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Puchany AJ, Hilmi I. Post-reperfusion syndrome in liver transplant recipients: What is new in prevention and management? World J Crit Care Med 2025; 14:101777. [DOI: 10.5492/wjccm.v14.i2.101777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/22/2024] [Accepted: 12/19/2024] [Indexed: 02/27/2025] Open
Abstract
Post-reperfusion syndrome (PRS) in liver transplant recipients remains one of the most dreaded complications in liver transplant surgery. PRS can impact the short-term and long-term patient and graft outcomes. The definition of PRS has evolved over the years, from changes in arterial blood pressures and heart and/or decreases in the systemic vascular resistance and cardiac output to including the fibrinolysis and grading the severity of PRS. However, all that did not reflect on the management of PRS or its impact on the outcomes. In recent years, new scientific techniques and new technology have been in the pipeline to better understand, manage and maybe prevent PRS. These new methods and techniques are still in the infancy, and they have to be proven not in prevention and management of PRS but their effects in the patient and graft outcomes. In this article, we will review the long history of PRS, its definition, etiology, management and most importantly the new advances in science and technology to prevent and properly manage PRS.
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Affiliation(s)
- Austin James Puchany
- Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Ibtesam Hilmi
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Department of Anesthesiology and Perioperative Medicine, Clinical and Translational Science Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, United States
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Peng S, Liang W, Liu Z, Ye S, Peng Z, Zhong Z, Ye Q. Hypothermic machine perfusion reduces donation after circulatory death liver ischemia-reperfusion injury through the SERPINA3-mediated PI3Kδ/Akt pathway. Hum Cell 2024; 37:420-434. [PMID: 38133876 DOI: 10.1007/s13577-023-01012-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023]
Abstract
Hypothermic machine perfusion (HMP) has been demonstrated to be more effective in mitigating ischemia-reperfusion injury (IRI) of donation after circulatory death (DCD) organs than cold storage (CS), yet the underlying mechanism remains obscure. We aimed to propose a novel therapeutic approach to ameliorate IRI in DCD liver transplantation. Twelve clinical liver samples were randomly assigned to HMP or CS treatment and subsequent transcriptomics analysis was performed. By combining in vivo HMP models, we discovered that HMP attenuated inflammation, oxidative stress, and apoptosis in DCD liver through a SEPRINA3-mediated PI3Kδ/AKT signaling cascade. Moreover, in the hypoxia/reoxygenation (H/R) model of BRL-3A, overexpression of SERPINA3 mitigated H/R-induced apoptosis, while SERPINA3 knockdown exacerbated cell injury. Idelalisib (IDE) treatment also reversed the protective effect of SERPINA3 overexpression. Overall, our research provided new insights into therapeutic strategies and identified potential novel molecular targets for therapeutic intervention against DCD liver.
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Affiliation(s)
- Sheng Peng
- Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Wenjin Liang
- Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Zhongzhong Liu
- Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Shaojun Ye
- Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Zhiyong Peng
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
| | - Zibiao Zhong
- Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
| | - Qifa Ye
- Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
- Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The 3rd Xiangya Hospital of Central South University, Changsha, 410013, China.
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Ohara M, Ishikawa J, Yoshimoto S, Hakamata Y, Kobayashi E. A rat model of dual-flow liver machine perfusion system. Acta Cir Bras 2023; 38:e387723. [PMID: 37909599 PMCID: PMC10664844 DOI: 10.1590/acb387723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/01/2023] [Indexed: 11/03/2023] Open
Abstract
PURPOSE As clinical liver perfusion systems use portal vein and artery flow, dual perfusion techniques are required even in small animal models in order to reproduce clinical setting. The aim of this study was to construct a new dual-flow perfusion system in rat model and optimized the oxygen supply to ensure the aerobic metabolization. METHODS The dual-flow circuit was fabricated using rat liver and whole blood samples as perfusates. The oxygen supply was controlled according to the amount of dissolved oxygen in the perfusate. Perfusate parameters and adenosine triphosphate (ATP) levels were analyzed to evaluate organ function and metabolic energy state. Stored whole blood also tested the suitability as perfusate. RESULTS Stored blood showed decrease oxygen delivery and liver function compared to fresh blood. Using fresh blood as perfusate with air only, the dissolved oxygen levels remained low and anaerobic metabolism increased. In contrast, with oxygen control at living body level, anaerobic metabolism was well suppressed, and tissue ATP content was increased. CONCLUSIONS We developed a new dual-flow system that enable to reproduce the clinical settings. The perfusion system showed the possibility to improve the energy metabolic state of the perfused organ under appropriate partial pressure of oxygen.
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Affiliation(s)
- Masayuki Ohara
- Nippon Veterinary and Life Science University – School of Veterinary Nursing and Technology – Tokyo, Japan
- Screen Holdings Co., Ltd. – Innovation Development Department – Tokyo, Japan
| | - Jun Ishikawa
- Nippon Veterinary and Life Science University – School of Veterinary Nursing and Technology – Tokyo, Japan
- Screen Holdings Co., Ltd. – Innovation Development Department – Tokyo, Japan
| | - Syuhei Yoshimoto
- Screen Holdings Co., Ltd. – Innovation Development Department – Tokyo, Japan
| | - Yoji Hakamata
- Nippon Veterinary and Life Science University – School of Veterinary Nursing and Technology – Tokyo, Japan
| | - Eiji Kobayashi
- Nippon Veterinary and Life Science University – School of Veterinary Nursing and Technology – Tokyo, Japan
- Jikei University School of Medicine – Department of Kidney Regenerative Medicine – Kyoto, Japan
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Khalil A, Quaglia A, Gélat P, Saffari N, Rashidi H, Davidson B. New Developments and Challenges in Liver Transplantation. J Clin Med 2023; 12:5586. [PMID: 37685652 PMCID: PMC10488676 DOI: 10.3390/jcm12175586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/15/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
Liver disease is increasing in incidence and is the third most common cause of premature death in the United Kingdom and fourth in the United States. Liver disease accounts for 2 million deaths globally each year. Three-quarters of patients with liver disease are diagnosed at a late stage, with liver transplantation as the only definitive treatment. Thomas E. Starzl performed the first human liver transplant 60 years ago. It has since become an established treatment for end-stage liver disease, both acute and chronic, including metabolic diseases and primary and, at present piloting, secondary liver cancer. Advances in surgical and anaesthetic techniques, refined indications and contra-indications to transplantation, improved donor selection, immunosuppression and prognostic scoring have allowed the outcomes of liver transplantation to improve year on year. However, there are many limitations to liver transplantation. This review describes the milestones that have occurred in the development of liver transplantation, the current limitations and the ongoing research aimed at overcoming these challenges.
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Affiliation(s)
- Amjad Khalil
- Liver Unit, Wellington Hospital, London NW8 9TA, UK
- Centre for Surgical Innovation, Organ Regeneration and Transplantation, University College London, London NW3 2PS, UK
- Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London NW3 2QG, UK
| | - Alberto Quaglia
- Cancer Institute, University College London, London WC1E 6DD, UK
| | - Pierre Gélat
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Nader Saffari
- Department of Mechanical Engineering, University College London, London WC1E 7JE, UK
| | - Hassan Rashidi
- Institute of Child Health, University College London, London WC1N 1EH, UK;
| | - Brian Davidson
- Liver Unit, Wellington Hospital, London NW8 9TA, UK
- Centre for Surgical Innovation, Organ Regeneration and Transplantation, University College London, London NW3 2PS, UK
- Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London NW3 2QG, UK
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Van Raemdonck D, Ceulemans LJ, Van Beersel D, Neyrinck A. Current achievements and future applications of ex vivo lung perfusion; where do we go from here? J Thorac Cardiovasc Surg 2023; 165:920-924. [PMID: 35931582 DOI: 10.1016/j.jtcvs.2022.06.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 11/25/2022]
Affiliation(s)
- Dirk Van Raemdonck
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Catholic University Leuven, Leuven, Belgium.
