by perfusion is a promising opportunity to make more organs available for transplantation. Protection of human donation after cardiac death (DCD) livers by a novel machine perfusion technique, hypothermic oxygenated perfusion (HOPE), was recently established. Herein, we tested whether HOPE is also useful for fatty liver grafts, using a rodent transplant model. METHODS Rats were fed over three weeks with a special methionine-choline-deficient diet (MCDD) to induce severe hepatic macrosteatosis (≥60%). Afterwards, livers were transplanted with either minimal or 12h cold storage. Additional liver grafts were treated after 12h cold storage with 1h HOPE before transplantation. Graft injury after orthotopic liver transplantation (OLT) was assessed in terms of oxidative stress, damage-associated molecular patterns release, toll-like receptor-4 activation, cytokine release, endothelial activation, and the development of necrosis and fibrosis. RESULTS Implantation of cold stored macrosteatotic liver grafts induced massive reperfusion injury after OLT, compared to controls (non-fatty livers). HOPE treatment after cold storage failed to change the degree of steatosis itself, but markedly decreased reperfusion injury after OLT, as detected by less oxidative stress, less nuclear injury, less Kupffer- and endothelial cell activation, as well as less fibrosis within one week after OLT. Protective effects were lost in the absence of oxygen in the HOPE perfusate. CONCLUSION HOPE after cold storage of fatty livers prevents significant reperfusion injury and improves graft function, comparable to the effects of HOPE in DCD livers and DCD kidneys. HOPE treatment is easy and may become a universal concept to further expand the donor pool. LAY SUMMARY An increasing number of donor livers contain fat. It is important to harness marginal livers, which may contain fat, as the stock of donor livers is limited. Hypothermic oxygenated perfusion (HOPE) prevents reperfusion injury and improves liver graft function. HOPE offers a simple and low-cost option for treating liver grafts in transplant centers, even after cold storage, instead of transporting machines to the place of procurement. HOPE could be used globally to expand the donor pool.
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Affiliation(s)
- Philipp Kron
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Andrea Schlegel
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Leandro Mancina
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Pierre-Alain Clavien
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland.
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12
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Liu S, Pang Q, Zhang J, Zhai M, Liu S, Liu C. Machine perfusion versus cold storage of livers: a meta-analysis. Front Med 2016; 10:451-464. [PMID: 27837413 DOI: 10.1007/s11684-016-0474-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 07/19/2016] [Indexed: 12/18/2022]
Abstract
Different organ preservation methods are key factors influencing the results of liver transplantation. In this study, the outcomes of experimental models receiving donation after cardiac death (DCD) livers preserved through machine perfusion (MP) or static cold storage (CS) were compared by conducting a meta-analysis. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated to compare pooled data from two animal species. Twenty-four studies involving MP preservation were included in the meta-analysis. Compared with CS preservation, MP can reduce the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and hyaluronic acid (HA) and the changes in liver weight. By contrast, MP can enhance bile production and portal vein flow (PVF). Alkaline phosphatase (ALP) levels and histological changes significantly differed between the two preservation methods. In conclusion, MP of DCD livers is superior to CS in experimental animals.
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Affiliation(s)
- Sushun Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Qing Pang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jingyao Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Mimi Zhai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Sinan Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Chang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China.
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13
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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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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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Regulated Oxygenation of Rewarming Machine Perfusion for Porcine Donation After Cardiac Death Liver Transplantation. Transplant Proc 2016; 48:1244-6. [DOI: 10.1016/j.transproceed.2015.12.098] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 12/30/2015] [Indexed: 01/31/2023]
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ANKRD53 interacts with DDA3 and regulates chromosome integrity during mitosis. Biochem Biophys Res Commun 2016; 470:484-491. [DOI: 10.1016/j.bbrc.2016.01.144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 01/22/2016] [Indexed: 12/14/2022]
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Schlegel A, Dutkowski P. Hypothermic liver perfusion. Liver Transpl 2015; 21 Suppl 1:S8-12. [PMID: 26334767 DOI: 10.1002/lt.24321] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/26/2015] [Accepted: 08/31/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Andrea Schlegel
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
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Abstract
The first liver transplantation (LT) was performed by Thomas E Starzl five decades ago, and yet it remains the only therapeutic option offering gold standard treatment for end-stage liver disease (ESLD) and acute liver failure (ALF) and certain early-stage liver tumors. Post-liver transplantation survival has also dramatically improved over the last few decades despite increasing donor and recipient age and more frequent use of marginal organs to overcome the organ shortage. Currently, the overall 1 year survival following LT in the United States is reported as 85 to 90%, while the 10 years survival rate is ~50% (http://www.unos.org). The improvements are mainly due to progress in surgical techniques, postoperative intensive care, and the advent of new immunosuppressive agents. There are a number of factors that influence the outcomes prior to transplantation. Since 2002, the model for end-stage liver disease (MELD) score has been considered a predicting variable. It has been used to prioritize patients on the transplant waiting list and is currently the standard method used to assess severity in all etiologies of cirrhosis. Hepatocellular carcinoma (HCC) is the most common standard MELD exception because the MELD does not necessarily reflect the medical urgency of patients with HCC. The criteria for candidates with HCC for receiving LT have evolved over the past decade. Now, patients with HCC who do not meet the traditional Milan (MC) or UCSF criteria for LT often undergo downstaging therapy I an effort to shrink the tumor size. The shortage of donor organs is a universal problem. In some countries, the development of a deceased organ donation program has been prevented due to socioeconomic, cultural, legal and other factors. Due to the shortage of cadaveric donors, several innovative techniques have been developed to expand the organ donor pool, such as split liver grafts, marginal- or extended-criteria donors, live donor liver transplantation (LDLT), and the use of organs donated after cardiac death. Herein, we briefly summarize recent advances in knowledge related to LT. We also report common causes of death after liver transplant, including the recurrence of hepatitis C virus (HCV) and its management, and coronary artery disease (CAD), including the role of the cardiac calcium score in identifying occult CAD. HOW TO CITE THIS ARTICLE Dogan S, Gurakar A. Liver Transplantation Update: 2014. Euroasian J Hepato-Gastroenterol 2015;5(2):98-106.
