|
1
|
Dandin O, Yildirim S, Karacayli D, Yilmaz C, Ormeci M, Ozsipahi AC, Vural V, Dogan NU, Tanriover G, Aslan M, Canpolat M. Assessment of Amniotic Fluid as a Preservation Solution in Pig Livers Undergoing Machine Perfusion. J Surg Res 2025; 309:39-61. [PMID: 40203486 DOI: 10.1016/j.jss.2025.02.043] [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: 07/29/2024] [Revised: 02/07/2025] [Accepted: 02/20/2025] [Indexed: 04/11/2025]
Abstract
INTRODUCTION Ischemia-reperfusion injury in organ transplantation highlights the need for advanced preservation techniques. This study evaluates the effectiveness of amniotic fluid (AF) compared to static cold storage and histidine-tryptophan-ketoglutarate (HTK) solution in preserving pig livers subjected to hypothermic oxygenated machine perfusion (HOMP) and ex vivo normothermic reperfusion. MATERIALS AND METHODS Fifteen pig livers underwent warm ischemia for 1 h, followed by preservation under three conditions: cold storage (group 1, n = 3), HOMP with HTK (group 2, n = 3), and HOMP with AF (group 3, n = 3). Perfusion lasted 4 h, followed by 2 h of ex vivo reperfusion. Assessments included hepatic bile production, sphingomyelin levels, reactive oxygen/nitrogen species, antioxidant capacity, tissue oxygen saturation, flow dynamics, blood gas analyses, biochemical markers, and histopathological and immunohistochemical evaluations. RESULTS AF-HOMP showed superior blood flow, lower vascular resistance, higher oxygen saturation, and better organ protection than HTK. Blood gas measurements demonstrated stable physiological levels after reperfusion. AF-HOMP improved bile production, sphingomyelin levels, glycogen preservation, and reduced parenchymal necrosis, hepatocyte vacuolization, and sinusoidal obstruction. Immunohistochemical analysis indicated protective effects on bile duct function, apoptosis, endothelial activation, and cell proliferation. CONCLUSIONS AF-HOMP outperformed HTK in preserving liver tissue during warm ischemia, HOMP, and reperfusion. AF is a promising, cost-effective, and accessible alternative for liver preservation, potentially expanding donor pools and improving transplantation outcomes. Further research is warranted to explore its broader applications.
Collapse
Affiliation(s)
- Ozgur Dandin
- Faculty of Medicine, Departments of General Surgery, Akdeniz University, Antalya, Turkey.
| | - Sendegul Yildirim
- Faculty of Medicine, Departments of Histology and Embryology, Akdeniz University, Antalya, Turkey
| | - Deniz Karacayli
- Faculty of Medicine, Departments of Biophysics, Akdeniz University, Antalya, Turkey
| | - Cagatay Yilmaz
- Faculty of Medicine, Departments of Medical Biochemistry, Akdeniz University, Antalya, Turkey
| | - Mustafa Ormeci
- Faculty of Medicine, Departments of General Surgery, Akdeniz University, Antalya, Turkey
| | - Arif Can Ozsipahi
- Faculty of Medicine, Departments of Obstetrics And Gynaecology, Akdeniz University, Antalya, Turkey
| | - Veli Vural
- Faculty of Medicine, Departments of General Surgery, Akdeniz University, Antalya, Turkey
| | - Nasuh Utku Dogan
- Faculty of Medicine, Departments of Obstetrics And Gynaecology, Akdeniz University, Antalya, Turkey
| | - Gamze Tanriover
- Faculty of Medicine, Departments of Histology and Embryology, Akdeniz University, Antalya, Turkey
| | - Mutay Aslan
- Faculty of Medicine, Departments of Medical Biochemistry, Akdeniz University, Antalya, Turkey
| | - Murat Canpolat
- Faculty of Medicine, Departments of Biophysics, Akdeniz University, Antalya, Turkey
| |
Collapse
|
|
2
|
Jeddou H, Tzedakis S, Chaouch MA, Sulpice L, Samson M, Boudjema K. Viability Assessment During Normothermic Machine Liver Perfusion: A Literature Review. Liver Int 2025; 45:e16244. [PMID: 39821671 PMCID: PMC11740183 DOI: 10.1111/liv.16244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 12/25/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
BACKGROUND AND OBJECTIVE The discrepancy between donor organ availability and demand leads to a significant waiting-list dropout rate and mortality. Although quantitative tools such as the Donor Risk Index (DRI) help assess organ suitability, many potentially viable organs are still discarded due to the lack of universally accepted markers to predict post-transplant outcomes. Normothermic machine perfusion (NMP) offers a platform to assess viability before transplantation. Thus, livers considered unsuitable for transplantation based on the DRI can be evaluated and potentially transplanted. During NMP, various viability criteria have been proposed. These criteria are neither homogeneous nor consensual. In this review, we aimed to describe the viability criteria during NMP and evaluate their ability to predict hepatic graft function following transplantation. We conducted a PubMed search using the terms 'liver transplantation', 'normothermic machine perfusion' and 'assessment', including only English publications up to February 2024. Viability assessment during NMP includes multiple hepatocellular and cholangiocellular criteria. Lactate clearance and bile production are commonly used indicators, but their ability to predict post-transplant outcomes varies significantly. The predictive value of cholangiocellular criteria such as bile pH, bicarbonate and glucose levels remains under investigation. Novel markers, such as microRNAs and proteomic profiles, offer the potential to enhance graft evaluation accuracy and provide insights into the molecular mechanisms underlying liver viability. Combining perfusion parameters with biomarkers may improve the prediction of long-term graft survival. Future research should focus on standardising viability assessment protocols and exploring real-time biomarker evaluations, which could enhance transplantation outcomes and expand the donor pool.
Collapse
Affiliation(s)
- Heithem Jeddou
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Stylianos Tzedakis
- Department of Hepato‐Biliary, Digestive and Endocrine SurgeryCochin Hospital, APHPParisFrance
- Université Paris CitéParisFrance
| | - Mohamed Ali Chaouch
- Department of Visceral and Digestive SurgeryMonastir University HospitalMonastirTunisia
| | - Laurent Sulpice
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- INSERM OSS U1242, University Hospital, Rennes 1 UniversityRennesFrance
| | - Michel Samson
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Karim Boudjema
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| |
Collapse
|
|
3
|
Groen PC, van Leeuwen OB, de Jonge J, Porte RJ. Viability assessment of the liver during ex-situ machine perfusion prior to transplantation. Curr Opin Organ Transplant 2024; 29:239-247. [PMID: 38764406 PMCID: PMC11224566 DOI: 10.1097/mot.0000000000001152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
PURPOSE OF REVIEW In an attempt to reduce waiting list mortality in liver transplantation, less-than-ideal quality donor livers from extended criteria donors are increasingly accepted. Predicting the outcome of these organs remains a challenge. Machine perfusion provides the unique possibility to assess donor liver viability pretransplantation and predict postreperfusion organ function. RECENT FINDINGS Assessing liver viability during hypothermic machine perfusion remains challenging, as the liver is not metabolically active. Nevertheless, the levels of flavin mononucleotide, transaminases, lactate dehydrogenase, glucose and pH in the perfusate have proven to be predictors of liver viability. During normothermic machine perfusion, the liver is metabolically active and in addition to the perfusate levels of pH, transaminases, glucose and lactate, the production of bile is a crucial criterion for hepatocyte viability. Cholangiocyte viability can be determined by analyzing bile composition. The differences between perfusate and bile levels of pH, bicarbonate and glucose are good predictors of freedom from ischemic cholangiopathy. SUMMARY Although consensus is lacking regarding precise cut-off values during machine perfusion, there is general consensus on the importance of evaluating both hepatocyte and cholangiocyte compartments. The challenge is to reach consensus for increased organ utilization, while at the same time pushing the boundaries by expanding the possibilities for viability testing.
Collapse
Affiliation(s)
- Puck C Groen
- Department of Surgery, Division of Hepato-Pancreato- Biliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | | | | |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
Li J, Lu H, Zhang J, Li Y, Zhao Q. Comprehensive Approach to Assessment of Liver Viability During Normothermic Machine Perfusion. J Clin Transl Hepatol 2023; 11:466-479. [PMID: 36643041 PMCID: PMC9817053 DOI: 10.14218/jcth.2022.00130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 06/14/2022] [Accepted: 08/10/2022] [Indexed: 01/18/2023] Open
Abstract
Liver transplantation is the most effective treatment of advanced liver disease, and the use of extended criteria donor organs has broadened the source of available livers. Although normothermic machine perfusion (NMP) has become a useful tool in liver transplantation, there are no consistent criteria that can be used to evaluate the viability of livers during NMP. This review summarizes the criteria, indicators, and methods used to evaluate liver viability during NMP. The shape, appearance, and hemodynamics of the liver can be analyzed at a macroscopic level, while markers of liver injury, indicators of liver and bile duct function, and other relevant indicators can be evaluated by biochemical analysis. The liver can also be assessed by tissue biopsy at the microscopic level. Novel methods for assessment of liver viability are introduced. The limitations of evaluating liver viability during NMP are discussed and suggestions for future clinical practice are provided.