| | - Laurens J Ceulemans
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Catholic University Leuven, Leuven, Belgium
| | - Dieter Van Beersel
- Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, Catholic University Leuven, Leuven, Belgium
| | - Arne Neyrinck
- Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, Catholic University Leuven, Leuven, Belgium
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Meurisse N, Mertens M, Fieuws S, Gilbo N, Jochmans I, Pirenne J, Monbaliu D. Effect of a Combined Drug Approach on the Severity of Ischemia-Reperfusion Injury During Liver Transplant: A Randomized Clinical Trial. JAMA Netw Open 2023; 6:e230819. [PMID: 36853611 PMCID: PMC9975910 DOI: 10.1001/jamanetworkopen.2023.0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/01/2023] Open
Abstract
IMPORTANCE In a porcine model of liver transplant, a combined drug approach that targeted the donor graft and graft recipient reduced ischemia-reperfusion injury, a major hurdle to the success of liver transplant. OBJECTIVE To assess the effect of a clinical form of a perioperative combined drug approach delivered immediately before implantation to the procured liver and to the liver recipient on the degree of ischemia-reperfusion injury. DESIGN, SETTING, AND PARTICIPANTS This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020. INTERVENTIONS Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase. MAIN OUTCOMES AND MEASURES The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival. RESULTS Of 93 randomized patients, 21 were excluded, resulting in 72 patients (36 per study arm) in the per protocol analysis (median recipient age, 60 years [IQR, 51.7-66.2 years]; 52 [72.2%] men). Peak AST serum levels were not different in the combined drug approach and control groups (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; P = .49) (to convert AST to μkat/L, multiply by 0.0167). There also were no significant differences in the secondary end points between the groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, the combined drug approach targeting the post-cold storage graft and the recipient did not decrease ischemic-reperfusion injury. The findings suggest that in addition to a downstream strategy that targets the preimplantation liver graft and the graft recipient, a clinically effective combined drug approach may need to include an upstream strategy that targets the donor graft during preservation. Dynamic preservation strategies may provide an appropriate delivery platform. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02251041.
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Affiliation(s)
- Nicolas Meurisse
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
- Department of Abdominal Surgery and Transplantation, CHU de Liège, University of Liège, Liège, Belgium
| | - Markoen Mertens
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Steffen Fieuws
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
- Interuniversity Institute for Biostatistics and Statistical Bioinformatics, KU Leuven—University of Leuven, Leuven, Belgium
| | - Nicholas Gilbo
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Ina Jochmans
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Jacques Pirenne
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium
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Riveros S, Marino C, Ochoa G, Soto D, Alegría L, Zenteno MJ, San Martín S, Brañes A, Achurra P, Rebolledo R. Customized normothermic machine perfusion decreases ischemia-reperfusion injury compared with static cold storage in a porcine model of liver transplantation. Artif Organs 2023; 47:148-159. [PMID: 36007920 DOI: 10.1111/aor.14390] [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: 05/01/2022] [Revised: 07/20/2022] [Accepted: 08/09/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Liver transplantation has been demonstrated to be the best treatment for several liver diseases, while grafts are limited. This has caused an increase in waiting lists, making it necessary to find ways to expand the number of organs available for transplantation. Normothermic perfusion (NMP) of liver grafts has been established as an alternative to static cold storage (SCS), but only a small number of perfusion machines are commercially available. METHODS Using a customized ex situ machine perfusion, we compared the results between ex situ NMP and SCS preservation in a porcine liver transplant model. RESULTS During NMP, lactate concentrations were 80% lower after the 3-h perfusion period, compared with SCS. Bile production had a 2.5-fold increase during the NMP period. After transplantation, aspartate transaminase (AST) and alanine transaminase (ALT) levels were 35% less in the NMP group, compared to the SCS group. In pathologic analyses of grafts after transplant, tissue oxidation did not change between groups, but the ischemia-reperfusion injury score was lower in the NMP group. CONCLUSION NMP reduced hepatocellular damage and ischemia-reperfusion injury when compared to SCS using a customized perfusion machine. This could be an alternative for low-income countries to include machine perfusion in their therapeutic options.
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Affiliation(s)
- Sergio Riveros
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlo Marino
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gabriela Ochoa
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Dagoberto Soto
- Department of Intensive Care Unit, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leyla Alegría
- Department of Intensive Care Unit, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Sebastián San Martín
- Biomedical Research Center, School of Medicine, Universidad de Valparaíso, Valparaíso, Chile
| | - Alejandro Brañes
- Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
| | - Pablo Achurra
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rolando Rebolledo
- Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile.,Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
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Gonzalez JM, Villarreal C, Fasci A, Rocco DD, Salazar S, Khalil A, Wearden B, Oseghale J, Garcia M, Portillo DJ, Hood RL. Evaluating the Performance of a Nonelectronic, Versatile Oxygenating Perfusion System across Viscosities Representative of Clinical Perfusion Solutions Used for Organ Preservation. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 10:bioengineering10010002. [PMID: 36671574 PMCID: PMC9854583 DOI: 10.3390/bioengineering10010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022]
Abstract
Introduction: On the United States' Organ Transplantation Waitlist, approximately 17 people die each day waiting for an organ. The situation continues to deteriorate as the discrepancy between harvested organs and the number of patients in need is increasing. Static cold storage is the clinical standard method for preserving a harvested organ but is associated with several drawbacks. Machine perfusion of an organ has been shown to improve preservation quality as well as preservation time over static cold storage. While there are machine perfusion devices clinically available, they are costly and limited to specific organs and preservation solutions. This study presents a versatile oxygenating perfusion system (VOPS) that supplies oxygen and pulsatile perfusion. Materials and Methods: Experiments evaluated the system's performance with a human kidney mimicking hydraulic analog using multiple compressed oxygen supply pressures and aqueous solutions with viscosities ranging from 1 to 6.5 cP, which simulated viscosities of commonly used organ preservation solutions. Results and Conclusions: The VOPS produced mean flow rates ranging from 0.6 to 28.2 mL/min and perfusion pressures from 4.8 to 96.8 mmHg, which successfully achieved the desired perfusion parameters for human kidneys. This work provides evidence that the VOPS described herein has the versatility to perfuse organs using many of the clinically available preservation solutions.
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Affiliation(s)
- Jose M. Gonzalez
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Carorina Villarreal
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Anjelyka Fasci
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - David Di Rocco
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Sophia Salazar
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Anis Khalil
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Brandt Wearden
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Jessica Oseghale
- Department of Biomedical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Mariana Garcia
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
| | - Daniel J. Portillo
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
- Correspondence: (D.J.P.); (R.L.H.)
| | - R. Lyle Hood
- Department of Mechanical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
- Department of Biomedical Engineering, The University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA
- Correspondence: (D.J.P.); (R.L.H.)
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Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury. Int J Mol Sci 2022; 23:ijms231710108. [PMID: 36077504 PMCID: PMC9456258 DOI: 10.3390/ijms231710108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.
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Moein M, Capelin J, Toth JF, Tylor D, Weiss ZM, Murugesan BG, Saidi RF. Role of normothermic machine perfusion in liver transplantation: Current trends and outcomes. SURGERY IN PRACTICE AND SCIENCE 2022; 9:100077. [PMID: 39845073 PMCID: PMC11750010 DOI: 10.1016/j.sipas.2022.100077] [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: 01/19/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 10/18/2022] Open
Abstract
Background Liver transplantation is the only known curative treatment option for end-stage liver diseases and failure; however, there is an imbalance between the number of available liver organs for transplant and the number of patients as recipients due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation to expand the donor organ pool. Studies showed that using normothermic machine perfusion can increase the pool of transplantable discarded livers and is a promising strategy to improve graft resilience and performance further. Methods A systematic literature search of PubMed and ClinicalTrials.gov registry was performed. A three-stage independent screening method was applied. Inclusion criteria for this review were published prospective, retrospective, clinical trials, and systematic reviews studies using normothermic machine perfusion devices. Results Twenty-two articles on normothermic liver machine perfusion with patients and graft survival rate were identified. These studies have demonstrated the safety and efficacy of normothermic liver machine perfusion for discarded liver preservation in both standard and expanded criteria donors following patients and graft follow-ups. The overall number of livers that went under NMP was 568 in all the studies in which 503 of the livers were transplanted (88.6%). The 30,90,180 days and 1-year patients and grafts survival rates were promising. Conclusion Normothermic machine perfusion is a novelty method recently being used in liver transplantation and can lead to the expansion of the liver donor pool by revitalizing discarded livers. Our study was able to show the promising outcomes for both patients and grafts, which were achieved in many human clinical studies around the world using normothermic machine perfusion as a method of liver preservation and revitalization.