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Affiliation(s)
- Serkan Dogan
- Department of Gastroenterology, Johns Hopkins School of Medicine, Maryland, United States
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Maryland, United States
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Schlegel A, Kron P, Dutkowski P. Hypothermic Oxygenated Liver Perfusion: Basic Mechanisms and Clinical Application. CURRENT TRANSPLANTATION REPORTS 2015; 2:52-62. [PMID: 26097802 PMCID: PMC4469295 DOI: 10.1007/s40472-014-0046-1] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dynamic preservation strategies such as hypothermic machine perfusion are increasingly discussed to improve liver graft quality before transplantation. This review summarizes current knowledge of this perfusion technique for liver preservation. We discuss optimization of perfusion conditions and current strategies to assess graft quality during cold perfusion. Next, we provide an overview of possible pathways of protection from ischemia-reperfusion injury. Finally, we report on recent clinical applications of human hypothermic machine liver perfusion.
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Affiliation(s)
- A. Schlegel
- Department of Surgery and Transplantation, University Hospital Zürich, Raemistr. 100, 8091 Zurich, Switzerland
| | - P. Kron
- Department of Surgery and Transplantation, University Hospital Zürich, Raemistr. 100, 8091 Zurich, Switzerland
| | - P. Dutkowski
- Department of Surgery and Transplantation, University Hospital Zürich, Raemistr. 100, 8091 Zurich, Switzerland
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Schlegel A, Kron P, Graf R, Dutkowski P, Clavien PA. Warm vs. cold perfusion techniques to rescue rodent liver grafts. J Hepatol 2014; 61:1267-75. [PMID: 25086285 DOI: 10.1016/j.jhep.2014.07.023] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Revised: 06/26/2014] [Accepted: 07/15/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS A variety of liver perfusion techniques have been proposed to protect liver grafts prior to implantation. We compared hypothermic and normothermic oxygenated perfusion techniques in a rat liver transplant model, using higher risk grafts obtained after cardiac arrest (DCD). METHODS Rat livers were subjected to 30 or 60 min in situ warm ischemia, without application of heparin. Livers were excised and stored for 4 h at 4°C, mimicking DCD organ procurement, followed by conventional organ transport. In experimental groups, DCD liver grafts received a 4 h normothermic oxygenated perfusion through the portal vein and the hepatic artery instead of cold storage. The perfusate consisted of either full blood or leukocyte-depleted blood (normothermic groups). Other livers underwent hypothermic oxygenated perfusion (HOPE) for 1 h after warm ischemia and 4 h cold storage (HOPE group). Liver injury was assessed during machine perfusion and after isolated liver reperfusion, and by orthotopic liver transplantation (OLT). RESULTS DCD livers, subjected to normothermic perfusion, disclosed reduced injury and improved survival compared to cold storage after limited warm ischemia of 30 min (70%; 7/10), but failed to protect from lethal injury in grafts exposed to 60 min warm ischemia (0%; 0/10). This finding was consistent with Kupffer and endothelial cell activation in cold stored and normothermic perfused livers. In contrast, HOPE protected from hepatocyte and non-parenchymal cell injury and led to 90% (9/10) and 63% (5/8) animal survival after 30 and 60 min of donor warm ischemia, respectively. CONCLUSIONS This is the first evidence that HOPE is superior to normothermic oxygenated perfusion in a clinically relevant model through modulation of the innate immunity and endothelial cell activation.
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Affiliation(s)
- Andrea Schlegel
- Department of Surgery, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Philipp Kron
- Department of Surgery, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Rolf Graf
- Department of Surgery, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Pierre-Alain Clavien
- Department of Surgery, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland.
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Graham JA, Guarrera JV. "Resuscitation" of marginal liver allografts for transplantation with machine perfusion technology. J Hepatol 2014; 61:418-31. [PMID: 24768755 DOI: 10.1016/j.jhep.2014.04.019] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 04/13/2014] [Accepted: 04/16/2014] [Indexed: 12/17/2022]
Abstract
As the rate of medically suitable donors remains relatively static worldwide, clinicians have looked to novel methods to meet the ever-growing demand of the liver transplant waiting lists worldwide. Accordingly, the transplant community has explored many strategies to offset this deficit. Advances in technology that target the ex vivo "preservation" period may help increase the donor pool by augmenting the utilization and improving the outcomes of marginal livers. Novel ex vivo techniques such as hypothermic, normothermic, and subnormothermic machine perfusion may be useful to "resuscitate" marginal organs by reducing ischemia/reperfusion injury. Moreover, other preservation techniques such as oxygen persufflation are explored as they may also have a role in improving function of "marginal" liver allografts. Currently, marginal livers are frequently discarded or can relegate the patient to early allograft dysfunction and primary non-function. Bench to bedside advances are rapidly emerging and hold promise for expanding liver transplantation access and improving outcomes.
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Affiliation(s)
- Jay A Graham
- Center for Liver Disease and Transplantation, Department of Surgery, Columbia University College of Physicians and Surgeons and New York Presbyterian Hospital, New York, NY 10032, USA
| | - James V Guarrera
- Center for Liver Disease and Transplantation, Department of Surgery, Columbia University College of Physicians and Surgeons and New York Presbyterian Hospital, New York, NY 10032, USA.
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Schlegel A, Dutkowski P. Role of hypothermic machine perfusion in liver transplantation. Transpl Int 2014; 28:677-89. [PMID: 24852621 DOI: 10.1111/tri.12354] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/05/2014] [Accepted: 05/19/2014] [Indexed: 12/15/2022]
Abstract
Machine liver perfusion has significantly evolved during the last ten years to optimize extended criteria liver grafts and to address the worldwide organ shortage. This review gives an overview on available ex vivo and in vivo data on hypothermic machine liver perfusion. We discuss also possible protective pathways and show most recent clinical applications of hypothermic machine liver perfusion in human.