Collapse
Affiliation(s)
| | | | | | | | - Qiang Zhao
- Correspondence to: Qiang Zhao, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. ORCID: https://orcid.org/0000-0002-6369-1393. Tel: +86-15989196835, E-mail:
| |
Collapse
|
|
6
|
Blondeel J, Monbaliu D, Gilbo N. Dynamic liver preservation: Are we still missing pieces of the puzzle? Artif Organs 2023; 47:248-259. [PMID: 36227006 DOI: 10.1111/aor.14397] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/11/2022] [Indexed: 02/03/2023]
Abstract
To alleviate the persistent shortage of donor livers, high-risk liver grafts are increasingly being considered for liver transplantation. Conventional preservation with static cold storage falls short in protecting these high-risk livers from ischemia-reperfusion injury, as evident from higher rates of post-transplant complications such as early allograft dysfunction and ischemic cholangiopathy. Moreover, static cold storage does not allow for a functional assessment of the liver prior to transplantation. To overcome these limitations, dynamic strategies of liver preservation have been proposed, designed to provide a protective effect while allowing pre-transplant functional assessment. In this review, we discuss how different dynamic preservation strategies exert their effects, where we stand in assessing liver function and what challenges are lying ahead.
Collapse
Affiliation(s)
- Joris Blondeel
- Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium.,Department of Abdominal Transplant Surgery and Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium.,Department of Abdominal Transplant Surgery and Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Nicholas Gilbo
- Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium.,Department of Abdominal Transplant Surgery and Coordination, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
7
|
Azizieh Y, Westhaver LP, Badrudin D, Boudreau JE, Gala-Lopez BL. Changing liver utilization and discard rates in clinical transplantation in the ex-vivo machine preservation era. FRONTIERS IN MEDICAL TECHNOLOGY 2023; 5:1079003. [PMID: 36908294 PMCID: PMC9996101 DOI: 10.3389/fmedt.2023.1079003] [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: 10/24/2022] [Accepted: 01/30/2023] [Indexed: 02/25/2023] Open
Abstract
Liver transplantation is a well-established treatment for many with end-stage liver disease. Unfortunately, the increasing organ demand has surpassed the donor supply, and approximately 30% of patients die while waiting for a suitable liver. Clinicians are often forced to consider livers of inferior quality to increase organ donation rates, but ultimately, many of those organs end up being discarded. Extensive testing in experimental animals and humans has shown that ex-vivo machine preservation allows for a more objective characterization of the graft outside the body, with particular benefit for suboptimal organs. This review focuses on the history of the implementation of ex-vivo liver machine preservation and how its enactment may modify our current concept of organ acceptability. We provide a brief overview of the major drivers of organ discard (age, ischemia time, steatosis, etc.) and how this technology may ultimately revert such a trend. We also discuss future directions for this technology, including the identification of new markers of injury and repair and the opportunity for other ex-vivo regenerative therapies. Finally, we discuss the value of this technology, considering current and future donor characteristics in the North American population that may result in a significant organ discard.
Collapse
Affiliation(s)
- Yara Azizieh
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | | | - David Badrudin
- Department of Surgery, Université de Montréal, Montréal, QC, Canada
| | - Jeanette E Boudreau
- Department of Pathology, Dalhousie University, Halifax, NS, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Boris L Gala-Lopez
- Department of Pathology, Dalhousie University, Halifax, NS, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada.,Department of Surgery, Dalhousie University, Halifax, NS, Canada
| |
Collapse
|
|
8
|
Young EN, Dogan M, Watkins C, Bajwa A, Eason JD, Kuscu C, Kuscu C. A Review of Defatting Strategies for Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms231911805. [PMID: 36233107 PMCID: PMC9569609 DOI: 10.3390/ijms231911805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/30/2022] Open
Abstract
Non-alcoholic fatty liver disease is a huge cause of chronic liver failure around the world. This condition has become more prevalent as rates of metabolic syndrome, type 2 diabetes, and obesity have also escalated. The unfortunate outcome for many people is liver cirrhosis that warrants transplantation or being unable to receive a transplant since many livers are discarded due to high levels of steatosis. Over the past several years, however, a great deal of work has gone into understanding the pathophysiology of this disease as well as possible treatment options. This review summarizes various defatting strategies including in vitro use of pharmacologic agents, machine perfusion of extracted livers, and genomic approaches targeting specific proteins. The goal of the field is to reduce the number of necessary transplants and expand the pool of organs available for use.
Collapse
|
|
9
|
Abstract
PURPOSE OF REVIEW Viability assessment is one of the main indications for machine perfusion (MP) in liver transplantation. This review summarizes the rationale, evolution and limitations of proposed viability criteria and suggests a framework for future studies. RECENT FINDINGS Liver viability is most frequently assessed during normothermic MP by combining parameters relative to perfusate and bile composition, vascular flows and macroscopic aspect. Assessment protocols are largely heterogeneous and have significantly evolved over time, also within the same group, reflecting the ongoing evolution of the subject. Several recent preclinical studies using discarded human livers or animal models have explored other approaches to viability assessment. During hypothermic MP, perfusate flavin mononucleotide has emerged as a promising biomarker of mitochondrial injury and function. Most studies on the subject suffer from limitations, including low numbers, lack of multicenter validation, and subjective interpretation of some viability parameters. SUMMARY MP adds a further element of complexity in the process of assessing the quality of a liver graft. Understanding the physiology of the parameters included in the different assessment protocols is necessary for their correct interpretation. Despite the possibility of assessing liver viability during MP, the importance of donor-recipient matching and operational variables should not be disregarded.
Collapse
Affiliation(s)
- Damiano Patrono
- General Surgery 2U - Liver Transplant Unit. Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino - University of Turin, Turin
| | - Caterina Lonati
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Renato Romagnoli
- General Surgery 2U - Liver Transplant Unit. Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino - University of Turin, Turin
| |
Collapse
|
|
10
|
Brüggenwirth IMA, van Leeuwen OB, Porte RJ, Martins PN. The Emerging Role of Viability Testing During Liver Machine Perfusion. Liver Transpl 2022; 28:876-886. [PMID: 33963657 DOI: 10.1002/lt.26092] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 04/30/2021] [Indexed: 12/23/2022]
Abstract
The transplant community continues to be challenged by the disparity between the need for liver transplantation and the shortage of suitable donor organs. At the same time, the number of unused donor livers continues to increase, most likely attributed to the worsening quality of these organs. To date, there is no reliable marker of liver graft viability that can predict good posttransplant outcomes. Ex situ machine perfusion offers additional data to assess the viability of donor livers before transplantation. Hence, livers initially considered unsuitable for transplantation can be assessed during machine perfusion in terms of appearance and consistency, hemodynamics, and metabolic and excretory function. In addition, postoperative complications such as primary nonfunction or posttransplant cholangiopathy may be predicted and avoided. A variety of viability criteria have been used in machine perfusion, and to date there is no widely accepted composition of criteria for clinical use. This review discusses potential viability markers for hepatobiliary function during machine perfusion, describes current limitations, and provides future recommendations for the use of viability criteria in clinical liver transplantation.
Collapse
Affiliation(s)
- Isabel M A Brüggenwirth
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Division of Organ Transplantation, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, MA
| | - Otto B van Leeuwen
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Robert J Porte
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, MA
| |
Collapse
|
|
11
|
Machine perfusion of the liver: applications in transplantation and beyond. Nat Rev Gastroenterol Hepatol 2022; 19:199-209. [PMID: 34997204 DOI: 10.1038/s41575-021-00557-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/17/2021] [Indexed: 12/14/2022]
Abstract
The shortage of donor livers considered suitable for transplantation has driven the development of novel methods for organ preservation and reconditioning. Machine perfusion techniques can improve the quality of marginal livers, extend the time for which they can be preserved and enable an objective assessment of their quality and viability. These benefits can help avoid the needless wastage of organs based on hypothetical concerns regarding quality. As machine perfusion techniques are gaining traction in clinical practice, attention has now shifted to their potential applications beyond transplantation. As well as providing an update on the current status of machine perfusion in clinical practice, this Perspective discusses how this technology is being used as a tool for therapeutic interventions including defatting of steatotic livers, immunomodulation and gene therapies.
Collapse
|
|
12
|
Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria. Cells 2022; 11:cells11040688. [PMID: 35203337 PMCID: PMC8870414 DOI: 10.3390/cells11040688] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/10/2022] Open
Abstract
Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.