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Affiliation(s)
| | - Jonathan Capelin
- Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Joseph F. Toth
- Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Dylan Tylor
- Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Zoe M. Weiss
- Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Bhavani G. Murugesan
- Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Reza F. Saidi
- Correspondence: Reza F. Saidi, MD, FICS, FACS, Associate Professor of Surgery, Chief of Transplantation, Director, Kidney Transplant Program, Surgical Director of Kidney Transplantation, Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210. Phone: (315) 464-7329; Fax: (315) 464-6250.
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11
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Riveros S, Marino C, Ochoa G, Morales E, Soto D, Alegría L, Zenteno MJ, Brañes A, Achurra P, Rebolledo RA. Implementation and design of customized ex vivo machine perfusion. Analysis of its first results. Artif Organs 2021; 46:210-218. [PMID: 34519358 DOI: 10.1111/aor.14060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 12/14/2022]
Abstract
The lack of organs available for transplantation is a global problem. The high mortality rates on the waiting list and the high number of discarded livers are reasons to develop new tools in the preservation and transplantation process. New tools should also be available for low-income countries. This article reports the development of customized normothermic machine perfusion (NMP). An ex vivo dual perfusion machine was designed, composed of a common reservoir organ box (CRO), a centrifugal pump (portal system, low pressure), and a roller pump (arterial system, high pressure). Porcine livers (n = 5) were perfused with an oxygenated normothermic (37℃) strategy for 3 hours. Hemodynamic variables, metabolic parameters, and bile production during preservation were analyzed. Arterial and portal flow remain stable during perfusion. Total bilirubin production was 11.25 mL (4-14.5) at 180 minutes. The median pH value reached 7.32 (7.25-7.4) at 180 minutes. Lactate values decreased progressively to normalization at 120 minutes. This perfusion setup was stable and able to maintain the metabolic activity of a liver graft in a porcine animal model. Design and initial results from this customized NMP are promising for a future clinical application in low-income countries.
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Affiliation(s)
- Sergio Riveros
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlo Marino
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gabriela Ochoa
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Emilio Morales
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Dagoberto Soto
- Department of Intensive Care, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leyla Alegría
- Department of Intensive Care, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Alejandro Brañes
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
| | - Pablo Achurra
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rolando A Rebolledo
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.,Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
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12
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van Rijn R, Schurink IJ, de Vries Y, van den Berg AP, Cortes Cerisuelo M, Darwish Murad S, Erdmann JI, Gilbo N, de Haas RJ, Heaton N, van Hoek B, Huurman VAL, Jochmans I, van Leeuwen OB, de Meijer VE, Monbaliu D, Polak WG, Slangen JJG, Troisi RI, Vanlander A, de Jonge J, Porte RJ. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial. N Engl J Med 2021; 384:1391-1401. [PMID: 33626248 DOI: 10.1056/nejmoa2031532] [Citation(s) in RCA: 376] [Impact Index Per Article: 94.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited. METHODS In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications. RESULTS A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups. CONCLUSIONS Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.).
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Affiliation(s)
- Rianne van Rijn
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Ivo J Schurink
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Yvonne de Vries
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Aad P van den Berg
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Miriam Cortes Cerisuelo
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Sarwa Darwish Murad
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Joris I Erdmann
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Nicholas Gilbo
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Robbert J de Haas
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Nigel Heaton
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Bart van Hoek
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Volkert A L Huurman
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Ina Jochmans
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Otto B van Leeuwen
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Vincent E de Meijer
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Diethard Monbaliu
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Wojciech G Polak
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Jules J G Slangen
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Roberto I Troisi
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Aude Vanlander
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Jeroen de Jonge
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
| | - Robert J Porte
- From the Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation (R.R., Y.V., O.B.L., V.E.M., R.J.P.), the Departments of Gastroenterology and Hepatology (A.P.B.) and Radiology (R.J.H., J.J.G.S.), University of Groningen, University Medical Center Groningen, Groningen, the Departments of Surgery (I.J.S., W.G.P., J.J.) and Gastroenterology and Hepatology (S.D.M.), Erasmus University Medical Center, Rotterdam, and the Departments of Surgery (J.I.E., V.A.L.H.) and Gastroenterology and Hepatology (B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London (M.C.C., N.H.); the Transplantation Research Group, the Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit Leuven, and the Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven (N.G., I.J., D.M.), and the Department of Transplant Surgery, Ghent University Hospital, Ghent (R.I.T., A.V.) - both in Belgium
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The Endothelial Glycocalyx and Organ Preservation-From Physiology to Possible Clinical Implications for Solid Organ Transplantation. Int J Mol Sci 2021; 22:ijms22084019. [PMID: 33924713 PMCID: PMC8070558 DOI: 10.3390/ijms22084019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 01/14/2023] Open
Abstract
The endothelial glycocalyx is a thin layer consisting of proteoglycans, glycoproteins and glycosaminoglycans that lines the luminal side of vascular endothelial cells. It acts as a barrier and contributes to the maintenance of vascular homeostasis and microperfusion. During solid organ transplantation, the endothelial glycocalyx of the graft is damaged as part of Ischemia Reperfusion Injury (IRI), which is associated with impaired organ function. Although several substances are known to mitigate glycocalyx damage, it has not been possible to use these substances during graft storage on ice. Normothermic machine perfusion (NMP) emerges as an alternative technology for organ preservation and allows for organ evaluation, but also offers the possibility to treat and thus improve organ quality during storage. This review highlights the current knowledge on glycocalyx injury during organ transplantation, presents ways to protect the endothelial glycocalyx and discusses potential glycocalyx protection strategies during normothermic machine perfusion.
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Tatum R, O'Malley TJ, Bodzin AS, Tchantchaleishvili V. Machine perfusion of donor organs for transplantation. Artif Organs 2021; 45:682-695. [PMID: 33349946 DOI: 10.1111/aor.13894] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/25/2020] [Accepted: 12/17/2020] [Indexed: 12/16/2022]
Abstract
The ever-widening gap between organ supply and demand has resulted in an organ shortage crisis that affects patients all over the world. For decades, static cold storage (SCS) was the gold standard preservation strategy because of its simplicity and cost-effectiveness, but the rising unmet demand for donor organ transplants has prompted investigation into preservation strategies that can expand the available donor pool. Through ex vivo functional assessment of the organ prior to transplant, newer methods to preserve organs such as perfusion-based therapy can potentially expand the available organ pool. This review will explain the physiologic rationale for SCS before exploring the advantages and disadvantages associated with the two broad classes of preservation strategies that have emerged to address the crisis: hypothermic and normothermic machine perfusion. A detailed analysis of how each preservation strategy works will be provided before investigating the current status of clinical data for each preservation strategy for the kidney, liver, pancreas, heart, and lung. For some organs there is robust data to support the use of machine perfusion technologies over SCS, and in others the data are less clear. Nonetheless, machine perfusion technologies represent an exciting frontier in organ preservation research and will remain a crucial component of closing the gap between organ supply and recipient demand.
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Affiliation(s)
- Robert Tatum
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Thomas J O'Malley
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam S Bodzin
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
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15
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Oxygen Transport during Ex Situ Machine Perfusion of Donor Livers Using Red Blood Cells or Artificial Oxygen Carriers. Int J Mol Sci 2020; 22:ijms22010235. [PMID: 33379394 PMCID: PMC7795786 DOI: 10.3390/ijms22010235] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/14/2020] [Accepted: 12/24/2020] [Indexed: 12/21/2022] Open
Abstract
Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use.