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Affiliation(s)
- Andrea Schlegel
- Department of Visceral Surgery and Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Zurich, Switzerland
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Schlegel A, Graf R, Clavien PA, Dutkowski P. Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation. J Hepatol 2013; 59:984-91. [PMID: 23820408 DOI: 10.1016/j.jhep.2013.06.022] [Citation(s) in RCA: 137] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Revised: 06/18/2013] [Accepted: 06/23/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS The use of livers from donors after cardiac arrest (DCD) is increasing in many countries to overcome organ shortage. Due to additional warm ischemia before preservation, those grafts are at higher risk of failure and bile duct injury. Several competing rescue strategies by machine perfusion techniques have been developed with, however, unclear effects on biliary injury. We analyze the impact of an end-ischemic Hypothermic Oxygenated PErfusion (HOPE) approach applied only through the portal vein for 1h before graft implantation. METHODS Rat livers were subjected to 30-min in situ warm ischemia, followed by subsequent 4-h cold storage, mimicking DCD-organ procurement and conventional organ transport. Livers in the HOPE group underwent also passive cold storage for 4h, but were subsequently machine perfused for 1h before implantation. Outcome was tested by liver transplantation (LT) at 12h after implantation (n=10 each group) and after 4 weeks (n=10 each group), focusing on early reperfusion injury, immune response, and later intrahepatic biliary injury. RESULTS All animals survived after LT. However, reperfusion injury was significantly decreased by HOPE treatment as tested by hepatocyte injury, Kupffer cell activation, and endothelial cell activation. Recipients receiving non-perfused DCD livers disclosed less body weight gain, increased bilirubin, and severe intrahepatic biliary fibrosis. In contrast, HOPE treated DCD livers were protected from biliary injury, as detected by cholestasis parameter and histology. CONCLUSIONS We demonstrate in a DCD liver transplant model that end-ischemic hypothermic oxygenated perfusion is a powerful strategy for protection against biliary injury.
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Affiliation(s)
- Andrea Schlegel
- Department of Surgery, Laboratory of the Swiss HPB and Liver Transplantation Center, University Hospital Zurich, Switzerland
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Izamis ML, Calhoun C, Uygun BE, Guzzardi MA, Price G, Luitje M, Saeidi N, Yarmush ML, Uygun K. SIMPLE MACHINE PERFUSION SIGNIFICANTLY ENHANCES HEPATOCYTE YIELDS OF ISCHEMIC AND FRESH RAT LIVERS. CELL MEDICINE 2013; 4:109-123. [PMID: 25431743 PMCID: PMC4243527 DOI: 10.3727/215517912x658927] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The scarcity of viable hepatocytes is a significant bottleneck in cell transplantation, drug discovery, toxicology, tissue engineering, and bioartificial assist devices, where trillions of high-functioning hepatocytes are needed annually. We took the novel approach of using machine perfusion to maximize cell recovery, specifically from uncontrolled cardiac death donors, the largest source of disqualified donor organs. In a rat model, we developed a simple 3 hour room temperature (20±2°C) machine perfusion protocol to treat non-premedicated livers exposed to 1 hour of warm (34°C) ischemia. Treated ischemic livers were compared to fresh, fresh-treated and untreated ischemic livers using viable hepatocyte yields and in vitro performance as quantitative endpoints. Perfusion treatment resulted in both a 25-fold increase in viable hepatocytes from ischemic livers, and a 40% increase from fresh livers. While cell morphology and function in suspension and plate cultures of untreated warm ischemic cells was significantly impaired, treated warm ischemic cells were indistinguishable from fresh hepatocytes. Further, a strong linear correlation between tissue ATP and cell yield enabled accurate evaluation of the extent of perfusion recovery. Maximal recovery of warm ischemic liver ATP content appears to be correlated with optimal flow through the microvasculature. These data demonstrate that the inclusion of a simple perfusion-preconditioning step can significantly increase the efficiency of functional hepatocyte yields and the number of donor livers that can be gainfully utilized.
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Affiliation(s)
- Maria-Louisa Izamis
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
| | - Candice Calhoun
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
| | - Basak E. Uygun
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
| | - Maria Angela Guzzardi
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
| | - Gavrielle Price
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
| | - Martha Luitje
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
| | - Nima Saeidi
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
| | - Martin L. Yarmush
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
- †Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Korkut Uygun
- *Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA, USA
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Lee CY, Mangino MJ. Preservation methods for kidney and liver. Organogenesis 2012; 5:105-12. [PMID: 20046672 DOI: 10.4161/org.5.3.9582] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2009] [Accepted: 07/20/2009] [Indexed: 02/06/2023] Open
Abstract
With the successful testing of the immunosuppressive effects of cyclosporine in transplant patients in 1978, the field of organ transplants began an exponential growth. With that, the field of organ preservation became increasingly important as the need to increase preservation time and improve graft function became paramount. However, for every patient that receives a transplanted organ, there are four more on the waiting list. In addition, a patient dies from the lack of a transplant almost every 1(1/2) hour. To alleviate this donor crisis, there is a need to expand the donor pool to marginal donor organs. The main reason these organs are underutilized is because the current method of static preservation, simple cold storage, is ineffective. This article will provide a general review of the methods of preservation including simple cold storage, hypothermic machine perfusion, normothermic machine perfusion, and oxygen persufflation. In addition, the article will provide a review of how these dynamic preservation methods have improved the recovery and preservation of marginal donor organs including Donation after Cardiac Death and Fatty livers.