Collapse
|
|
13
|
Quintini C, Del Prete L, Simioni A, Del Angel L, Diago Uso T, D'Amico G, Hashimoto K, Aucejo F, Fujiki M, Eghtesad B, Sasaki K, Kwon CHD, Cywinski J, Bennett A, Bilancini M, Miller C, Liu Q. Transplantation of declined livers after normothermic perfusion. Surgery 2022; 171:747-756. [PMID: 35065791 DOI: 10.1016/j.surg.2021.10.056] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/29/2021] [Accepted: 10/27/2021] [Indexed: 01/07/2023]
Abstract
BACKGROUND The persistent shortage of liver allografts contributes to significant waitlist mortality despite efforts to increase organ donation. Normothermic machine perfusion holds the potential to enhance graft preservation, extend viability, and allow liver function evaluation in organs previously discarded because considered too high-risk for transplant. METHODS Discarded livers from other transplant centers were transplanted after assessment and reconditioning with our institutionally developed normothermic machine perfusion device. We report here our preliminary data. RESULTS Twenty-one human livers declined for transplantation were enrolled for assessment with normothermic machine perfusion. Six livers (28.5%) were ultimately discarded after normothermic machine perfusion because of insufficient lactate clearance (>4.1 mmol/L after 4 hours), limited bile production (<0.5 mI/h), or moderate macrosteatosis, whereas 15 (71.5%) were considered suitable for transplantation. Normothermic machine perfusion duration was from 3 hours, 49 minutes to 10 hours, 29 minutes without technical problems or adverse events. No intraoperative or major early postoperative complications occurred in all transplanted recipients. No primary nonfunction occurred after transplantation. Seven livers had early allograft dysfunction with fast recovery, and 1 patient developed ischemic cholangiopathy after 4 months treated with biliary stents. All other patients had good liver function with a follow-up time of 8 weeks to 14 months. CONCLUSION In total, 71.5% of discarded livers subjected to ex vivo normothermic machine perfusion were successfully transplanted after organ perfusion and assessment using an institutionally built device. This study challenges the current viability criteria reported in the literature and calls for a standardization of viability markers collection, an essential condition for the advancement of the field.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Masato Fujiki
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | | | | | | | - Ana Bennett
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | | | - Qiang Liu
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| |
Collapse
|
|
14
|
Mitochondrial respiratory chain and Krebs cycle enzyme function in human donor livers subjected to end-ischaemic hypothermic machine perfusion. PLoS One 2021; 16:e0257783. [PMID: 34710117 PMCID: PMC8553115 DOI: 10.1371/journal.pone.0257783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/09/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Marginal human donor livers are highly susceptible to ischaemia reperfusion injury and mitochondrial dysfunction. Oxygenation during hypothermic machine perfusion (HMP) was proposed to protect the mitochondria but the mechanism is unclear. Additionally, the distribution and uptake of perfusate oxygen during HMP are unknown. This study aimed to examine the feasibility of mitochondrial function analysis during end-ischaemic HMP, assess potential mitochondrial viability biomarkers, and record oxygenation kinetics. METHODS This was a randomised pilot study using human livers retrieved for transplant but not utilised. Livers (n = 38) were randomised at stage 1 into static cold storage (n = 6), hepatic artery HMP (n = 7), and non-oxygen supplemented portal vein HMP (n = 7) and at stage 2 into oxygen supplemented and non-oxygen supplemented portal vein HMP (n = 11 and 7, respectively). Mitochondrial parameters were compared between the groups and between low- and high-risk marginal livers based on donor history, organ steatosis and preservation period. The oxygen delivery efficiency was assessed in additional 6 livers using real-time measurements of perfusate and parenchymal oxygen. RESULTS The change in mitochondrial respiratory chain (complex I, II, III, IV) and Krebs cycle enzyme activity (aconitase, citrate synthase) before and after 4-hour preservation was not different between groups in both study stages (p > 0.05). Low-risk livers that could have been used clinically (n = 8) had lower complex II-III activities after 4-hour perfusion, compared with high-risk livers (73 nmol/mg/min vs. 113 nmol/mg/min, p = 0.01). Parenchymal pO2 was consistently lower than perfusate pO2 (p ≤ 0.001), stabilised in 28 minutes compared to 3 minutes in perfusate (p = 0.003), and decreased faster upon oxygen cessation (75 vs. 36 minutes, p = 0.003). CONCLUSIONS Actively oxygenated and air-equilibrated end-ischaemic HMP did not induce oxidative damage of aconitase, and respiratory chain complexes remained intact. Mitochondria likely respond to variable perfusate oxygen levels by adapting their respiratory function during end-ischaemic HMP. Complex II-III activities should be further investigated as viability biomarkers.
Collapse
|
|
15
|
Tara A, Dominic JL, Patel JN, Garg I, Yeon J, Memon MS, Gergal Gopalkrishna Rao SR, Bugazia S, Dhandapani TPM, Kannan A, Kantamaneni K, Win M, Went TR, Yanamala VL, Mostafa JA. Mitochondrial Targeting Therapy Role in Liver Transplant Preservation Lines: Mechanism and Therapeutic Strategies. Cureus 2021; 13:e16599. [PMID: 34430181 PMCID: PMC8378417 DOI: 10.7759/cureus.16599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 07/23/2021] [Indexed: 01/02/2023] Open
Abstract
The normal function of mitochondria in the hepatic parenchyma can be disrupted by ischemia/reperfusion (I/R) damage during liver transplantation. The pathology of these insults involves various cellular and molecular steps of events that have been extensively researched over decades but are yet to provide complete answers. This review discusses the brief mechanism of the pathophysiology following ischemia/reperfusion injury (IRI) and various targeting strategies that could result in improved graft function. The traditional treatment for end-stage liver disease i.e., liver transplantation, has been complicated by I/R damage. The poor graft function or primary non-function found after liver transplantation may be due to mitochondrial dysfunction following IRI. As a result, determining the sequence of incidents that cause human hepatic mitochondrial dysfunction is crucial; it might contribute to further improvements in the outcome of liver transplantation. Early discovery of novel prognostic factors involved in IRI could serve as a primary endpoint for predicting the outcome of liver grafts as well as promoting the early implementation of novel IRI-prevention strategies. In this review, recent developments in the study of mitochondrial dysfunction and I/R damage are discussed, specifically those concerning liver transplantation. Furthermore, we also explore different pharmacological therapeutic methods that may be used and their connections to mitochondrion-related processes and goals. Although significant progress has been made in our understanding of IRI and mitochondrial dysfunction, further research is needed to elucidate the cellular and molecular pathways underlying these processes to help identify biomarkers that can aid donor organ evaluation.
Collapse
Affiliation(s)
- Anjli Tara
- General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA.,General Surgery, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro, PAK
| | - Jerry Lorren Dominic
- General Surgery, Vinayaka Mission's Kirupananda Variyar Medical College, Salem, IND.,General Surgery, Stony Brook Southampton Hospital, New York, USA.,General Surgery and Orthopaedic Surgery, Cornerstone Regional Hospital, Edinburg, USA.,General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Jaimin N Patel
- Family Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Ishan Garg
- Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Jimin Yeon
- Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Marrium S Memon
- Research, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | | | - Seif Bugazia
- Faculty of Medicine, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Tamil Poonkuil Mozhi Dhandapani
- Internal Medicine/Family Medicine, California Institute of Behavioral Neuroscience & Pyshology (CIBNP), Fairfield, USA.,Internal Medicine, Medical City Plano, Plano, USA
| | - Amudhan Kannan
- Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, IND.,General Surgery Research, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Ketan Kantamaneni
- Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA.,Surgery, Dr.Pinnamaneni Siddhartha Institute of Medical Sciences and Research Foundation, Gannavaram, IND
| | - Myat Win
- General Surgery, Nottingham University Hospitals NHS Trust, Nottingham, GBR.,General Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Terry R Went
- Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Vijaya Lakshmi Yanamala
- Surgery, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| | - Jihan A Mostafa
- Psychiatry and Behavioral Sciences, California Institute of Behavioral Neurosciences & Psychology (CIBNP), Fairfield, USA
| |
Collapse
|
|
16
|
Lembach Jahnsen H, Mergental H, Perera MTPR, Mirza DF. Ex-situ liver preservation with machine preservation. Curr Opin Organ Transplant 2021; 26:121-132. [PMID: 33650995 DOI: 10.1097/mot.0000000000000864] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE OF REVIEW To summarize key studies in liver preservation published over the last 3 years and evaluate benefits and limitations of the different perfusion techniques. Selected experimental applications that may be translated to the clinical use will be also discussed. RECENT FINDINGS Normothermic machine perfusion (NMP) has transitioned into clinical practice. Viability assessment is a reliable tool for clinical decision-making, and safety of the back-to-base approach has facilitated adoption of the technology. Data supporting well tolerated use of declined livers after NMP and new protocols selecting complex recipients aim to improve access to suitable organs. Hypothermic machine perfusion (HMP) is showing promising clinical results by decreasing biliary complications in recipients' receiving organs donated after circulatory death (DCD) and improving early graft function in extended criteria organs. Long-term data of HMP on DCD livers shows improved graft survival over standard SCS. Novel approaches utilizing sequential HMP--NMP or ischaemia-free preservation aim to improve outcomes of extended criteria organs. SUMMARY Machine perfusion for organ transplantation has become an established technique but the field is rapidly evolving. Ongoing research focuses on evaluation of the intervention efficacy and finding optimal indications to use each perfusion strategy according to graft type and clinical scenario.
Collapse
Affiliation(s)
- Hanns Lembach Jahnsen
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - M Thamara P R Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| |
Collapse
|
|
17
|
Mazilescu LI, Selzner M, Selzner N. Defatting strategies in the current era of liver steatosis. JHEP Rep 2021; 3:100265. [PMID: 34027337 PMCID: PMC8121960 DOI: 10.1016/j.jhepr.2021.100265] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 02/14/2021] [Accepted: 02/19/2021] [Indexed: 12/25/2022] Open
Abstract
Liver steatosis is emerging as a major cause of chronic liver disease worldwide, mainly due to the increasing rate of obesity, type 2 diabetes, and metabolic syndrome. Because of the increased incidence of liver steatosis, many organs are currently declined for transplantation despite high demand and waiting list mortality. Defatting strategies have recently emerged as a means of rapidly reducing liver steatosis to expand the pool of available organs. This review summarises advances in defatting strategies in experimental and human models of liver steatosis over the last 20 years.