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Nösser M, Gassner JMGV, Moosburner S, Wyrwal D, Claussen F, Hillebrandt KH, Horner R, Tang P, Reutzel-Selke A, Polenz D, Arsenic R, Pratschke J, Sauer IM, Raschzok N. Development of a Rat Liver Machine Perfusion System for Normothermic and Subnormothermic Conditions. Tissue Eng Part A 2020; 26:57-65. [DOI: 10.1089/ten.tea.2019.0152] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Maximilian Nösser
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Joseph Maria George Vernon Gassner
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Simon Moosburner
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - David Wyrwal
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Felix Claussen
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Karl Herbert Hillebrandt
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Rosa Horner
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Peter Tang
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anja Reutzel-Selke
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Dietrich Polenz
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ruza Arsenic
- Department of Pathology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Igor Maximilian Sauer
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Experimental Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- BIH Charité Clinician Scientist Program, Berlin Institute of Health (BIH), Berlin, Germany
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17
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Jia JJ, Xie HY, Li JH, He Y, Jiang L, He N, Zhou L, Wang W, Zheng SS. Graft protection of the liver by hypothermic machine perfusion involves recovery of graft regeneration in rats. J Int Med Res 2019; 47:427-437. [PMID: 30791830 PMCID: PMC6384453 DOI: 10.1177/0300060518787726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective This study was performed to evaluate the impact and underlying mechanisms of hypothermic machine perfusion (HMP) on half-size liver graft regeneration. Methods Forty rats were randomly assigned to five groups: two in vitro groups (static cold storage [SCS] and HMP) and three in vivo groups (orthotopic liver transplantation, SCS, and HMP). Perfusates and plasma samples were collected for analysis of hepatic enzymes. Liver tissue was obtained for evaluation of histology, immunohistochemistry (Ki67 and proliferating cell nuclear antigen [PCNA]), and the regeneration rate. Cell cycle genes were analyzed by quantitative real-time polymerase chain reaction, and cyclin D1 and cyclin E1 were semiquantified by western blot. Results HMP improved histopathological outcomes and decreased hepatic enzyme release. The expression of Ki67 and PCNA demonstrated a greater proliferation activity in the HMP than SCS group, and the expression of almost all cell cycle genes was elevated following HMP. Western blot results showed higher protein levels of cyclin D1 and cyclin E1 in the HMP than SCS group. Conclusions Our findings suggest for the first time that half-size liver graft protection by HMP involves recovery of graft regeneration.
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Affiliation(s)
- Jun-Jun Jia
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,*These authors contributed equally to this work
| | - Hai-Yang Xie
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.,*These authors contributed equally to this work
| | - Jian-Hui Li
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yong He
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Jiang
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ning He
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Lin Zhou
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Weilin Wang
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Shu-Sen Zheng
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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18
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Álvarez-Mercado AI, Gulfo J, Romero Gómez M, Jiménez-Castro MB, Gracia-Sancho J, Peralta C. Use of Steatotic Grafts in Liver Transplantation: Current Status. Liver Transpl 2019; 25:771-786. [PMID: 30740859 DOI: 10.1002/lt.25430] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/02/2019] [Indexed: 12/12/2022]
Abstract
In the field of liver transplantation, the demand for adequate allografts greatly exceeds the supply. Therefore, expanding the donor pool to match the growing demand is mandatory. The present review summarizes current knowledge of the pathophysiology of ischemia/reperfusion injury in steatotic grafts, together with recent pharmacological approaches aimed at maximizing the utilization of these livers for transplantation. We also describe the preclinical models currently available to understand the molecular mechanisms controlling graft viability in this specific type of donor, critically discussing the heterogeneity in animal models, surgical methodology, and therapeutic interventions. This lack of common approaches and interventions makes it difficult to establish the pathways involved and the relevance of isolated discoveries, as well as their transferability to clinical practice. Finally, we discuss how new therapeutic strategies developed from experimental studies are promising but that further studies are warranted to translate them to the bedside.
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Affiliation(s)
- Ana I Álvarez-Mercado
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - José Gulfo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Manuel Romero Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Inter-Centre Unit of Digestive Diseases, Virgen del Rocio University Hospitals, Sevilla, Spain; Institute of Biomedicine of Seville, Seville, Spain
- Institute of Biomedicine of Seville, Seville, Spain
| | | | - Jordi Gracia-Sancho
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Universidad Internacional de Cataluña, Barcelona, Spain
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19
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Krezdorn N, Tasigiorgos S, Wo L, Turk M, Lopdrup R, Kiwanuka H, Win TS, Bueno E, Pomahac B. Tissue conservation for transplantation. Innov Surg Sci 2017; 2:171-187. [PMID: 31579751 PMCID: PMC6754021 DOI: 10.1515/iss-2017-0010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023] Open
Abstract
Pathophysiological changes that occur during ischemia and subsequent reperfusion cause damage to tissues procured for transplantation and also affect long-term allograft function and survival. The proper preservation of organs before transplantation is a must to limit these injuries as much as possible. For decades, static cold storage has been the gold standard for organ preservation, with mechanical perfusion developing as a promising alternative only recently. The current literature points to the need of developing dedicated preservation protocols for every organ, which in combination with other interventions such as ischemic preconditioning and therapeutic additives offer the possibility of improving organ preservation and extending it to multiple times its current duration. This review strives to present an overview of the current body of knowledge with regard to the preservation of organs and tissues destined for transplantation.
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Affiliation(s)
- Nicco Krezdorn
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Hannover Medical School, Hannover, Germany
| | - Sotirios Tasigiorgos
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Luccie Wo
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Marvee Turk
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Rachel Lopdrup
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Harriet Kiwanuka
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Thet-Su Win
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Ericka Bueno
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Bohdan Pomahac
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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20
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Vairetti M, Ferrigno A, Gringeri E, Cillo U. Representing Subnormothermic Machine Perfusion in Fatty Livers: The Complete Picture? Am J Transplant 2017; 17:1421-1422. [PMID: 28066998 DOI: 10.1111/ajt.14196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- M Vairetti
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - A Ferrigno
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - E Gringeri
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
| | - U Cillo
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy
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21
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Okamura Y, Hata K, Uemoto S. Reply to "Representing Subnormothermic Machine Perfusion in Fatty Livers: The Complete Picture?". Am J Transplant 2017; 17:1423-1424. [PMID: 28251800 DOI: 10.1111/ajt.14254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Y Okamura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - K Hata
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - S Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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22
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Zumrutdal E, Karateke F, Eser PE, Turan U, Ozyazici S, Sozutek A, Gulkaya M, Kunt M. The Effects of Direct Oxygen Supply During Static Cold Preservation of Rat Livers: An Experimental Study. EXP CLIN TRANSPLANT 2016; 14:650-655. [PMID: 26325344 DOI: 10.6002/ect.2015.0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES We aimed to determine the biochemical and histopathologic effects of direct oxygen supply to the preservation fluid of static cold storage system with a simple method on rat livers. MATERIALS AND METHODS Sixteen rats were randomly divided into 2 groups: the control group, which contained Ringer's lactate as preservation fluid; and the oxygen group, which contained oxygen and Ringer's lactate for preservation. Each liver was placed in a bag containing 50 mL Ringer's lactate and placed in ice-filled storage containers. One hundred percent oxygen supplies were given via a simple, inexpensive system created in our laboratory, to the livers in oxygen group. We obtained samples for histopathologic evaluation in the 12th hour. In addition, 3 mL of preservation fluid was subjected to biochemical analysis at 0, sixth, and twelfth hours. Aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and pH levels were measured from the preservation fluid. RESULTS In oxygen-supplemented group, the acceleration speed of increase in alanine aminotransferase and lactate dehydrogenase levels at sixth hour and lactate dehydrogenase, alanine aminotransferase, and lactate dehydrogenase levels at 12th hour were statistically significantly reduced. In histopathologic examination, all parameters except ballooning were statistically significantly better in the oxygen-supplemented group. CONCLUSIONS This simple system for oxygenation of liver tissues during static cold storage was shown to be effective with good results in biochemical and histopathologic assessments. Because this is a simple, inexpensive, and easily available method, larger studies are warranted to evaluate its effects (especially in humans).