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Affiliation(s)
- Charles Y Lee
- Department of Mechanical Engineering and Engineering Science; University of North Carolina; Charlotte, NC USA
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Le Dinh H, de Roover A, Kaba A, Lauwick S, Joris J, Delwaide J, Honoré P, Meurisse M, Detry O. Donation after cardio-circulatory death liver transplantation. World J Gastroenterol 2012; 18:4491-506. [PMID: 22969222 PMCID: PMC3435774 DOI: 10.3748/wjg.v18.i33.4491] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 03/27/2012] [Accepted: 03/29/2012] [Indexed: 02/06/2023] Open
Abstract
The renewed interest in donation after cardio-circulatory death (DCD) started in the 1990s following the limited success of the transplant community to expand the donation after brain-death (DBD) organ supply and following the request of potential DCD families. Since then, DCD organ procurement and transplantation activities have rapidly expanded, particularly for non-vital organs, like kidneys. In liver transplantation (LT), DCD donors are a valuable organ source that helps to decrease the mortality rate on the waiting lists and to increase the availability of organs for transplantation despite a higher risk of early graft dysfunction, more frequent vascular and ischemia-type biliary lesions, higher rates of re-listing and re-transplantation and lower graft survival, which are obviously due to the inevitable warm ischemia occurring during the declaration of death and organ retrieval process. Experimental strategies intervening in both donors and recipients at different phases of the transplantation process have focused on the attenuation of ischemia-reperfusion injury and already gained encouraging results, and some of them have found their way from pre-clinical success into clinical reality. The future of DCD-LT is promising. Concerted efforts should concentrate on the identification of suitable donors (probably Maastricht category III DCD donors), better donor and recipient matching (high risk donors to low risk recipients), use of advanced organ preservation techniques (oxygenated hypothermic machine perfusion, normothermic machine perfusion, venous systemic oxygen persufflation), and pharmacological modulation (probably a multi-factorial biologic modulation strategy) so that DCD liver allografts could be safely utilized and attain equivalent results as DBD-LT.
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Perk S, Izamis ML, Tolboom H, Uygun B, Yarmush ML, Uygun K. A fitness index for transplantation of machine-perfused cadaveric rat livers. BMC Res Notes 2012; 5:325. [PMID: 22731806 PMCID: PMC3441584 DOI: 10.1186/1756-0500-5-325] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Accepted: 05/28/2012] [Indexed: 12/19/2022] Open
Abstract
Background The 110,000 patients currently on the transplant waiting list reflect the critical shortage of viable donor organs. However, a large pool of unused organs, from donors after cardiac death (DCD) that are disqualified because of extensive ischemic injury, may prove transplantable after machine perfusion treatment, fundamentally impacting the availability of treatment for end-stage organ failure. Machine perfusion is an ex-vivo organ preservation and treatment procedure that has the capacity to quantitatively evaluate and resuscitate cadaveric organs for transplantation. Methods To diagnose whether an organ was fresh or ischemic, an initial assessment of liver quality was conducted via dynamic discriminant analysis. Subsequently, to determine whether the organs were sufficiently viable for successful implantation, fitness indices for transplantation were calculated based on squared prediction errors (SPE) for fresh and ischemic livers. Results With just three perfusate metabolites, glucose, urea and lactate, the developed MPLSDA model distinguished livers as fresh or ischemic with 90% specificity. The SPE analyses revealed that fresh livers with SPEF < 10.03 and WI livers with SPEWI < 3.92 yield successful transplantation with 95% specificity. Conclusions The statistical methods used here can discriminate between fresh and ischemic livers based on simple metabolic indicators measured during perfusion. The result is a predictive fitness index for transplantation of rat livers procured after cardiac death. The translational implications of this study are that any donor organ procured from controlled, but most especially from uncontrolled cardiac death donors, will be objectively assessed and its recovery monitored over time, minimizing the critical loss of otherwise viable organs.
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Affiliation(s)
- Sinem Perk
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and the Shriners Hospitals for Children, Boston, MA 02114, USA
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Izamis ML, Berendsen T, Uygun K, Yarmush M. Addressing the Donor Liver Shortage withEX VIVOMachine Perfusion. JOURNAL OF HEALTHCARE ENGINEERING 2012. [DOI: 10.1260/2040-2295.3.2.279] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Berendsen TA, Bruinsma BG, Lee J, D'Andrea V, Liu Q, Izamis ML, Uygun K, Yarmush ML. A simplified subnormothermic machine perfusion system restores ischemically damaged liver grafts in a rat model of orthotopic liver transplantation. Transplant Res 2012; 1:6. [PMID: 23369351 PMCID: PMC3552573 DOI: 10.1186/2047-1440-1-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023] Open
Abstract
Background Liver donor shortages stimulate the development of strategies that incorporate damaged organs into the donor pool. Herein we present a simplified machine perfusion system without the need for oxygen carriers or temperature control, which we validated in a model of orthotopic liver transplantation. Methods Rat livers were procured and subnormothermically perfused with supplemented Williams E medium for 3 hours, then transplanted into healthy recipients (Fresh-SNMP group). Outcome was compared with static cold stored organs (UW-Control group). In addition, a rat liver model of donation after cardiac death was adapted using a 60-minute warm ischemic period, after which the grafts were either transplanted directly (WI group) or subnormothermically perfused and transplanted (WI-SNMP group). Results One-month survival was 100% in the Fresh-SNMP and UW-Control groups, 83.3% in the WI-SNMP group and 0% in the WI group. Clinical parameters, postoperative blood work and histology did not differ significantly between survivors. Conclusion This work demonstrates for the first time in an orthotopic transplantation model that ischemically damaged livers can be regenerated effectively using practical subnormothermic machine perfusion without oxygen carriers.
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Affiliation(s)
- Tim A Berendsen
- Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital, 51 Blossom Street, Boston, MA, 02114, USA.
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Perk S, Izamis ML, Tolboom H, Uygun B, Berthiaume F, Yarmush ML, Uygun K. A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers. PLoS One 2011; 6:e28518. [PMID: 22194843 PMCID: PMC3237452 DOI: 10.1371/journal.pone.0028518] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 11/09/2011] [Indexed: 12/27/2022] Open
Abstract
With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD). A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD), recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP), and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE) as log(SPE) >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.