Collapse
Key Words
- GDNF, glial cell-line derived neurotrophic factor
- HFD, high-fat diet
- HIEC, hepatic endothelial cells
- HOPE, hypothermic machine perfusion
- LDs, lipid droplets
- Macrosteatosis
- NAFL, non-alcoholic fatty liver
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NEsLP, normothermic ex situ machine perfusion
- PHHs, primary human hepatocytes
- PPAR, peroxisome proliferator-activated receptor
- PXR, pregnane X receptor
- SCS, static cold storage
- SRS, steatosis reduction supplements
- TG, triglyceride
- ischemia-reperfusion injury
- liver transplantation
- machine perfusion
Collapse
Affiliation(s)
- Laura Ioana Mazilescu
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Markus Selzner
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
| | - Nazia Selzner
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
- Corresponding author. Address: Multi-Organ Transplant Program, Toronto General Hospital, 585 University Avenue, 11 PMB-178 Toronto, ON, Canada M5G 2N2.
| |
Collapse
|
|
18
|
Panconesi R, Flores Carvalho M, Mueller M, Meierhofer D, Dutkowski P, Muiesan P, Schlegel A. Viability Assessment in Liver Transplantation-What Is the Impact of Dynamic Organ Preservation? Biomedicines 2021; 9:biomedicines9020161. [PMID: 33562406 PMCID: PMC7915925 DOI: 10.3390/biomedicines9020161] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023] Open
Abstract
Based on the continuous increase of donor risk, with a majority of organs classified as marginal, quality assessment and prediction of liver function is of utmost importance. This is also caused by the notoriously lack of effective replacement of a failing liver by a device or intensive care treatment. While various parameters of liver function and injury are well-known from clinical practice, the majority of specific tests require prolonged diagnostic time and are more difficult to assess ex situ. In addition, viability assessment of procured organs needs time, because the development of the full picture of cellular injury and the initiation of repair processes depends on metabolic active tissue and reoxygenation with full blood over several hours or days. Measuring injury during cold storage preservation is therefore unlikely to predict the viability after transplantation. In contrast, dynamic organ preservation strategies offer a great opportunity to assess organs before implantation through analysis of recirculating perfusates, bile and perfused liver tissue. Accordingly, several parameters targeting hepatocyte or cholangiocyte function or metabolism have been recently suggested as potential viability tests before organ transplantation. We summarize here a current status of respective machine perfusion tests, and report their clinical relevance.
Collapse
Affiliation(s)
- Rebecca Panconesi
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, 50134 Florence, Italy; (R.P.); (M.F.C.); (P.M.)
| | - Mauricio Flores Carvalho
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, 50134 Florence, Italy; (R.P.); (M.F.C.); (P.M.)
| | - Matteo Mueller
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, 8091 Zurich, Switzerland; (M.M.); (P.D.)
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, 14195 Berlin, Germany;
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, 8091 Zurich, Switzerland; (M.M.); (P.D.)
| | - Paolo Muiesan
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, 50134 Florence, Italy; (R.P.); (M.F.C.); (P.M.)
| | - Andrea Schlegel
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, 50134 Florence, Italy; (R.P.); (M.F.C.); (P.M.)
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, 8091 Zurich, Switzerland; (M.M.); (P.D.)
- Correspondence:
| |
Collapse
|
|
19
|
The importance of adequate oxygenation during hypothermic machine perfusion. JHEP Rep 2020; 3:100194. [PMID: 33305200 PMCID: PMC7718475 DOI: 10.1016/j.jhepr.2020.100194] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/29/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
|
|
20
|
Perfusate Analysis During Dual Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Correlations With Donor Factors and Early Outcomes. Transplantation 2020; 104:1929-1942. [PMID: 32769628 DOI: 10.1097/tp.0000000000003398] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver graft viability assessment has long been considered a limit of hypothermic oxygenated machine perfusion (HOPE). Aim of this study was assessing correlations of easily available perfusate parameters (PP) (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glucose, lactate, and pH) with graft features and outcome. METHODS In the period October 2018-February 2020, perfusate samples were obtained every 30 minutes during 50 dual-HOPE (D-HOPE) procedures. Correlations of PP with graft factors, 90-day graft loss, early allograft dysfunction (EAD), L-GrAFT score, acute kidney injury, and comprehensive complication index were analyzed using Pearson coefficient, receiver-operating characteristics analysis and by univariable and multivariable regression. RESULTS Median D-HOPE time was 122 minutes. All parameters were normalized to liver weight. Only macrovesicular steatosis (MaS) significantly impacted PP levels and slope. Grafts with ≥30% MaS exhibited significantly different PP values and slope. Graft loss and EAD rate were 2% (n = 1) and 26% (n = 13). All PP except lactate correlated with EAD, 90-minute alanine aminotransferase showing the highest area under the receiver-operating characteristics curve (0.84). However, at multivariable analysis, the only factor independently associated with EAD was MaS (odds ratio, 5.44; confidence interval, 1.05-28.21; P = 0.04). Ninety minutes lactate dehydrogenase had the strongest correlation with L-GrAFT (R = 0.70; P < 0.001). PP correlated poorly with comprehensive complication index and grades 2-3 acute kidney injury rate. CONCLUSIONS PP were predictive of graft function after transplant, but their association with graft survival and clinical outcomes requires further evaluation. MaS influenced levels of PP and was the only independent predictor of EAD.
Collapse
|
|
21
|
Lai Q, Ruberto F, Pawlik TM, Pugliese F, Rossi M. Use of machine perfusion in livers showing steatosis prior to transplantation: a systematic review. Updates Surg 2020; 72:595-604. [PMID: 32449031 DOI: 10.1007/s13304-020-00797-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 05/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The role of machine perfusion (MP) in the evaluation of liver grafts with macrovesicular steatosis (MaS) remains ill-defined as only a limited number of studies has been reported. The objective of the current study was to provide a systematic review to evaluate the role of MP in the setting of MaS livers. METHODS A systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed. Eligible articles published up to April 2019 were included using the MEDLINE, Scopus, and Google Scholar databases. RESULTS Among the 422 articles screened, only 16 papers met the inclusion criteria. A total of 54 cases of MP use before liver transplantation were included. Sixteen (29.6%) grafts were from donors after circulatory death. In 22 (40.7%) cases, hypothermic machine perfusion was performed. Normothermic machine perfusion was done in the remaining 32 (59.3%) cases. According to the histological results of the donor core biopsy, a MaS value < 30% was observed in 41 (75.9%) cases, whereas 13 (24.1%) patients had moderate-to-severe (≥ 30%) MaS. Following categorization of the pooled population according to the presence of moderate-to-severe (≥ 30%) MaS in the donor graft, no differences were noted in terms of post-transplant death or severe complications following MP. There was no correlation between the proportion of MaS in the donor graft relative to post-transplant peak ALT among patients treated with MP. Among the entire pooled cohort, there was also no correlation between MaS values and ALT peak (R = 0.13; P = 0.42). CONCLUSIONS MP appears to be feasible and safe in MaS livers. Experience to date has been very limited, and the benefit of MP remains not determined. Prospective studies will need to define better the potential effect of "defatting" drugs used during the perfusion process on MaS.
Collapse
Affiliation(s)
- Quirino Lai
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
| | - Franco Ruberto
- Department of Anaesthesiology, Critical Care Medicine and Pain Therapy, Sapienza University of Rome, Rome, Italy
| | - Timothy M Pawlik
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Francesco Pugliese
- Department of Anaesthesiology, Critical Care Medicine and Pain Therapy, Sapienza University of Rome, Rome, Italy
| | - Massimo Rossi
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| |
Collapse
|
|
22
|
Bonaccorsi-Riani E, Brüggenwirth IMA, Buchwald JE, Iesari S, Martins PN. Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials. Semin Liver Dis 2020; 40:264-281. [PMID: 32557478 DOI: 10.1055/s-0040-1713118] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.
Collapse
Affiliation(s)
- E Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.,Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium
| | - I M A Brüggenwirth
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J E Buchwald
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
| | - S Iesari
- Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - P N Martins
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
| |
Collapse
|
|
23
|
Hu X, Wang W, Zeng C, He W, Zhong Z, Liu Z, Wang Y, Ye Q. Appropriate timing for hypothermic machine perfusion to preserve livers donated after circulatory death. Mol Med Rep 2020; 22:2003-2011. [PMID: 32582977 PMCID: PMC7411412 DOI: 10.3892/mmr.2020.11257] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 05/28/2020] [Indexed: 12/17/2022] Open
Abstract
Hypothermic machine perfusion (HMP) is a method that can be more effective in preserving donor organs compared with cold storage (CS). However, the optimal duration and the exact mechanisms of the protevtive effects of HMP remain unknow. The present study aimed to investigate the adequate perfusion time and mechanisms underlying HMP to protect livers donated after circulatory death (DCD). After circulatory death, adult male Sprague-Dawley rat livers were subjected to 30 min of warm ischemia (WI) and were subsequently preserved by HMP or CS. To determine the optimal perfusion time, liver tissues were analyzed at 0, 1, 3, 5, 12 and 24 h post-preservation to evaluate injury and assess the expression of relevant proteins. WI livers were preserved by HMP or CS for 3 h, and liver viability was evaluated by normothermic reperfusion (NR). During NR, oxygen consumption, bile production and the activities of hepatic enzymes in the perfusate were assessed. Following 2 h of NR, levels of inflammation and oxidative stress were determined in the livers and perfusate. HMP for 3 h resulted in the highest expression of myocyte enhancer factor 2C (MEF2C) and kruppel-like factor 2 (KLF2) and the lowest expression of NF-κB p65, tumor necrosis factor (TNF)-α and interleukin (IL)-1β among the different timepoints, which indicated that 3 h may be the optimal time for HMP induction of the KLF2-dependent signaling pathway. Compared with CS-preserved livers, HMP-preserved livers displayed significantly higher oxygen consumption, lower hepatic enzyme levels in the perfusate following NR. Following HMP preservation, the expression levels of MEF2C, KLF2, endothelial nitric oxide synthase and nitric oxide were increased, whereas the expression levels of NF-κB p65, IL-1β and TNF-α were decreased compared with CS preservation. The results indicated that 3 h may be the optimal time for HMP to protect DCD rat livers. Furthermore, HMP may significantly reduce liver inflammation and oxidative stress injury by mediating the KLF2/NF-κB/eNOS-dependent signaling pathway.