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Affiliation(s)
- Emin Zumrutdal
- From the Departments of General Surgery, Adana Numune Training and Research Hospital, Adana, Turkey
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23
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Zhao LY, Liu S, Chen ZG, Zou JZ, Wu F. Cavitation enhances coagulated size during pulsed high-intensity focussed ultrasound ablation in an isolated liver perfusion system. Int J Hyperthermia 2016; 33:343-353. [DOI: 10.1080/02656736.2016.1255918] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Lu-Yan Zhao
- State Key Laboratory of Ultrasound Engineering in Medicine, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
- Department of Gynecology and Obstetrics, Xi'dian Group Hospital, Shaanxi Xi’an, China
| | - Shan Liu
- State Key Laboratory of Ultrasound Engineering in Medicine, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Zong-Gui Chen
- State Key Laboratory of Ultrasound Engineering in Medicine, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Jian-Zhong Zou
- State Key Laboratory of Ultrasound Engineering in Medicine, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Feng Wu
- State Key Laboratory of Ultrasound Engineering in Medicine, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Sadowsky D, Zamora R, Barclay D, Yin J, Fontes P, Vodovotz Y. Machine Perfusion of Porcine Livers with Oxygen-Carrying Solution Results in Reprogramming of Dynamic Inflammation Networks. Front Pharmacol 2016; 7:413. [PMID: 27867357 PMCID: PMC5095594 DOI: 10.3389/fphar.2016.00413] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Accepted: 10/18/2016] [Indexed: 01/28/2023] Open
Abstract
Background:Ex vivo machine perfusion (MP) can better preserve organs for transplantation. We have recently reported on the first application of an MP protocol in which liver allografts were fully oxygenated, under dual pressures and subnormothermic conditions, with a new hemoglobin-based oxygen carrier (HBOC) solution specifically developed for ex vivo utilization. In those studies, MP improved organ function post-operatively and reduced inflammation in porcine livers. Herein, we sought to refine our knowledge regarding the impact of MP by defining dynamic networks of inflammation in both tissue and perfusate. Methods: Porcine liver allografts were preserved either with MP (n = 6) or with cold static preservation (CSP; n = 6), then transplanted orthotopically after 9 h of preservation. Fourteen inflammatory mediators were measured in both tissue and perfusate during liver preservation at multiple time points, and analyzed using Dynamic Bayesian Network (DyBN) inference to define feedback interactions, as well as Dynamic Network Analysis (DyNA) to define the time-dependent development of inflammation networks. Results: Network analyses of tissue and perfusate suggested an NLRP3 inflammasome-regulated response in both treatment groups, driven by the pro-inflammatory cytokine interleukin (IL)-18 and the anti-inflammatory mediator IL-1 receptor antagonist (IL-1RA). Both DyBN and DyNA suggested a reduced role of IL-18 and increased role of IL-1RA with MP, along with increased liver damage with CSP. DyNA also suggested divergent progression of responses over the 9 h preservation time, with CSP leading to a stable pattern of IL-18-induced liver damage and MP leading to a resolution of the pro-inflammatory response. These results were consistent with prior clinical, biochemical, and histological findings after liver transplantation. Conclusion: Our results suggest that analysis of dynamic inflammation networks in the setting of liver preservation may identify novel diagnostic and therapeutic modalities.
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Affiliation(s)
- David Sadowsky
- Department of Surgery, University of Pittsburgh, Pittsburgh PA, USA
| | - Ruben Zamora
- Department of Surgery, University of Pittsburgh, PittsburghPA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PittsburghPA, USA
| | - Derek Barclay
- Department of Surgery, University of Pittsburgh, Pittsburgh PA, USA
| | - Jinling Yin
- Department of Surgery, University of Pittsburgh, Pittsburgh PA, USA
| | - Paulo Fontes
- Department of Surgery, University of Pittsburgh, PittsburghPA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PittsburghPA, USA; Department of Surgery, Thomas E. Starzl Transplantation Institute, PittsburghPA, USA
| | - Yoram Vodovotz
- Department of Surgery, University of Pittsburgh, PittsburghPA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PittsburghPA, USA
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Op den Dries S, Karimian N, Westerkamp AC, Sutton ME, Kuipers M, Wiersema-Buist J, Ottens PJ, Kuipers J, Giepmans BN, Leuvenink HGD, Lisman T, Porte RJ. Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers. Liver Transpl 2016; 22:994-1005. [PMID: 26946466 DOI: 10.1002/lt.24436] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Revised: 02/04/2016] [Accepted: 02/14/2016] [Indexed: 12/21/2022]
Abstract
Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 ± 0.02 and 7.74 ± 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 ± 0.02 and 7.49 ± 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD.
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Affiliation(s)
- Sanna Op den Dries
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Negin Karimian
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Andrie C Westerkamp
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Michael E Sutton
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel Kuipers
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Janneke Wiersema-Buist
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Petra J Ottens
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jeroen Kuipers
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ben N Giepmans
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Henri G D Leuvenink
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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26
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Banan B, Watson R, Xu M, Lin Y, Chapman W. Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers. Liver Transpl 2016; 22:979-93. [PMID: 27027254 DOI: 10.1002/lt.24451] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 03/08/2016] [Accepted: 03/21/2016] [Indexed: 12/23/2022]
Abstract
Donor organ shortages have led to an increased interest in finding new approaches to recover organs from extended criteria donors (ECD). Normothermic extracorporeal liver perfusion (NELP) has been proposed as a superior preservation method to reduce ischemia/reperfusion injury (IRI), precondition suboptimal grafts, and treat ECD livers so that they can be successfully used for transplantation. The aim of this study was to investigate the beneficial effects of a modified NELP circuit on discarded human livers. Seven human livers that were rejected for transplantation were placed on a modified NELP circuit for 8 hours. Perfusate samples and needle core biopsies were obtained at hourly intervals. A defatting solution that contained exendin-4 (50 nM) and L-carnitine (10 mM) was added to the perfusate for 2 steatotic livers. NELP provided normal temperature, electrolytes, and pH and glucose levels in the perfusate along with physiological vascular flows and pressures. Functional, biochemical, and microscopic evaluation revealed no additional injuries to the grafts during NELP with an improved oxygen extraction ratio (>0.5) and stabilized markers of hepatic injury. All livers synthesized adequate amounts of bile and coagulation factors. We also demonstrated a mild reduction (10%) of macroglobular steatosis with the use of the defatting solution. Histology demonstrated normal parenchymal architecture and a minimal to complete lack of IRI at the end of NELP. In conclusion, a modified NELP circuit preserved hepatocyte architecture, recovered synthetic functions, and hepatobiliary parameters of ECD livers without additional injuries to the grafts. This approach has the potential to increase the donor pool for clinical transplantation. Liver Transplantation 22 979-993 2016 AASLD.
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Affiliation(s)
- Babak Banan
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Rao Watson
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.,Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Min Xu
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Yiing Lin
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
| | - William Chapman
- Departments of Surgery, Washington University School of Medicine, St. Louis, MO
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Houben P, Manzini G, Kremer M, Arend J, Berlakovich GA, Klar E, Klempnauer J, Lerut J, Otto G, Pirenne J, Rogiers X, Seehofer D, Stippel DL, Schemmer P. Graft rinse prior to reperfusion in liver transplantation: literature review and online survey within the Eurotransplant community. Transpl Int 2015; 28:1291-1298. [PMID: 26147505 DOI: 10.1111/tri.12631] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Revised: 12/30/2014] [Accepted: 06/22/2015] [Indexed: 01/27/2023]
Abstract
Graft rinse prior reperfusion in liver transplantation (LT) is believed to reduce the incidence of postreperfusion syndrome and improve clinical outcome. A MEDLINE search was performed to obtain a comprehensive review of the published literature dealing with graft rinse in LT. Moreover, all thirty-four LT centers in the Eurotransplant (ET) region were invited to participate in an online survey to whether or not graft rinse is performed and whether further research in the field is needed. Seventeen reports have been found to investigate graft rinse protocols in 1894 LT recipients. Eighteen of the thirty centers that participated in the online survey performed graft rinse prior reperfusion in LT. The most commonly used rinse solution was albumin. Nineteen centers stated interest in participating in a multicenter RCT in the field. The published literature does not provide concluding appraisal of the benefit of graft rinse in LT. Graft rinse protocols are not standardized and are based on personal experience. Appropriately designed clinical trials addressing the topic are demanded. The online survey appears to be a helpful tool for the evaluation of clinical practice and future research topics in the transplant community.