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Affiliation(s)
- Sinem Perk
- Center for Engineering in Medicine, Harvard Medical School, Massachusetts General Hospital, and the Shriners Hospitals for Children, Boston, Massachusetts, United States of America
| | - Maria-Louisa Izamis
- Center for Engineering in Medicine, Harvard Medical School, Massachusetts General Hospital, and the Shriners Hospitals for Children, Boston, Massachusetts, United States of America
| | - Herman Tolboom
- Division of Cardiac and Vascular Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Basak Uygun
- Center for Engineering in Medicine, Harvard Medical School, Massachusetts General Hospital, and the Shriners Hospitals for Children, Boston, Massachusetts, United States of America
| | - Francois Berthiaume
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - Martin L. Yarmush
- Center for Engineering in Medicine, Harvard Medical School, Massachusetts General Hospital, and the Shriners Hospitals for Children, Boston, Massachusetts, United States of America
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - Korkut Uygun
- Center for Engineering in Medicine, Harvard Medical School, Massachusetts General Hospital, and the Shriners Hospitals for Children, Boston, Massachusetts, United States of America
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Minor T, Lüer B, Efferz P. Dopamine improves hypothermic machine preservation of the liver. Cryobiology 2011; 63:84-9. [DOI: 10.1016/j.cryobiol.2011.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 05/15/2011] [Accepted: 05/20/2011] [Indexed: 12/14/2022]
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Tolboom H, Izamis ML, Sharma N, Milwid JM, Uygun B, Berthiaume F, Uygun K, Yarmush ML. Subnormothermic machine perfusion at both 20°C and 30°C recovers ischemic rat livers for successful transplantation. J Surg Res 2011; 175:149-56. [PMID: 21550058 DOI: 10.1016/j.jss.2011.03.003] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 02/26/2011] [Accepted: 03/02/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Utilizing livers from donors after cardiac death could significantly expand the donor pool. We have previously shown that normothermic (37°C) extracorporeal liver perfusion significantly improves transplantation outcomes of ischemic rat livers. Here we investigate whether recovery of ischemic livers is possible using sub-normothermic machine perfusion at 20°C and 30°C. METHODS Livers from male Lewis rats were divided into five groups after 1 h of warm ischemia (WI): (1) WI only, (2) 5 h of static cold storage (SCS), or 5 h of MP at (3) 20°C, (4) 30°C, and (5) 37°C. Long-term graft performance was evaluated for 28 d post-transplantation. Acute graft performance was evaluated during a 2 h normothermic sanguineous reperfusion ex vivo. Fresh livers with 5 h of SCS were positive transplant controls while fresh livers were positive reperfusion controls. RESULTS Following machine perfusion (MP) (Groups 3, 4, and 5), ischemically damaged livers could be orthotopically transplanted into syngeneic recipients with 100% survival (N ≥ 4) after 4 wk. On the other hand, animals from WI only, or WI + SCS groups all died within 24 h of transplantation. Fresh livers preserved using SCS had the highest alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the lowest bile production during reperfusion, while at 28 d post-transplantation, livers preserved at 20°C and 30°C had the highest total bilirubin values. CONCLUSIONS MP at both 20°C and 30°C eliminated temperature control in perfusion systems and recovered ischemically damaged rat livers. Postoperatively, low transaminases suggest a beneficial effect of sub-normothermic perfusion, while rising total bilirubin levels suggest inadequate prevention of ischemia- or hypothermia-induced biliary damage.
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Affiliation(s)
- Herman Tolboom
- Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Koetting M, Minor T. Donation After Cardiac Death: Dynamic Graft Reconditioning During or After Ischemic Preservation? Artif Organs 2011; 35:565-71. [DOI: 10.1111/j.1525-1594.2010.01138.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Shi Y, Rehman H, Wright GL, Zhong Z. Inhibition of inducible nitric oxide synthase prevents graft injury after transplantation of livers from rats after cardiac death. Liver Transpl 2010; 16:1267-77. [PMID: 21031542 PMCID: PMC2967449 DOI: 10.1002/lt.22148] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This study investigated the roles of inducible nitric oxide synthase (iNOS) in the failure of rat liver grafts from cardiac death donors (GCDD). Livers were explanted after 30-minute aorta clamping and implanted after 4-hour storage in University of Wisconsin solution. The iNOS expression increased slightly in grafts from non-cardiac death donors (GNCDD) but markedly in GCDD. Serum nitrite and nitrate and hepatic 3-nitrotyrosine adducts, indicators of NO and peroxynitrite production, respectively, were substantially higher after transplantation of GCDD than GNCDD. Production of reactive nitrogen species (RNS) was largely blocked by 1400W (N-[1-naphthyl]ethylenediamine dihydrochloride; 5 μM), a specific iNOS inhibitor. Alanine aminotransferase release, bilirubin, necrosis, and apoptosis were 6.4-fold, 6.5-fold, 2.3-fold, and 2.7-fold higher, respectively, after transplantation of GCDD than GNCDD. The inhibitor 1400W effectively blocked these alterations and also increased survival of GCDD to 80% from 33%. Increased RNS production and failure of GCDD were associated with activation of c-Jun-N-terminal kinase (JNK), an effect that was blocked by inhibition of iNOS. Inhibition of JNK also improved the outcome after transplantation of GCDD. Together, the data indicate that iNOS increases substantially in GCDD, leading to RNS overproduction, JNK activation, and more severe graft injury. Inhibitors of iNOS are suggested as effective therapies to improve the outcome after transplantation of GCDD.
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Affiliation(s)
- Yanjun Shi
- Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
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Taylor MJ, Baicu SC. Current state of hypothermic machine perfusion preservation of organs: The clinical perspective. Cryobiology 2010; 60:S20-35. [PMID: 19857479 PMCID: PMC2891866 DOI: 10.1016/j.cryobiol.2009.10.006] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Revised: 10/01/2009] [Accepted: 10/20/2009] [Indexed: 01/16/2023]
Abstract
This review focuses on the application of hypothermic perfusion technology as a topic of current interest with the potential to have a salutary impact on the mounting clinical challenges to improve the quantity and quality of donor organs and the outcome of transplantation. The ex vivo perfusion of donor organs on a machine prior to transplant, as opposed to static cold storage on ice, is not a new idea but is being re-visited because of the prospects of making available more and better organs for transplantation. The rationale for pursuing perfusion technology will be discussed in relation to emerging data on clinical outcomes and economic benefits for kidney transplantation. Reference will also be made to on-going research using other organs with special emphasis on the pancreas for both segmental pancreas and isolated islet transplantation. Anticipated and emerging benefits of hypothermic machine perfusion of organs are: (i) maintaining the patency of the vascular bed, (ii) providing nutrients and low demand oxygen to support reduced energy demands, (iii) removal of metabolic by-products and toxins, (iv) provision of access for administration of cytoprotective agents and/or immunomodulatory drugs, (v) increase of available assays for organ viability assessment and tissue matching, (vi) facilitation of a change from emergency to elective scheduled surgery with reduced costs and improved outcomes, (vii) improved clinical outcomes as demonstrated by reduced PNF and DGF parameters, (viii) improved stabilization or rescue of ECD kidneys or organs from NHBD that increase the size of the donor pool, (ix) significant economic benefit for the transplant centers and reduced health care costs, and (x) provision of a technology for ex vivo use of non-transplanted human organs for pharmaceutical development research.