Collapse
Affiliation(s)
- Xiaoyan Hu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Wei Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Cheng Zeng
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Weiyang He
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Zibiao Zhong
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Zhongzhong Liu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| |
Collapse
|
|
24
|
Patrono D, Martini S, Romagnoli R. Liver Transplantation and NAFLD/NASH. NON-ALCOHOLIC FATTY LIVER DISEASE 2020:343-362. [DOI: 10.1007/978-3-319-95828-6_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
25
|
Bral M, Aboelnazar N, Hatami S, Thiesen A, Bigam DL, Freed DH, Shapiro AMJ. Clearance of transaminases during normothermic ex situ liver perfusion. PLoS One 2019; 14:e0215619. [PMID: 31017974 PMCID: PMC6481840 DOI: 10.1371/journal.pone.0215619] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 04/04/2019] [Indexed: 01/02/2023] Open
Abstract
Background One of the most promising applications of liver normothermic machine perfusion (NMP) is the potential to directly assess graft viability and injury. In most NMP studies, perfusate transaminases are utilized as markers of graft injury. Our aim was to further elucidate the metabolism of transaminases by healthy porcine livers during NMP, specifically whether such livers could clear circuit perfusate transaminases. Methods A highly concentrated transaminase solution was prepared from homogenized liver, with an aspartate aminotransferase (AST) level of 107,427 U/L. Three livers in the treatment group were compared to three controls, during 48 hours of NMP. In the treatment group, the circuit perfusate was injected with the transaminase solution to artificially raise the AST level to a target of 7,500 U/L. Perfusate samples were taken at two-hour intervals and analyzed for biochemistry until NMP end. Graft oxygen consumption and vascular parameters were monitored. Results Compared to controls, treated perfusions demonstrated abrupt elevations in transaminase levels (p>0.0001) and lactate dehydrogenase (LDH) (p>0.0001), which decreased over time, but never to control baseline. Liver function, as demonstrated by lactate clearance and oxygen consumption was not different between groups. The treatment group demonstrated a higher portal vein resistance (p = 0.0003), however hepatic artery resistance was similar. Treated livers had higher bile production overall (p<0.0001). Conclusions Addition of high levels of transaminases and LDH to a healthy porcine liver during ex situ perfusion results in progressive clearance of these enzymes, suggesting preserved liver metabolism. Such tolerance tests may provide valuable indicators of prospective graft function.
Collapse
Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | | - Sanaz Hatami
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Aducio Thiesen
- Department of Pathology, University of Alberta, Edmonton, Canada
| | - David L. Bigam
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Darren H. Freed
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | |
Collapse
|
|
26
|
Bral M, Gala-Lopez B, Thiesen A, Hatami S, Bigam DL, Freed DM, James Shapiro AM. Determination of Minimal Hemoglobin Level Necessary for Normothermic Porcine Ex Situ Liver Perfusion. Transplantation 2019; 102:1284-1292. [PMID: 29757899 DOI: 10.1097/tp.0000000000002272] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND In current studies of ex situ liver perfusion there exists considerable variability in perfusate composition, including the type of oxygen carrier. Herein, we aim to clarify the minimal hemoglobin level necessary during normothermic porcine ex situ liver perfusion. METHODS Livers procured from 35 to 45 kg domestic pigs were connected to our experimental ex situ circuit (n = 10). In the treatment group, perfusate was sequentially diluted hourly to predetermined hemoglobin levels. At the end of each hemoglobin dilution, perfusate samples were analyzed for liver transaminases, lactate dehydrogenase (LD), total bilirubin, and lactate levels. Liver oxygen consumption was measured. In the control group, livers were perfused continually for a duration of 24 hours at target hemoglobin levels of 30 and 20 g/L. RESULTS Rising liver transaminases, significantly higher lactate (P < 0.001), and LD levels (P < 0.001) were noted at lower perfusate hemoglobin levels in the treatment group. Liver oxygen utilization (P < 0.001) and hepatic artery oxygen delivery (P < 0.001) were significantly lower at lower hemoglobin levels, whereas liver vessel resistance remained relatively constant. Histology demonstrated increasing parenchymal damage at lower hemoglobin levels. In control livers, higher perfusate transaminases, higher lactate, and LD levels were noted at a perfusion hemoglobin level of 20 g/L. CONCLUSIONS Ex situ liver function decompensated during perfusion between a mean hemoglobin level of 30 to 20 g/L, as evidenced by notably rising lactate and LD levels. This study demonstrates optimal hemoglobin concentration during normothermic ex situ liver perfusion to ensure a fully metabolically functioning graft.
Collapse
Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - Boris Gala-Lopez
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - Aducio Thiesen
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Sanaz Hatami
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - David L Bigam
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Darren M Freed
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| |
Collapse
|
|
27
|
Rampes S, Ma D. Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies. J Biomed Res 2019; 33:221-234. [PMID: 32383437 DOI: 10.7555/jbr.32.20180087] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatic ischemia-reperfusion injury is a major cause of liver transplant failure, and is of increasing significance due to increased use of expanded criteria livers for transplantation. This review summarizes the mechanisms and protective strategies for hepatic ischemia-reperfusion injury in the context of liver transplantation. Pharmacological therapies, the use of pre-and post-conditioning and machine perfusion are discussed as protective strategies. The use of machine perfusion offers significant potential in the reconditioning of liver grafts and the prevention of hepatic ischemia-reperfusion injury, and is an exciting and active area of research, which needs more study clinically.
Collapse
Affiliation(s)
- Sanketh Rampes
- Faculty of Life Sciences & Medicine, King's College London, London SE1 1U, UK
| | - Daqing Ma
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, UK
| |
Collapse
|
|
28
|
Boteon YL, Boteon APCS, Attard J, Mergental H, Mirza DF, Bhogal RH, Afford SC. Ex situ machine perfusion as a tool to recondition steatotic donor livers: Troublesome features of fatty livers and the role of defatting therapies. A systematic review. Am J Transplant 2018; 18:2384-2399. [PMID: 29947472 DOI: 10.1111/ajt.14992] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/13/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023]
Abstract
Long-standing research has shown that increased lipid content in donor livers is associated with inferior graft outcomes posttransplant. The global epidemic that is obesity has increased the prevalence of steatosis in organ donors, to the extent that it has become one of the main reasons for declining livers for transplantation. Consequently, it is one of the major culprits behind the discrepancy between the number of donor livers offered for transplantation and those that go on to be transplanted. Steatotic livers are characterized by poor microcirculation, depleted energy stores because of an impaired capacity for mitochondrial recovery, and a propensity for an exaggerated inflammatory response following reperfusion injury culminating in poorer graft function postoperatively. Ex situ machine perfusion, currently a novel method in graft preservation, is showing great promise in providing a tool for the recovery and reconditioning of marginal livers. Hence, reconditioning these steatotic livers using machine perfusion has the potential to increase the number of liver transplants performed. In this review, we consider the problematic issues associated with fatty livers in the realm of transplantation and discuss pharmacological and nonpharmacological options that are being developed to enhance recovery of these organs using machine perfusion and defatting strategies.
Collapse
Affiliation(s)
- Yuri L Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
| | - Amanda P C S Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Joseph Attard
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ricky H Bhogal
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon C Afford
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
| |
Collapse
|
|
29
|
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]
|
|
30
|
Abudhaise H, Davidson BR, DeMuylder P, Luong TV, Fuller B. Evolution of dynamic, biochemical, and morphological parameters in hypothermic machine perfusion of human livers: A proof-of-concept study. PLoS One 2018; 13:e0203803. [PMID: 30216378 PMCID: PMC6138380 DOI: 10.1371/journal.pone.0203803] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 08/07/2018] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION Hypothermic machine perfusion (HMP) is increasingly investigated as a means to assess liver quality, but data on viability markers is inconsistent and the effects of different perfusion routes and oxygenation on perfusion biomarkers are unclear. METHODS This is a single-centre, randomised, multi-arm, parallel study using discarded human livers for evaluation of HMP using arterial, oxygen-supplemented venous and non-oxygen-supplemented venous perfusion. The study included 2 stages: in the first stage, 25 livers were randomised into static cold storage (n = 7), hepatic artery HMP (n = 10), and non-oxygen-supplemented portal vein HMP (n = 8). In the second stage, 20 livers were randomised into oxygen-supplemented and non-oxygen-supplemented portal vein HMP (n = 11 and 9, respectively). Changes in dynamic, biochemical, and morphologic parameters during 4-hour preservation were compared between perfusion groups, and between potentially transplantable and non-transplantable livers. RESULTS During arterial perfusion, resistance was higher and flow was lower than venous perfusion (p = 0.001 and 0.01, respectively); this was associated with higher perfusate markers during arterial perfusion (p>0.05). Supplementary oxygen did not cause a significant alteration in the studied parameters. Morphology was similar between static and dynamic preservation groups. Perfusate markers were 2 fold higher in non-transplantable livers (p>0.05). CONCLUSIONS Arterial only perfusion might not be adequate for graft perfusion. Hepatocellular injury markers are accessible and easy to perform and could offer insight into graft quality, but large randomised trials are needed to identify reliable quality assessment biomarkers.