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Affiliation(s)
- Philipp Houben
- Department of General and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Giulia Manzini
- Department of General and Visceral Surgery, University of Ulm, Ulm, Germany
| | - Michael Kremer
- Department of General and Visceral Surgery, University of Ulm, Ulm, Germany
| | - Joerg Arend
- Department of General, Visceral and Vascular Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Gabriela A Berlakovich
- Division of Transplantation, Department of Surgery, University of Vienna, Vienna, Austria
| | - Ernst Klar
- Department of General, Thoracic, Vascular and Transplantation Surgery, University of Rostock, Rostock, Germany
| | - Jürgen Klempnauer
- Department of General, Visceral and Transplant Surgery, Klinikum der Medizinischen Hochschule, Hannover, Germany
| | - Jan Lerut
- Department of Liver Transplant Surgery, University Clinic Saint-Luc, Bruxelles, Belgium
| | - Gerd Otto
- Department of Transplant and Hepato-Biliary-Pancreatic Surgery, Johannes-Gutenberg-University, Mainz, Germany
| | - Jacques Pirenne
- Department of Abdominal Transplant Surgery, University of Leuven, Leuven, Belgium
| | - Xavier Rogiers
- Department of Transplant Surgery, University of Gent, Gent, Belgium
| | - Daniel Seehofer
- Department of General, Visceral and Transplantation Surgery, University of Berlin, Berlin, Germany
| | - Dirk L Stippel
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany
| | - Peter Schemmer
- Department of General and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
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Abstract
PURPOSE OF REVIEW Shortage of donor organs has increased consideration for use of historically excluded grafts. Ex-vivo machine perfusion is an emerging technology that holds the potential for organ resuscitation and reconditioning, potentially increasing the quality and number of organs available for transplantation. This article aims to review the recent advances in machine perfusion and organ preservation solutions. RECENT FINDINGS Flow and pressure-based machine perfusion has shown improved kidney graft function and survival, especially among expanded criteria donors. Pressure-based machine perfusion is demonstrating promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. August 2014 marked Food and Drug Administration approval of XPS XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA), a device for preserving and resuscitating lung allografts initially considered unsuitable for transplantation. Although there is no consensus among physicians about the optimal preservation solution, adding antiapoptotic and cell protective agents to preservation solutions is an interesting research area that offers potential to improve preservation. SUMMARY Ex-vivo machine perfusion of solid organs is a promising method that provides the opportunity for resuscitation and reconditioning of suboptimal grafts, expanding the number and quality of donor organs.
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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.
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31
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Weeder PD, van Rijn R, Porte RJ. Machine perfusion in liver transplantation as a tool to prevent non-anastomotic biliary strictures: Rationale, current evidence and future directions. J Hepatol 2015; 63:265-75. [PMID: 25770660 DOI: 10.1016/j.jhep.2015.03.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 02/25/2015] [Accepted: 03/02/2015] [Indexed: 02/08/2023]
Abstract
The high incidence of non-anastomotic biliary strictures (NAS) after transplantation of livers from extended criteria donors is currently a major barrier to widespread use of these organs. This review provides an update on the most recent advances in the understanding of the etiology of NAS. These new insights give reason to believe that machine perfusion can reduce the incidence of NAS after transplantation by providing more protective effects on the biliary tree during preservation of the donor liver. An overview is presented regarding the different endpoints that have been used for assessment of biliary injury and function before and after transplantation, emphasizing on methods used during machine perfusion. The wide spectrum of different approaches to machine perfusion is discussed, including the many different combinations of techniques, temperatures and perfusates at varying time points. In addition, the current understanding of the effect of machine perfusion in relation to biliary injury is reviewed. Finally, we explore directions for future research such as the application of (pharmacological) strategies during machine perfusion to further improve preservation. We stress the great potential of machine perfusion to possibly expand the donor pool by reducing the incidence of NAS in extended criteria organs.
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Affiliation(s)
- Pepijn D Weeder
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rianne van Rijn
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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Karimian N, Matton APM, Westerkamp AC, Burlage LC, Op den Dries S, Leuvenink HGD, Lisman T, Uygun K, Markmann JF, Porte RJ. Ex Situ Normothermic Machine Perfusion of Donor Livers. J Vis Exp 2015:e52688. [PMID: 26067131 DOI: 10.3791/52688] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In contrast to conventional static cold preservation (0-4 °C), ex situ machine perfusion may provide better preservation of donor livers. Continuous perfusion of organs provides the opportunity to improve organ quality and allows ex situ viability assessment of donor livers prior to transplantation. This video article provides a step by step protocol for ex situ normothermic machine perfusion (37 °C) of human donor livers using a device that provides a pressure and temperature controlled pulsatile perfusion of the hepatic artery and continuous perfusion of the portal vein. The perfusion fluid is oxygenated by two hollow fiber membrane oxygenators and the temperature can be regulated between 10 °C and 37 °C. During perfusion, the metabolic activity of the liver as well as the degree of injury can be assessed by biochemical analysis of samples taken from the perfusion fluid. Machine perfusion is a very promising tool to increase the number of livers that are suitable for transplantation.
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Affiliation(s)
- Negin Karimian
- Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen
| | - Alix P M Matton
- Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen
| | - Andrie C Westerkamp
- Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen
| | - Laura C Burlage
- Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen
| | - Sanna Op den Dries
- Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen
| | - Henri G D Leuvenink
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen
| | - Ton Lisman
- Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen
| | - Korkut Uygun
- Center of Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital
| | - James F Markmann
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - Robert J Porte
- Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen;
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Ravikumar R, Leuvenink H, Friend PJ. Normothermic liver preservation: a new paradigm? Transpl Int 2015; 28:690-9. [PMID: 25847684 DOI: 10.1111/tri.12576] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 09/29/2014] [Accepted: 03/27/2015] [Indexed: 12/14/2022]
Abstract
Despite increasing donor numbers, waiting lists and pre-transplant mortality continue to grow in many countries. The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury (IRI). Transplantation of marginal donor organs has led to renewed interest in new techniques which have the potential to improve the quality of preservation, assess the quality of the organ and allow repair of the donor organ prior to transplantation. If successful, such techniques would not only improve the outcome of currently transplanted marginal livers, but also increase the donor pool. Experimental evidence suggests that preservation under near physiological conditions of temperature and oxygenation abrogates IRI. Normothermic perfusion maintains the organ in a physiological state, avoiding the depletion of cellular energy and the accumulation of waste products, which occurs with static cold storage. It enables viability assessment prior to transplantation thereby reducing the risk of transplanting inherently marginal organs. Here we review the use of normothermic machine perfusion as a means of organ preservation.
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Affiliation(s)
- Reena Ravikumar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Henri Leuvenink
- Groningen Transplant Center, University Medical Center, Groningen, The Netherlands
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Bruinsma BG, Avruch JH, Weeder PD, Sridharan GV, Uygun BE, Karimian NG, Porte RJ, Markmann JF, Yeh H, Uygun K. Functional human liver preservation and recovery by means of subnormothermic machine perfusion. J Vis Exp 2015:52777. [PMID: 25938299 PMCID: PMC4420550 DOI: 10.3791/52777] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
There is currently a severe shortage of liver grafts available for transplantation. Novel organ preservation techniques are needed to expand the pool of donor livers. Machine perfusion of donor liver grafts is an alternative to traditional cold storage of livers and holds much promise as a modality to expand the donor organ pool. We have recently described the potential benefit of subnormothermic machine perfusion of human livers. Machine perfused livers showed improving function and restoration of tissue ATP levels. Additionally, machine perfusion of liver grafts at subnormothermic temperatures allows for objective assessment of the functionality and suitability of a liver for transplantation. In these ways a great many livers that were previously discarded due to their suboptimal quality can be rescued via the restorative effects of machine perfusion and utilized for transplantation. Here we describe this technique of subnormothermic machine perfusion in detail. Human liver grafts allocated for research are perfused via the hepatic artery and portal vein with an acellular oxygenated perfusate at 21 °C.
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Affiliation(s)
- Bote G Bruinsma
- Center for Engineering in Medicine, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - James H Avruch
- Transplant Center, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - Pepijn D Weeder
- Center for Engineering in Medicine, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - Gautham V Sridharan
- Center for Engineering in Medicine, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - Basak E Uygun
- Center for Engineering in Medicine, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - Negin G Karimian
- Center for Engineering in Medicine, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen
| | - James F Markmann
- Transplant Center, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School
| | - Heidi Yeh
- Transplant Center, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School;
| | - Korkut Uygun
- Center for Engineering in Medicine, Dept. of Surgery, Massachusetts General Hospital, Harvard Medical School;
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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: 199] [Impact Index Per Article: 19.9] [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.
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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.
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Ferrigno A, Pasqua LGD, Bianchi A, Richelmi P, Vairetti M. Metabolic shift in liver: Correlation between perfusion temperature and hypoxia inducible factor-1α. World J Gastroenterol 2015; 21:1108-1116. [PMID: 25632183 PMCID: PMC4306154 DOI: 10.3748/wjg.v21.i4.1108] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 08/01/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To study at what temperature the oxygen carried by the perfusate meets liver requirements in a model of organ perfusion.