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Fuller B, Guibert E, Rodríguez J. Lessons from Natural Cold-Induced Dormancy to Organ Preservation in Medicine and Biotechnology: From the “Backwoods to the Bedside”. DORMANCY AND RESISTANCE IN HARSH ENVIRONMENTS 2010. [DOI: 10.1007/978-3-642-12422-8_14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
The growing numbers of potential transplant recipients on waiting lists is increasingly disproportionate to the supply of cadaveric donor organs. The hope for the next 20 years is that supply will satisfy demand. This requires both a reduction in indications for the procedure and an increase in the transplants performed. A multi-pronged approach is needed to increase cadaveric organ donation, generating enthusiasm for donation among both the general public and hospital staff. Accurate assessment of marginal grafts with stringent criteria known to predict graft function will diminish wastage of organs. Methods of rehabilitating marginal grafts during extracorporeal perfusion will increase organ availability. Supply of non-heart beating donors can be greatly expanded and protocols developed with ethical consent to optimize their initial function despite warm ischemia. Splitting livers that fulfill selection criteria, thus providing for two recipients, should be universally applied with acceptable incentives to those units who do not directly benefit. A proportion of recipients, though not those transplanted for autoimmune disease, will be spared the side-effects of immunosuppression thanks to immune tolerance. Protocols for close monitoring of those patients for rejection during treatment withdrawal must be carefully observed. In addition to gene therapy, it is highly likely that hepatocyte transplantation will replace orthotopic grafting in patients without cirrhosis, especially for inherited metabolic diseases. It is much more difficult to envisage that heterologous stem cell transplantation or xenotransplantation will have clinical impact in the next 20 years, although research in those areas has obvious long-term potential.
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Affiliation(s)
- M Thamara P R Perera
- The Liver Unit, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Birmingham, UK
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de Rougemont O, Lehmann K, Clavien PA. Preconditioning, organ preservation, and postconditioning to prevent ischemia-reperfusion injury to the liver. Liver Transpl 2009; 15:1172-82. [PMID: 19790166 DOI: 10.1002/lt.21876] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ischemia and reperfusion lead to injury of the liver. Ischemia-reperfusion injury is inevitable in liver transplantation and trauma and, to a great extent, in liver resection. This article gives an overview of the mechanisms involved in this type of injury and summarizes protective and treatment strategies in clinical use today. Intervention is possible at different time points: during harvesting, during the period of preservation, and during implantation. Liver preconditioning and postconditioning can be applied in the transplant setting and for liver resection. Graft optimization is merely possible in the period between the harvest and the implantation. Given that there are 3 stages in which a surgeon can intervene against ischemia-reperfusion injury, we have structured the review as follows. The first section reviews the approaches using surgical interventions, such as ischemic preconditioning, as well as pharmacological applications. In the second section, static organ preservation and machine perfusion are addressed. Finally, the possibility of treating the recipient or postconditioning is discussed.
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Affiliation(s)
- Olivier de Rougemont
- Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland
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41
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Pine JK, Aldouri A, Young AL, Davies MH, Attia M, Toogood GJ, Pollard SG, Lodge JPA, Prasad KR. Liver transplantation following donation after cardiac death: an analysis using matched pairs. Liver Transpl 2009; 15:1072-82. [PMID: 19718634 DOI: 10.1002/lt.21853] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Grafts from donation after cardiac death (DCD) donors are used to increase the number of organs available for liver transplantation. There is concern that warm ischemia may impair graft function. We compared our DCD recipients with a case-matched group of donation after brain death (DBD) recipients. Between January 2002 and April 2008, 39 DCD grafts were transplanted. These were matched with 39 DBD recipients on the basis of identified variables that had a significant impact on mortality. These were used to individually match DCD and DBD patients with similar predictive mortality. We compared patient/graft survival, primary non-function (PNF), and rates of complications. Of all liver transplants, 6.1% were DCD grafts. PNF occurred twice in the DCD group. The incidence of nonanastomotic biliary strictures (NABS; 20.5% versus 0%, P = 0.005) and hepatic artery stenosis (HAS; 12.8% versus 0%, P = 0.027) in the DCD group was higher. One-year (79.5% versus 97.4%, P = 0.029) and 3-year (63.6% versus 97.4%, P = 0.001) graft survival was lower in the DCD group. Three-year patient survival was also lower (68.2% versus 100%, P < 0.0001). Our study is the first to use case-matched patients and compare groups with similar predictive mortality. There was a higher incidence of NABS and HAS in the DCD group. NABS were likely a result of warm ischemia. HAS may have been due to ischemia or arterial injury during retrieval. The DCD group had significantly poorer outcomes, but DCD grafts remain a valuable resource. With careful donor/recipient selection, minimization of ischemia, and good postoperative care, acceptable results can be achieved.