Collapse
Affiliation(s)
- H. Abudhaise
- UCL Division of Surgery and Interventional Sciences, Royal Free Hospital, London, United Kingdom
- * E-mail:
| | - B. R. Davidson
- UCL Division of Surgery and Interventional Sciences, Royal Free Hospital, London, United Kingdom
| | | | - T. V. Luong
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - B. Fuller
- UCL Division of Surgery and Interventional Sciences, Royal Free Hospital, London, United Kingdom
| |
Collapse
|
|
31
|
Gullón L, Gutiérrez-Gutiérrez J, Sánchez del Arco RT, Rivera A, Fernández I, Del Cañizo JF. Development of an automated liver perfusion system: The benefit of a hemofilter. Int J Artif Organs 2018; 41:723-729. [DOI: 10.1177/0391398818783851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Introduction: Liver perfusion machines are close to becoming a reality in the transplantation field. However, depending on the techniques used and the goals pursued, their application is limited in the research field. Here, we present the entire development of a perfusion system with self-made engineering, completely autonomous controls, and a high degree of versatility that allows the design of different studies on liver functionality. Methods: A user-friendly interface permits real-time monitoring and remote control by the devices within the circuit. Centrifugal pumps allow the perfusate enter the organ with controlled pressures and flows at both hepatic artery and portal vein. The implementation of a hemofilter as a novel tool permits to control and maintain homeostasis. Peristaltic pumps adjust pH, extraction rate, and total volume by means of sensors. Results: Real-time monitoring facilitates liver functionality assessment. The controlled system shows rapid stabilization and quick responses to changes during 6 h of perfusion experiments. Furthermore, the integration of a hemofilter helps the system to eliminate toxic waste and maintain homeostasis. Discussion: The machine provides the basis of a perfusion system with autonomous controls and the implementation of a hemofilter that enables a more efficient control of hemostasis. Moreover, the developed hardware and software are subjected to further tuning for additional purposes such as pathophysiologic studies, suboptimal grafts recovery, or recellularization of decellularized scaffolds among others.
Collapse
Affiliation(s)
- Lucía Gullón
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - Judit Gutiérrez-Gutiérrez
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Fundación para la Investigación Biomédica del Hospital Gregorio Marañón (FIBHGM), Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Robert T Sánchez del Arco
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Fundación para la Investigación Biomédica del Hospital Gregorio Marañón (FIBHGM), Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Andrés Rivera
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Ignacio Fernández
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Juan F Del Cañizo
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Fundación para la Investigación Biomédica del Hospital Gregorio Marañón (FIBHGM), Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Pabellón de Medicina y Cirugía Experimental, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| |
Collapse
|
|
32
|
Lai Q, Melandro F, Rossi M, Ruberto F, Pugliese F, Mennini G. Role of perfusion machines in the setting of clinical liver transplantation: A qualitative systematic review. Clin Transplant 2018; 32:e13310. [PMID: 29876967 DOI: 10.1111/ctr.13310] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2018] [Indexed: 02/06/2023]
Abstract
Growing enthusiasm around machine perfusion (MP) in clinical liver transplantation (LT) may be the preamble for standardized practice to expand the donors' pool. The present systematic review investigated all the liver transplantations performed using grafts treated with MP. A systematic review of 309 papers was performed. Eventually, 27 articles were enrolled for the study. A total number of 173 cases were reported. Only 12 cohort studies were identified: the remaining ones were case reports or case series. Hypothermic machine perfusion was performed in 102 (59.0%), normothermic machine perfusion in 65 (37.6%), and controlled oxygenated rewarming in the remaining 6 (3.4%) cases. Donor characteristics, evaluation of graft quality, and endpoints were not homogeneous among the studies. Overall, post-LT results were excellent, with 1.2 and 4.0% of patients experienced primary non-function and ischemic-type biliary lesions, respectively. CONCLUSION Until now, no study exists that addresses the role of MP in selecting liver grafts available for LT. All the published studies mainly focused on the feasibility and safety of this new technology. Further research investigating the selection process of marginal donors is required.
Collapse
Affiliation(s)
- Quirino Lai
- Hepato-bilio-pancreatic and Liver Transplant Unit, Department of Surgery, Sapienza University of Rome, Rome, Italy
| | - Fabio Melandro
- Hepato-bilio-pancreatic and Liver Transplant Unit, Department of Surgery, Sapienza University of Rome, Rome, Italy
| | - Massimo Rossi
- Hepato-bilio-pancreatic and Liver Transplant Unit, Department of Surgery, Sapienza University of Rome, Rome, Italy
| | - Franco Ruberto
- Department of Anaesthesiology, Critical Care Medicine and Pain Therapy, Sapienza University of Rome, Rome, Italy
| | - Francesco Pugliese
- Department of Anaesthesiology, Critical Care Medicine and Pain Therapy, Sapienza University of Rome, Rome, Italy
| | - Gianluca Mennini
- Hepato-bilio-pancreatic and Liver Transplant Unit, Department of Surgery, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
33
|
Bral M, Gala-Lopez B, Bigam DL, Freed DH, Shapiro AMJ. Ex situ liver perfusion: Organ preservation into the future. Transplant Rev (Orlando) 2018; 32:132-141. [PMID: 29691119 DOI: 10.1016/j.trre.2018.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 03/27/2018] [Accepted: 03/27/2018] [Indexed: 12/15/2022]
Abstract
In recent years, remarkable progress has occurred in the development of technologies to support ex situ liver perfusion. Building upon extensive preclinical studies in large animal models, pilot and randomized clinical trials have been initiated, and preliminary outcomes suggest more optimal protection of both standard and extended criteria liver grafts. There currently exists an incredible opportunity and need to further refine this technology, determine appropriate viability measures to predict usable liver grafts, and to explore potent protective additive strategies to further optimize the quality of extended criteria organs. These findings will have major bearing in expanding the limited liver donor pool, and may save lives where up to a quarter of listed patients die on wait-lists. Herein we offer a brief overview of the history and current status of ex situ liver perfusion, and discuss future directions that will likely have major impact on the practice of clinical liver transplantation.
Collapse
Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - Boris Gala-Lopez
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - David L Bigam
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - Darren H Freed
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - A M James Shapiro
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| |
Collapse
|
|
34
|
Faitot F, Besch C, Battini S, Ruhland E, Onea M, Addeo P, Woehl-Jaeglé ML, Ellero B, Bachellier P, Namer IJ. Impact of real-time metabolomics in liver transplantation: Graft evaluation and donor-recipient matching. J Hepatol 2018; 68:699-706. [PMID: 29191459 DOI: 10.1016/j.jhep.2017.11.022] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 11/09/2017] [Accepted: 11/15/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS There is an emerging need to assess the metabolic state of liver allografts especially in the novel setting of machine perfusion preservation and donor in cardiac death (DCD) grafts. High-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS-NMR) could be a useful tool in this setting as it can extemporaneously provide untargeted metabolic profiling. The purpose of this study was to evaluate the potential value of HR-MAS-NMR metabolomic analysis of back-table biopsies for the prediction of early allograft dysfunction (EAD) and donor-recipient matching. METHOD The metabolic profiles of back-table biopsies obtained by HR-MAS-NMR, were compared according to the presence of EAD using partial least squares discriminant analysis. Network analysis was used to identify metabolites which changed significantly. The profiles were compared to native livers to identify metabolites for donor-recipient matching. RESULTS The metabolic profiles were significantly different in grafts that caused EAD compared to those that did not. The constructed model can be used to predict the graft outcome with excellent accuracy. The metabolites showing the most significant differences were lactate level >8.3 mmol/g and phosphocholine content >0.646 mmol/g, which were significantly associated with graft dysfunction with an excellent accuracy (AUROClactates = 0.906; AUROCphosphocholine = 0.816). Native livers from patients with sarcopenia had low lactate and glycerophosphocholine content. In patients with sarcopenia, the risk of EAD was significantly higher when transplanting a graft with a high-risk graft metabolic score. CONCLUSION This study underlines the cost of metabolic adaptation, identifying lactate and choline-derived metabolites as predictors of poor graft function in both native livers and liver grafts. HR-MAS-NMR seems a valid technique to evaluate graft quality and the consequences of cold ischemia on the graft. It could be used to assess the efficiency of graft resuscitation on machine perfusion in future studies. LAY SUMMARY Real-time metabolomic profiles of human grafts during back-table can accurately predict graft dysfunction. High lactate and phosphocholine content are highly predictive of graft dysfunction whereas low lactate and phosphocholine content characterize patients with sarcopenia. In these patients, the cost of metabolic adaptation may explain the poor outcomes.