METHODS: In this study, we correlated hypoxia inducible factor (HIF)-1α expression to the perfusion temperature and the hepatic oxygen uptake in a model of isolated perfused rat liver. Livers from Wistar rats were perfused for 6 h with an oxygenated medium at 10, 20, 30 and 37 °C. Oxygen uptake was measured by an oxygen probe; lactate dehydrogenase activity, lactate release and glycogen were measured spectrophotometrically; bile flow was gravitationally determined; pH of the perfusate was also evaluated; HIF-1α mRNA and protein expression were analyzed by real time-polymerase chain reaction and ELISA, respectively.
RESULTS: Livers perfused at 10 and 20 °C showed no difference in lactate dehydrogenase release after 6 h of perfusion (0.96 ± 0.23 vs 0.93 ± 0.09 mU/min per g) and had lower hepatic damage as compared to 30 and 37 °C (5.63 ± 0.76 vs 527.69 ± 45.27 mU/min per g, respectively, Ps < 0.01). After 6 h, tissue ATP was significantly higher in livers perfused at 10 and 20 °C than in livers perfused at 30 and 37 °C (0.89 ± 0.06 and 1.16 ± 0.05 vs 0.57 ± 0.09 and 0.33 ± 0.08 nmol/mg, respectively, Ps < 0.01). No sign of hypoxia was observed at 10 and 20 °C, as highlighted by low lactate release respect to livers perfused at 30 and 37 °C (121.4 ± 12.6 and 146.3 ± 7.3 vs 281.8 ± 45.3 and 1094.5 ± 71.7 nmol/mL, respectively, Ps < 0.02), and low relative HIF-1α mRNA (0.40 ± 0.08 and 0.20 ± 0.03 vs 0.60 ± 0.20 and 1.47 ± 0.30, respectively, Ps < 0.05) and protein (3.72 ± 0.16 and 3.65 ± 0.06 vs 4.43 ± 0.41 and 6.44 ± 0.82, respectively, Ps < 0.05) expression.
CONCLUSION: Livers perfused at 10 and 20 °C show no sign of liver injury or anaerobiosis, in contrast to livers perfused at 30 and 37 °C.
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Sutton ME, op den Dries S, Karimian N, Weeder PD, de Boer MT, Wiersema-Buist J, Gouw ASH, Leuvenink HGD, Lisman T, Porte RJ. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion. PLoS One 2014; 9:e110642. [PMID: 25369327 PMCID: PMC4219693 DOI: 10.1371/journal.pone.0110642] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 09/24/2014] [Indexed: 12/23/2022] Open
Abstract
Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.
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Affiliation(s)
- Michael E. Sutton
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Sanna op den Dries
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Negin Karimian
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Pepijn D. Weeder
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marieke T. de Boer
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Janneke Wiersema-Buist
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Annette S. H. Gouw
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Henri G. D. Leuvenink
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J. Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- * E-mail:
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Ciubotaru A, Haverich A. Ex vivo approach to treat failing organs: expanding the limits. Eur Surg Res 2014; 54:64-74. [PMID: 25358862 DOI: 10.1159/000367942] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 08/26/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND Advanced organ failure is often classified as an end-stage disease where the treatment options are limited only to transplantation. As an alternative, different attempts have been undertaken to improve the outcome of the treatment of failing organs by using targeted ex vivo approaches. This may solve the issue of organ shortage by treating the donor organs before transplantation and the number of patients requiring transplantation may also be reduced by applying extensive ex vivo treatment followed by autotransplantation. METHODS We performed a literature review of PubMed and included articles published between 1962 and 2013. The following keywords were used (and; or): ex vivo, therapy, surgery, organ perfusion and autotransplantation. This review includes specific methods and attempts related to ex vivo organ perfusion and preservation, temporary life support systems, surgical and other therapeutic approaches, and diagnostic methods applied ex vivo to an isolated organ. RESULTS For the practical clinical use of ex vivo therapies, we could identify three major directions: (1) ex vivo pretransplant organ reconditioning, (2) ex vivo surgery and (3) ex vivo medical treatment. Different attempts have been made worldwide in the above-mentioned areas focusing on ex vivo organ preservation and treatment. We summarize in the present review the developments in the field of ex vivo organ recovery and evaluate the possibilities of combining and applying different technologies such as organ perfusion and storage, ex vivo exact topographical diagnosis, ex vivo locoregional medical treatment and ex vivo surgical correction. CONCLUSION Ex vivo therapies open new horizons in the treatment of end-stage organ pathologies.
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Affiliation(s)
- Anatol Ciubotaru
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
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Abstract
Liver transplantation is the best therapy in end-stage liver disease. Donor organ shortage and efforts to expand the donor organ pool are permanent issues given that advances in perioperative management and immunosuppressive therapy have brought the procedure into widespread clinical use. The management of organ procurement, including donor preconditioning and adequate organ storage, has a key role in transplantation. However, the organ procurement process can differ substantially between transplant centres, depending on local and national preferences. Advances in the field have come from experimental and clinical research on dynamic storage systems, such as machine perfusion devices, as an alternative to static cold storage. Determination of the clinical significance of these new systems is a topic worthy of future investigations.
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Tarantola E, Bertone V, Milanesi G, Gruppi C, Ferrigno A, Vairetti M, Barni S, Freitas I. Dipeptidylpeptidase-IV activity and expression reveal decreased damage to the intrahepatic biliary tree in fatty livers submitted to subnormothermic machine-perfusion respect to conventional cold storage. Eur J Histochem 2014; 58:2414. [PMID: 25308846 PMCID: PMC4194394 DOI: 10.4081/ejh.2014.2414] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 05/07/2014] [Accepted: 05/08/2014] [Indexed: 02/08/2023] Open
Abstract
Graft steatosis is a risk factor for poor initial function after liver transplantation. Biliary complications are frequent even after normal liver transplantation. A subnormothermic machine perfusion (MP20) preservation procedure was developed by our group with high potential for reducing injury to hepatocytes and sinusoidal cells of lean and fatty livers respect to conventional cold storage (CS). We report the response of the biliary tree to CS or MP20, in lean and obese Zucker rat liver. Dipeptidylpeptidase-IV (DPP-IV), crucial for the inactivation of incretins and neuropeptides, was used as a marker. Liver morphology and canalicular network of lean livers were similar after CS/reperfusion or MP20/reperfusion. CS preservation of fatty livers induced serious damage to the parenchyma and to the canalicular activity/ expression of DPP-IV, whereas with MP20 the morphology and canalicular network were similar to those of untreated lean liver. CS and MP20 had similar effects on DPP-IV activity and expression in the upper segments of the intrahepatic biliary tree of fatty livers. DPP-IV expression was significantly increased after MP20 respect to CS or to the controls, both for lean and obese animals. Our data support the superiority of MP20 over CS for preserving fatty livers. Dipeptidylpeptidase-IV activity and expression reveal decreased damage to the intrahepatic biliary tree in fatty livers submitted to subnormothermic machine-perfusion respect to conventional cold storage.
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Schlegel A, Dutkowski P. Role of hypothermic machine perfusion in liver transplantation. Transpl Int 2014; 28:677-89. [PMID: 24852621 DOI: 10.1111/tri.12354] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/05/2014] [Accepted: 05/19/2014] [Indexed: 12/15/2022]
Abstract
Machine liver perfusion has significantly evolved during the last ten years to optimize extended criteria liver grafts and to address the worldwide organ shortage. This review gives an overview on available ex vivo and in vivo data on hypothermic machine liver perfusion. We discuss also possible protective pathways and show most recent clinical applications of hypothermic machine liver perfusion in human.
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Affiliation(s)
- Andrea Schlegel
- Department of Visceral Surgery and Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Zurich, Switzerland
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Validation and Calibration of an Electrical Analog Model of Human Liver Perfusion Based on Hypothermic Machine Perfusion Experiments. Int J Artif Organs 2014; 37:486-98. [DOI: 10.5301/ijao.5000337] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2014] [Indexed: 11/20/2022]
Abstract
Purpose Hypothermic machine perfusion (HMP) is reviving as a better preservation method for donor livers than the golden standard of cold storage, but still faces challenges such as the risk for endothelial damage and flow competition between the arterial and portal venous inflow. Therefore, we previously developed an electrical analog model to investigate the effect of HMP settings on the human liver hemodynamics. While the model provided plausible results, it is based on a number of assumptions and its performance was never subjected to experimental validation. To this end, we present a new methodology to validate and calibrate this model to a specific liver. Methods and Results HMP experiments were performed to capture the perfusion behavior of a human liver during varying perfusion settings. Simultaneous pressure and flow signals were acquired at the hepatic artery, portal vein, and vena cava inferior. The calculation of hydraulic input impedances enabled reduced Windkessel models to be fitted to the global hepatic perfusion properties as an intermediate step. Based on these Windkessel models, the extended electrical analog model was calibrated to the specific available liver. Results revealed that literature values of one of the critical model parameters (wall viscoelasticity) are a few orders of magnitude off, having important consequences for simulated (pulsatile) hemodynamic variables. Conclusions A novel methodology, based on HMP experiments, signal processing and unconstrained nonlinear optimization was developed to validate and calibrate the liver-specific extended electrical model. Future research may focus on extending this approach to other applications (e.g. liver pathologies such as cirrhosis).