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Affiliation(s)
- James K Pine
- Department of Hepatobiliary/Transplant Surgery, St. James's University Hospital, Beckett Street, United Kingdom
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Saad S, Minor T. Short-term resuscitation of predamaged donor livers by brief machine perfusion: the influence of temperature. Transplant Proc 2009; 40:3321-6. [PMID: 19100381 DOI: 10.1016/j.transproceed.2008.06.058] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2007] [Revised: 04/18/2008] [Accepted: 06/16/2008] [Indexed: 10/21/2022]
Abstract
Short-term machine perfusion after liver retrieval from non-heart-beating donors has been considered a beneficial means to reverse deleterious priming of the predamaged organ. In this study, the possible impact of different temperatures during aerobic perfusion was addressed, focusing on liver metabolic functions, structural integrity, and vascular activation. Livers retrieved 30 minutes after cardiac arrest of male Wistar rats (200-300 g) were preserved with histidine-tryptophan-ketoglutarate (HTK) solution for 18 hours by simple cold storage (CS) or subjected to short-term resuscitation (STR) with oxygenated (pO(2) > 500 mm Hg) machine perfusion with HTK at 4 degrees C, 12 degrees C, or 22 degrees C for 2 hours with subsequent CS for 16 hours at 4 degrees C. Upon reperfusion in a normothermic perfusion circuit, STR significantly improved enzyme leakage (alanine aminotransferase, glutamate dehydrogenase) and metabolic recovery (tissue levels of ATP) providing best values at 12 degrees C or 22 degrees C. Moreover, a hugely increased gene expression of the adhesion molecule ICAM-1 as well as major histocompatibility complex (MHC) class II antigen was seen after CS, but significantly alleviated by STR at 4 degrees C or 12 degrees C. However, mRNA for both surface proteins rose significantly after STR at 22 degrees C compared with CS. In conclusion, STR by oxygenated perfusion is beneficial to the predamaged graft, facilitating later transportation and supervision of the graft compared with continuous machine preservation. However, increased perfusion temperature should be recommended only up to the limit of 12 degrees C to prevent overactivation of surface antigen expression.
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Affiliation(s)
- S Saad
- Surgical Research Division, University Clinic of Surgery, Bonn, Germany
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Stegemann J, Hirner A, Rauen U, Minor T. Gaseous oxygen persufflation or oxygenated machine perfusion with Custodiol-N for long-term preservation of ischemic rat livers? Cryobiology 2009; 58:45-51. [DOI: 10.1016/j.cryobiol.2008.10.127] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2008] [Revised: 10/08/2008] [Accepted: 10/08/2008] [Indexed: 02/08/2023]
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Tolboom H, Pouw RE, Izamis ML, Milwid JM, Sharma N, Soto-Gutierrez A, Nahmias Y, Uygun K, Berthiaume F, Yarmush ML. Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion. Transplantation 2009; 87:170-7. [PMID: 19155970 PMCID: PMC2743395 DOI: 10.1097/tp.0b013e318192df6b] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver transplantation is currently the only established treatment of end-stage liver disease, but it is limited by a severe shortage of viable donor livers. Donors after cardiac death (DCD) are an untapped source that could significantly increase the pool of available livers. Preservation of these DCD livers by conventional static cold storage (SCS) is associated with an unacceptable risk of primary nonfunction and delayed graft failure. Normothermic extracorporeal liver perfusion (NELP) has been suggested as an improvement over SCS. Livers recovered from male Lewis rats were subjected to 1 hr of warm ischemia and preserved with 5 hr of SCS or NELP, and transplanted into syngeneic recipients. As additional controls, non-ischemic livers preserved with 6 hr of SCS or NELP and unpreserved ischemic livers were transplanted. After NELP, ischemically damaged livers could be orthotopically transplanted into syngeneic recipients with 92% survival (n=13) after 4 weeks, which was comparable with control animals that received healthy livers preserved by SCS (n=9) or NELP (n=11) for 6 hr. On the other hand, animals from ischemia/SCS control group all died within 12 hr postoperatively (n=6). Similarly, animals that received ischemic livers without preservation all died within 24 hr after transplantation (n=6). These results suggest that NELP has the potential to reclaim warm ischemic livers that would not be transplantable otherwise. The rat model in this study is a useful platform to further optimize NELP as a method of recovery and preservation of DCD livers.
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Affiliation(s)
- Herman Tolboom
- Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Use of a new modified HTK solution for machine preservation of marginal liver grafts. J Surg Res 2008; 160:155-62. [PMID: 19541327 DOI: 10.1016/j.jss.2008.10.021] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2008] [Revised: 10/08/2008] [Accepted: 10/22/2008] [Indexed: 12/13/2022]
Abstract
BACKGROUND The present study was undertaken to investigate the putative benefit of a new, modified HTK solution for hypothermic machine perfusion using a model of rat livers from non-heart beating donors. METHODS Livers were retrieved 30 min after cardiac arrest of male Wistar rats and put on a recirculating machine perfusion device. Hypothermic machine perfusion (HMP) was performed for 18 h at 4 degrees C and a rate of 0.5 mL/g(-1) min(-1) while the preservation solution was oxygenated with 100% O(2). Each liver was randomly assigned to the use of one of the following preservation solutions: HTK (histidine-tryptophan-ketoglutarate solution); Custodiol-N base solution (modified HTK-solution) without additives or with the addition of 25 microM deferoxamine + 2.5 microM (Custodiol-N, 2.5) or 7.5 microM (Custodiol-N) of the permeable iron chelator LK 614. Viability of livers was evaluated upon reperfusion in vitro with Krebs-Henseleit buffer according to previously validated techniques for 120 min at 37 degrees C. RESULTS The use of Custodiol-N base solution led to a significantly decreased release of ALT or LDH during HMP and after reperfusion, which was further reduced by Custodiol-N and minimal use of Custodiol-N, 2.5. Only the use of Custodiol-N, 2.5 resulted in an improvement of metabolic activity upon reperfusion, as evaluated by hepatic production of C0(2), significantly reduced cleavage of caspase 9, and abrogated positive signs of cellular of apoptosis [terminal deoxynucleotide transferase-mediated deoxy-UTP nick-end labeling (TUNEL)-test)]. CONCLUSION The data presented provide first experimental evidence for enhanced organ protective potential of the new Custodiol-N solution compared with HTK upon hypothemic machine preservation of marginal liver grafts. Moreover, for continuous perfusion preservation the dosage of the lipophilic chelator LK 614 should probably be lower than for static cold storage.