Collapse
Affiliation(s)
- Francois Faitot
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, CHU de Strasbourg, France; Laboratoire ICube, UMR7357, University of Strasbourg, France
| | - Camille Besch
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, CHU de Strasbourg, France
| | | | - Elisa Ruhland
- Laboratoire ICube, UMR7357, University of Strasbourg, France
| | - Mihaela Onea
- Pathology Department, Hopital de Hautepierre, CHU de Strasbourg, France
| | - Pietro Addeo
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, CHU de Strasbourg, France
| | - Marie-Lorraine Woehl-Jaeglé
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, CHU de Strasbourg, France
| | - Bernard Ellero
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, CHU de Strasbourg, France
| | - Philippe Bachellier
- Hepatobiliopancreatic Surgery and Transplantation Department, Hopital de Hautepierre, CHU de Strasbourg, France
| | - Izzie-Jacques Namer
- Laboratoire ICube, UMR7357, University of Strasbourg, France; Nuclear Medicine Department, Hôpital de Hautepierre, CHU de Strasbourg, France.
| |
Collapse
|
|
35
|
Pushing the Limits: Machine Preservation of the Liver as a Tool to Recondition High-Risk Grafts. CURRENT TRANSPLANTATION REPORTS 2018; 5:113-120. [PMID: 29774176 PMCID: PMC5945712 DOI: 10.1007/s40472-018-0188-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Purpose of the Review Machine perfusion (MP) is a novel technology recently introduced in liver transplantation, redefining the current practice of organ preservation and pushing the limits of high-risk liver utilisation. This review highlights the key benefits of machine perfusion over conventional static cold storage (SCS), demonstrated in human liver research and clinical transplants. Recent Findings The first clinical trials have demonstrated both safety and feasibility of MP. The most recent transplant series and result from a randomised trial suggest the technology is superior to SCS. The key benefits include extended period of organ preservation, decreased incidence of early allograft dysfunction and reduction of biliary complications. Normothermic liver perfusion allows viability testing to guide transplantability of the highest-risk organs. This technology also provides opportunities for therapeutic interventions to improve liver function and quality in organs that are currently declined for clinical use. Summary Machine perfusion is likely to transform the liver preservation pathway and to improve utilisation of high-risk grafts.
Collapse
|
|
36
|
Liu Q, Nassar A, Buccini L, Iuppa G, Soliman B, Pezzati D, Hassan A, Blum M, Baldwin W, Bennett A, Chavin K, Okamoto T, Uso TD, Fung J, Abu-Elmagd K, Miller C, Quintini C. Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 hours of normothermic machine perfusion. Liver Transpl 2018; 24:233-245. [PMID: 29125712 DOI: 10.1002/lt.24972] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/18/2017] [Accepted: 11/05/2017] [Indexed: 02/07/2023]
Abstract
Normothermic machine perfusion (NMP) is an emerging technology to preserve liver allografts more effectively than cold storage (CS). However, little is known about the effect of NMP on steatosis and the markers indicative of hepatic quality during NMP. To address these points, we perfused 10 discarded human livers with oxygenated NMP for 24 hours after 4-6 hours of CS. All livers had a variable degree of steatosis at baseline. The perfusate consisted of packed red blood cells and fresh frozen plasma. Perfusate analysis showed an increase in triglyceride levels from the 1st hour (median, 127 mg/dL; interquartile range [IQR], 95-149 mg/dL) to 24th hour of perfusion (median, 203 mg/dL; IQR, 171-304 mg/dL; P = 0.004), but tissue steatosis did not decrease. Five livers produced a significant amount of bile (≥5 mL/hour) consistently throughout 24 hours of NMP. Lactate in the perfusate cleared to <3 mmol/L in most livers within 4-8 hours of NMP, which was independent of bile production rate. This is the first study to characterize the lipid profile and functional assessment of discarded human livers at 24 hours of NMP. Liver Transplantation 24 233-245 2018 AASLD.
Collapse
Affiliation(s)
- Qiang Liu
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Ahmed Nassar
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Laura Buccini
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | - Basem Soliman
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | - Ahmed Hassan
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Matthew Blum
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | - Ana Bennett
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Kenneth Chavin
- University Hospital, Case Western Reserve University, Cleveland, OH
| | | | | | - John Fung
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | | | | |
Collapse
|
|
37
|
Czigany Z, Schöning W, Ulmer TF, Bednarsch J, Amygdalos I, Cramer T, Rogiers X, Popescu I, Botea F, Froněk J, Kroy D, Koch A, Tacke F, Trautwein C, Tolba RH, Hein M, Koek GH, Dejong CHC, Neumann UP, Lurje G. Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): a prospective multicentre randomised controlled trial (HOPE ECD-DBD). BMJ Open 2017; 7:e017558. [PMID: 29018070 PMCID: PMC5652559 DOI: 10.1136/bmjopen-2017-017558] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. In an attempt to improve the availability of donor allografts and reduce waiting list mortality, graft acceptance criteria were extended increasingly over the decades. The use of extended criteria donor (ECD) allografts is associated with a higher incidence of primary graft non-function and/or delayed graft function. As such, several strategies have been developed aiming at reconditioning poor quality ECD liver allografts. Hypothermic oxygenated machine perfusion (HOPE) has been successfully tested in preclinical experiments and in few clinical series of donation after cardiac death OLT. METHODS AND ANALYSIS HOPE ECD-DBD is an investigator-initiated, open-label, phase-II, prospective multicentre randomised controlled trial on the effects of HOPE on ECD allografts in donation after brain death (DBD) OLT. Human whole organ liver grafts will be submitted to 1-2 hours of HOPE (n=23) via the portal vein before implantation and are going to be compared with a control group (n=23) of patients transplanted after conventional cold storage. Primary (peak and Δ peak alanine aminotransferase within 7 days) and secondary (aspartate aminotransferase, bilirubin and international normalised ratio, postoperative complications, early allograft dysfunction, duration of hospital and intensive care unit stay, 1-year patient and graft survival) endpoints will be analysed within a 12-month follow-up. Extent of ischaemia-reperfusion (I/R) injury will be assessed using liver tissue, perfusate, bile and serum samples taken during the perioperative phase of OLT. ETHICS AND DISSEMINATION The study was approved by the institutional review board of the RWTH Aachen University, Aachen, Germany (EK 049/17). The current paper represent the pre-results phase. First results are expected in 2018. TRIAL REGISTRATION NUMBER NCT03124641.
Collapse
Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Wenzel Schöning
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Thorsten Cramer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Xavier Rogiers
- Department of Solid Organ Transplantation, Ghent University Hospital and Medical School, Ghent, Belgium
| | - Irinel Popescu
- Department of General Surgery and Liver transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Florin Botea
- Department of General Surgery and Liver transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Jiří Froněk
- Department of Transplantation Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Daniela Kroy
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Alexander Koch
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Rene H Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Marc Hein
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ger H Koek
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Cornelis H C Dejong
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| |
Collapse
|
|
38
|
|
|
39
|
Quillin RC, Guarrera JV. Machine Perfusion for the Assessment and Resuscitation of Marginal Donors in Liver Transplantation. CURRENT TRANSPLANTATION REPORTS 2016. [DOI: 10.1007/s40472-016-0131-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
|
|
40
|
Abstract
BACKGROUND The high demand for livers for transplantation has led to organs of limited quality being accepted to expand the donor pool. This is associated with inferior outcomes due to more pronounced preservation injury. Accordingly, recent research has aimed to develop preservation modalities for improved preservation as well as strategies for liver viability assessment and liver reconditioning. METHODS The PubMed database was searched using the terms 'perfusion', 'liver', 'preservation', and 'reconditioning' in various combinations, and the according literature was reviewed. RESULTS Several perfusion techniques have been developed in recent years with the potential for liver reconditioning. Preclinical and first emerging clinical data suggest feasibility, safety, and superiority over the current gold standard of cold storage. CONCLUSION This review outlines current advances in the field of liver preservation with an emphasis on liver reconditioning methods.
Collapse
Affiliation(s)
- Dieter P Hoyer
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Thomas Minor
- General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| |
Collapse
|
|
41
|
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.
Collapse
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
| |
Collapse
|
|
42
|
Jochmans I, Akhtar MZ, Nasralla D, Kocabayoglu P, Boffa C, Kaisar M, Brat A, O'Callaghan J, Pengel LHM, Knight S, Ploeg RJ. Past, Present, and Future of Dynamic Kidney and Liver Preservation and Resuscitation. Am J Transplant 2016; 16:2545-55. [PMID: 26946212 DOI: 10.1111/ajt.13778] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 02/03/2016] [Accepted: 02/23/2016] [Indexed: 01/25/2023]
Abstract
The increased demand for organs has led to the increased usage of "higher risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, preimplantation) and temperatures (hypo-, sub, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes ongoing research and emerging clinical trials.