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Liu Q, Berendsen T, Izamis ML, Uygun B, Yarmush ML, Uygun K. Perfusion defatting at subnormothermic temperatures in steatotic rat livers. Transplant Proc 2014; 45:3209-13. [PMID: 24182786 DOI: 10.1016/j.transproceed.2013.05.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 05/22/2013] [Indexed: 01/12/2023]
Abstract
Hepatic steatosis is a major risk factor in liver transplantation. Use of machine perfusion to reduce steatosis has been reported previously at normothermic (37°C) temperatures, with minimal media as well as specialized defatting cocktails. In this work, we tested if subnormothermic (room temperature) machine perfusion, a more practical version of machine perfusion approach that does not require temperature control or oxygen carriers, could also be used to reduce fat content in steatotic livers. Steatotic livers recovered from obese Zucker rats were perfused for 6 hours. A significant increase of very low density lipoprotein (VLDL) and triglyceride (TG) content in perfusate, with or without a defatting cocktail, was observed although the changes in histology were minimal and changes in intracellular TG content were not statistically significant. The oxygen uptake rate, VLDL secretion, TG secretion, and venous resistance were similar in both groups. This study confirms lipid export during subnormothermic machine perfusion; however, the duration of perfusion necessary appears much higher than required in normothermic perfusion.
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Affiliation(s)
- Q Liu
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital, Boston, MA
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op den Dries S, Westerkamp AC, Karimian N, Gouw ASH, Bruinsma BG, Markmann JF, Lisman T, Yeh H, Uygun K, Martins PN, Porte RJ. Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures. J Hepatol 2014; 60:1172-9. [PMID: 24560661 DOI: 10.1016/j.jhep.2014.02.010] [Citation(s) in RCA: 146] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 01/19/2014] [Accepted: 02/04/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS The peribiliary glands of large bile ducts have been identified as a niche of progenitor cells that contribute to regeneration of biliary epithelium after injury. We aimed to determine whether injury to the peribiliary glands of donor livers is a risk factor for development of non-anastomotic biliary strictures (NAS) after liver transplantation. METHODS In 128 liver transplant procedures, biopsies were taken from the donor bile duct and injury was assessed using an established histological grading system. Histological severity of injury was subsequently compared in liver grafts that later developed biliary structures vs. uncomplicated liver grafts. RESULTS Luminal biliary epithelial loss >50% was observed in 91.8% of the grafts before transplantation, yet NAS occurred in only 16.4%. Periluminal peribiliary glands were more severely injured than deep peribiliary glands located near the fibromuscular layer (>50% loss in 56.9% vs. 17.5%, respectively; p<0.001). Injury of deep peribiliary glands was more prevalent and more severe in livers that later developed NAS, compared to grafts without NAS (>50% loss in 50.0% vs. 9.8%, respectively; p=0.004). In parallel, injury of the peribiliary vascular plexus was more severe in livers that developed NAS, compared to grafts without NAS (>50% vascular changes in 57.1% vs. 20.3%; p=0.006). CONCLUSION Injury of peribiliary glands and vascular plexus before transplantation is strongly associated with the occurrence of biliary strictures after transplantation. This suggests that insufficient regeneration due to loss of peribiliary glands or impaired blood supply may explain the development of biliary strictures.
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Affiliation(s)
- Sanna op den Dries
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Andrie C Westerkamp
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Negin Karimian
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Annette S H Gouw
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bote G Bruinsma
- Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital, Boston, MA, United States
| | - James F Markmann
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Heidi Yeh
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Korkut Uygun
- Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital, Boston, MA, United States
| | - Paulo N Martins
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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Rubbini M. Perfusion machines for liver transplantation: technology and multifunctionality. Updates Surg 2014; 66:101-108. [DOI: 10.1007/s13304-013-0234-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 09/06/2013] [Indexed: 12/19/2022]
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EPR spectroscopy as a predictive tool for the assessment of marginal donor livers perfused on a normothermic ex vivo perfusion circuit. Med Hypotheses 2014; 82:627-30. [PMID: 24629357 DOI: 10.1016/j.mehy.2014.02.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 02/24/2014] [Indexed: 12/16/2022]
Abstract
Liver transplantation is a highly successful treatment for end-stage liver disease. While liver transplantation is often the only effective treatment for cirrhosis there is a critical shortage of donor organs, leading to death of many potential recipients on the waiting list. Marginal liver grafts are increasingly being used in an attempt to increase the number of donor livers utilized for transplantation. Marginal donor livers often have complications and worse outcomes for recipients receiving these types of transplant. The ability to predict the outcome with the use of marginal grafts is difficult and often imprecise leading decreased use of potentially suitable grafts. The development and maturation of normothermic ex vivo perfusion as a platform for the assessment of donor organs presents an opportunity to increase the number of usable donor livers available for transplantation. Furthermore, direct measurement of reactive oxygen species (ROS) present in the donor liver on an ex vivo perfusion circuit by electron paramagnetic resonance (EPR) spectroscopy would allow for precise real-time quantification of donor organ injury. The combination normothermic ex vivo liver perfusion with EPR spectroscopy could therefore present a powerful platform to increase the number of donor organs utilized for transplantation.
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Abstract
The history of medicine is that what was inconceivable yesterday and barely achievable today often becomes routine tomorrow. Liver transplantation began with almost no resources at the same time as the tentative first steps were taken to land a man on the moon. Because human lives would be at stake, both objectives had a sacramental element from the outset: a solemnly binding commitment to perfection. The gift of an organ is really a gift of life, and something as valuable as a life-saving organ is more important to a suffering patient than wealth or power. The concept of a team approach to the care of the transplant patient is an important factor in the development of a successful program. This has resulted in recipient survival rates reaching 90% at one year.
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Affiliation(s)
- Michael Ramsay
- Department of Anesthesiology and Pain Management, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA.
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Op den Dries S, Karimian N, Porte RJ. Normothermic machine perfusion of discarded liver grafts. Am J Transplant 2013; 13:2504. [PMID: 23919300 DOI: 10.1111/ajt.12374] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- S Op den Dries
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Assessing warm ischemic injury of pig livers at hypothermic machine perfusion. J Surg Res 2013; 186:379-89. [PMID: 24035230 DOI: 10.1016/j.jss.2013.07.034] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 07/01/2013] [Accepted: 07/16/2013] [Indexed: 01/12/2023]
Abstract
BACKGROUND Livers originating from donation after circulatory death (DCD) donors are exposed to warm ischemia (WI) before liver transplantation (LTx). Currently, there are no objective tests to evaluate the damage sustained before LTx. This study aims to identify surrogate markers for liver injury that can be assessed during hypothermic machine perfusion (HMP) preservation. In addition, we want to use mathematical equation modeling combining these markers to improve our assessment of DCD livers for transplantation. MATERIALS AND METHODS Porcine livers were exposed to incremental periods of WI (0-120 min) and subsequently HMP preserved for 4 h. Biochemical and hemodynamic parameters were repeatedly measured in the perfusate during HMP. Subsequently, to mimic LTx, normothermic isolated-liver perfusion was applied for 2 h and the injury assessed using a morphological score. RESULTS With increasing WI periods, the perfusate became more acidotic, and levels of aspartate aminotransferase (AST), liver fatty acid binding protein, redox-active iron, and arterial vascular resistance increased. A damage index, combining AST and pH (damage index = 2 - 37 × β(AST) - 257 × β(pH)) based on multifactorial analysis of the changing pattern of these markers, had increased sensitivity and specificity to reflect WI and reperfusion injury. CONCLUSIONS This proof of concept study demonstrated the potential role for objective evaluation of DCD porcine livers during HMP and the advantage to use multifactorial analysis on the markers' changing pattern.
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