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Vekemans K, Liu Q, Pirenne J, Monbaliu D. Artificial circulation of the liver: machine perfusion as a preservation method in liver transplantation. Anat Rec (Hoboken) 2008; 291:735-40. [PMID: 18484620 DOI: 10.1002/ar.20662] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Due to the sharp increase in liver transplant candidates and the subsequent shortage of suitable donor livers, an extension of the current donor criteria is necessary. Simple cold storage, the current standard in organ preservation has proven to be insufficient to preserve extended criteria donor livers. Therefore a renewed interest grew toward alternative methods for liver preservation, such as hypothermic machine perfusion and normothermic machine perfusion. These "new" preservation methods were primarily assessed in rat models, and only a few clinically relevant large animal models have been described so far. This review will elaborate on these alternative preservation methods.
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Affiliation(s)
- Katrien Vekemans
- Abdominal Transplant Surgery, Catholic University of Leuven (KULeuven), Leuven, Belgium.
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Abstract
Due to the critical shortage of deceased donor grafts, clinicians are continually expanding the criteria for an acceptable liver donor to meet the waiting list demands. However, the reduced ischemic tolerance of those extended criteria grafts jeopardizes organ viability during cold storage. Machine perfusion has been developed to limit ischemic liver damage but despite its proven biochemical benefit, machine liver perfusion is not yet considered clinically due to its low practicability. In this review, we summarize our understanding of the role of machine perfusion in marginal liver preservation. The goal is to highlight advantages or disadvantages of current perfusion techniques and to explain the underlying mechanisms. We provide evidence for the need of a liver perfusion performance shortly before implantation, and point out promising designs.
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Affiliation(s)
- P Dutkowski
- Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Visceral and Transplantation Surgery, University Hospital Zürich, Zurich, Switzerland
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Bagul A, Hosgood SA, Kaushik M, Kay MD, Waller HL, Nicholson ML. Experimental renal preservation by normothermic resuscitation perfusion with autologous blood. Br J Surg 2008; 95:111-8. [PMID: 17696214 DOI: 10.1002/bjs.5909] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Normothermic perfusion (NP) has the potential to improve metabolic support and maintain the viability of ischaemically damaged organs. This study investigated the effects of NP compared with current methods of organ preservation in a model of controlled non-heart-beating donor (NHBD) kidneys. METHODS Porcine kidneys (n = 6 in each group) were subjected to 10 min warm ischaemia and then preserved as follows: 2 h cold storage (CS) in ice (CS2 group), 18 h CS (CS18 group), 18 h cold machine perfusion (CP group) or 16 h CS + 2 h NP (NP group). Renal haemodynamics and function were measured during 3 h reperfusion with autologous blood using an isolated organ perfusion system. RESULTS Increasing CS from 2 to 18 h reduced renal blood flow (mean(s.d.) area under the curve (AUC) 444(57) versus 325(70) ml per 100 g; P = 0.004), but this was restored by NP (563(119) ml per 100 g; P = 0.035 versus CS18). Renal function was also better in CS2, CP and NP groups than in the CS18 group (mean(s.d.) serum creatinine fall 92(6), 79(9) and 64(17) versus 44(13) per cent respectively; P = 0.001). The AUC for serum creatinine was significantly lower with CS for 2 h than for 18 h (mean(s.d.) 1102(2600) versus 2156(401) micromol/l.h; P = 0.001), although values in CP and NP groups were not significantly different from those in the CS2 group (1354(300) and 1756(280) micromol/l.h respectively). Two hours of NP increased the adenosine 3'-triphosphate : adenosine 3'-diphosphate ratio to a significantly higher level than the preperfusion values in all other groups (P = 0.046). CONCLUSION NP with oxygenated blood was able to restore depleted ATP levels and reverse some of the deleterious effects of CS.
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Affiliation(s)
- A Bagul
- Department of Transplant Surgery, University Hospitals of Leicester, Leicester, UK
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Manekeller S, Schuppius A, Stegemann J, Hirner A, Minor T. Role of perfusion medium, oxygen and rheology for endoplasmic reticulum stress-induced cell death after hypothermic machine preservation of the liver. Transpl Int 2007; 21:169-77. [PMID: 18005084 DOI: 10.1111/j.1432-2277.2007.00595.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Recently, the endoplasmic reticulum (ER) has been disclosed as subcellular target reactive to ischaemia/reperfusion and possibly influenced by hypothermic machine preservation. Here, the respective role of perfusate, perfusion itself, and the effect of continuous oxygenation to trigger ER-stress in the graft should be investigated. Livers were retrieved 30 min after cardiac arrest of male Wistar rats and preserved by cold storage (CS) in histidine-tryptophan-ketoglutarate (HTK) for 18 h at 4 degrees C. Other organs were subjected to aerobic conditions either by oxygenated machine perfusion with HTK (MP-HTK) or Belzer solution (MP-Belzer) at 4 degrees C or by venous insufflation of gaseous oxygen during cold storage (VSOP). Viability of livers was evaluated upon reperfusion in vitro according to previously validated techniques for 120 min at 37 degrees C. Oxygenation during preservation (MP-HTK, MP-Belzer or VSOP) concordantly improved functional recovery (bile flow, ammonia clearance), reduced parenchymal enzyme leakage and histological signs of necrosis and significantly attenuated mitochondrial induction of apoptosis (cleavage of caspase 9) compared to CS. However, MP with either medium produced about 500% elevated protein expression of CHOP/GADD153, suggesting pro-apoptotic ER-stress responses, paralleled by a significant elevation of caspase-12 enzyme activity compared to CS or VSOP. Although MP also promoted a slight (20%) induction of the cytoprotective ER-protein Bax inhibitor protein (BI-1), prevailing of proapoptotic reactions was seen by increased cleavage of caspase-3 and poly (ADP-Ribase)-polymerase (PARP) in both MP-groups. Endoplasmic stress activation is conjectured a specific side effect of long-term machine preservation irrespective of the medium, actually promoting cellular apoptosis via activation of caspase-12. The simple insufflation of gaseous O2 may be considered a feasible alternative, apparently indifferent to the endoplasmic reticulum.
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50
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Machine perfusion preservation of the liver: a worthwhile clinical activity? Curr Opin Organ Transplant 2007; 12:224-230. [DOI: 10.1097/mot.0b013e32814e6bc2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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