Collapse
Affiliation(s)
- I Jochmans
- Abdominal Transplant Surgery, KU Leuven, University Hospitals Leuven, Leuven, Belgium
| | - M Z Akhtar
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - D Nasralla
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - P Kocabayoglu
- Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany
| | - C Boffa
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - M Kaisar
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - A Brat
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - J O'Callaghan
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - L H M Pengel
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - S Knight
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - R J Ploeg
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| |
Collapse
|
|
43
|
Nemes B, Gámán G, Polak WG, Gelley F, Hara T, Ono S, Baimakhanov Z, Piros L, Eguchi S. Extended-criteria donors in liver transplantation Part II: reviewing the impact of extended-criteria donors on the complications and outcomes of liver transplantation. Expert Rev Gastroenterol Hepatol 2016; 10:841-59. [PMID: 26831547 DOI: 10.1586/17474124.2016.1149062] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Extended-criteria donors (ECDs) have an impact on early allograft dysfunction (EAD), biliary complications, relapse of hepatitis C virus (HCV), and survivals. Early allograft dysfunction was frequently seen in grafts with moderate and severe steatosis. Donors after cardiac death (DCD) have been associated with higher rates of graft failure and biliary complications compared to donors after brain death. Extended warm ischemia, reperfusion injury and endothelial activation trigger a cascade, leading to microvascular thrombosis, resulting in biliary necrosis, cholangitis, and graft failure. The risk of HCV recurrence increased by donor age, and associated with using moderately and severely steatotic grafts. With the administration of protease inhibitors sustained virological response was achieved in majority of the patients. Donor risk index and EC donor scores (DS) are reported to be useful, to assess the outcome. The 1-year survival rates were 87% and 40% respectively, for donors with a DS of 0 and 3. Graft survival was excellent up to a DS of 2, however a DS >2 should be avoided in higher-risk recipients. The 1, 3 and 5-year survival of DCD recipients was comparable to optimal donors. However ECDs had minor survival means of 85%, 78.6%, and 72.3%. The graft survival of split liver transplantation (SLT) was comparable to that of whole liver orthotopic liver transplantation. SLT was not regarded as an ECD factor in the MELD era any more. Full-right-full-left split liver transplantation has a significant advantage to extend the high quality donor pool. Hypothermic oxygenated machine perfusion can be applied clinically in DCD liver grafts. Feasibility and safety were confirmed. Reperfusion injury was also rare in machine perfused DCD livers.
Collapse
Affiliation(s)
- Balázs Nemes
- a Department of Organ Transplantation, Faculty of Medicine, Institute of Surgery , University of Debrecen , Debrecen , Hungary
| | - György Gámán
- b Clinic of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | - Wojciech G Polak
- c Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC , University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Fanni Gelley
- d Dept of Internal medicine and Gastroenterology , Polyclinic of Hospitallers Brothers of St. John of God , Budapest , Hungary
| | - Takanobu Hara
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Shinichiro Ono
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Zhassulan Baimakhanov
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Laszlo Piros
- b Clinic of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | - Susumu Eguchi
- e Department of Surgery , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| |
Collapse
|
|
44
|
Barbas AS, Goldaracena N, Dib MJ, Selzner M. Ex-vivo liver perfusion for organ preservation: Recent advances in the field. Transplant Rev (Orlando) 2016; 30:154-60. [PMID: 27158081 DOI: 10.1016/j.trre.2016.03.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 02/15/2016] [Accepted: 03/01/2016] [Indexed: 01/13/2023]
Abstract
Liver transplantation is the optimal treatment for end-stage liver disease but is limited by the severe shortage of donor organs. This shortage has prompted increased utilization of marginal grafts from DCD and extended criteria donors, which poorly tolerate cold storage in comparison to standard criteria grafts. Ex-vivo liver perfusion (EVLP) technology has emerged as a potential alternative to cold storage for organ preservation, but there is no consensus regarding the optimal temperature or conditions for EVLP. Herein, we review recent advances in both pre-clinical and clinical studies, organized by perfusion temperature (hypothermic, subnormothermic, normothermic).
Collapse
Affiliation(s)
- A S Barbas
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada.
| | - N Goldaracena
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
| | - M J Dib
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
| | - M Selzner
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
| |
Collapse
|
|
45
|
Sutherland AI, Oniscu GC. Challenges and advances in optimizing liver allografts from donation after circulatory death donors. J Nat Sci Biol Med 2016; 7:10-5. [PMID: 27003962 PMCID: PMC4780154 DOI: 10.4103/0976-9668.175017] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
In recent years, there has been a shift in the donor demographics with an increase in donation after circulatory death (DCD). Livers obtained from DCD donors are known to have poorer outcomes when compared to donors after brainstem death and currently only a small proportion of DCD livers are used. This review outlines the recent technological developments in liver DCD donation, including clinical studies using normothermic regional perfusion and extracorporal machine perfusion of livers from DCD donors.
Collapse
Affiliation(s)
| | - Gabriel C Oniscu
- Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
46
|
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
| |
Collapse
|
|
47
|
Mas VR. Ischemia/reperfusion, does temperature matter? Laboratory perspective. Liver Transpl 2015; 21 Suppl 1:S1-5. [PMID: 26334928 DOI: 10.1002/lt.24322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/24/2015] [Accepted: 09/01/2015] [Indexed: 01/13/2023]
Affiliation(s)
- Valeria R Mas
- Translational Genomics Transplant Laboratory, Transplant Division, Department of Surgery, University of Virginia, Charlottesville, VA
| |
Collapse
|
|
48
|
Jia JJ, Zhang J, Li JH, Chen XD, Jiang L, Zhou YF, He N, Xie HY, Zhou L, Zheng SS. Influence of perfusate on liver viability during hypothermic machine perfusion. World J Gastroenterol 2015; 21:8848-8857. [PMID: 26269674 PMCID: PMC4528027 DOI: 10.3748/wjg.v21.i29.8848] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 04/12/2015] [Accepted: 06/10/2015] [Indexed: 02/07/2023] Open
Abstract
AIM: To optimize the perfusates used for hypothermic machine perfusion (HMP).
METHODS: Sprague-Dawley rats were assigned randomly to three groups (n = 12 per group) that received either saline, University of Wisconsin cold-storage solution (UW) or histidine-tryptophan-ketoglutarate solution (HTK) as the perfusate. Each group was divided into two subgroups: static cold storage (SCS) and HMP (n = 6 per subgroup). The liver graft was retrieved according to the method described by Kamada. For the SCS group, the graft was directly placed into cold perfusate (0-4 °C) for 6 h after liver isolation while the portal vein of the graft was connected to the perfusion machine for the HMP group. Then the perfusates were collected at different time points for analysis of aspartate aminotransferase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) levels. Liver tissues were obtained for evaluation of histology, dry/wet weight (D/W) ratio, and malondialdehyde (MDA) and adenosine-triphosphate (ATP) levels. The portal vein pressure and velocity were monitored in real time in all HMP subgroups.
RESULTS: Comparison of HMP and SCS: Regardless of the perfusate, HMP improved the architecture of donor graft in reducing the congestion around sinusoids and central vein and maintaining sinusoid lining in morphology; HMP improved liver function in terms of ALT, AST and LDH, especially during the 3-6 h period (SCS vs HMP using saline: ALT3, 225.00 ± 105.62 vs 49.50 ± 18.50, P = 0.047; LDH3, 1362.17 ± 563.30 vs 325.75 ± 147.43, P = 0.041; UW: LDH6, 2880.14 ± 948.46 vs 2135.00 ± 174.27, P = 0.049; HTK, AST6, 307.50 ± 52.95 vs 185.20 ± 20.46, P = 0.041); HMP decreased MDA level (saline, 2.79 ± 0.30 vs 1.09 ± 0.09, P = 0.008; UW, 3.01 ± 0.77 vs 1.23 ± 0.68, P = 0.005; HTK, 3.30 ± 0.52 vs 1.56 ± 0.22, P = 0.006). Comparison among HMP subgroups: HTK showed less portal vein resistance than UW and saline (vs saline, 3.41 ± 0.49 vs 5.00 ± 0.38, P < 0.001; vs UW, 3.41 ± 0.49 vs 4.52 ± 0.63, P = 0.007); UW reduced edema most efficiently (vs saline, 0.68 ± 0.02 vs 0.79 ± 0.05, P = 0.013), while HTK maintained ATP levels best (vs saline, 622.60 ± 29.11 vs 327.43 ± 44.66, P < 0.001; vs UW, 622.60 ± 29.11 vs 301.80 ± 37.68, P < 0.001).
CONCLUSION: HMP is superior to SCS in maintaining both architecture and function of liver grafts. Further, HTK was found to be the optimal perfusate for HMP.
Collapse
|
|
49
|
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: 53] [Impact Index Per Article: 5.3] [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.
Collapse
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
| |
Collapse
|
|
50
|
Dutkowski P, Linecker M, DeOliveira ML, Müllhaupt B, Clavien PA. Challenges to liver transplantation and strategies to improve outcomes. Gastroenterology 2015; 148:307-23. [PMID: 25224524 DOI: 10.1053/j.gastro.2014.08.045] [Citation(s) in RCA: 191] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 08/29/2014] [Accepted: 08/29/2014] [Indexed: 02/07/2023]
Abstract
Liver transplantation (LT) is a highly successful treatment for many patients with nonmalignant and malignant liver diseases. However, there is a worldwide shortage of available organs; many patients deteriorate or die while on waiting lists. We review the important clinical challenges to LT and the best use of the scarce organs. We focus on changes in indications for LT and discuss scoring systems to best match donors with recipients and optimize outcomes, particularly for the sickest patients. We also cover controversial guidelines for the use of LT in patients with hepatocellular carcinoma and cholangiocarcinoma. Strategies to increase the number of functional donor organs involve techniques to perfuse the organs before implantation. Partial LT (living donor and split liver transplantation) techniques might help to overcome organ shortages, and we discuss small-for-size syndrome. Many new developments could increase the success of this procedure, which is already one of the major achievements in medicine during the second part of the 20th century.
Collapse
Affiliation(s)
- Philipp Dutkowski
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Michael Linecker
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Michelle L DeOliveira
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Beat Müllhaupt
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Pierre-Alain Clavien
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland.
| |
Collapse
|