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Archie WH, Baimas-George M, Haynes N, Kundu S, Peterson K, Wehrle CJ, Huckleberry D, Eskind L, Levi D, Soto JR, Denny R, Casingal V, Cochran A, Rein EH, Vrochides D. Upper limit of normothermic machine preservation of liver grafts from donation after circulatory death yet to be defined. World J Transplant 2025; 15:99170. [DOI: 10.5500/wjt.v15.i2.99170] [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: 07/15/2024] [Revised: 11/07/2024] [Accepted: 12/11/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND The normothermic machine perfusion pump (NMPP) could shape the future of transplantation. Providing ex-vivo optimization, NMPP attenuates ischemic insult while replenishing energy. An understanding of machine perfusion time (MPT) impact and potential clinical benefits is paramount and necessitates exploration.
AIM To investigate the relationship between MPT and post-transplant graft function.
METHODS Retrospective review of the first 50 donation after circulatory death (DCD) grafts preserved using NMPP in a tertiary institution was performed. Essential preservation time points, graft parameters, recipient information, and postoperative outcomes were prospectively recorded. Early allograft dysfunction (EAD), L-Graft7 score and 90-day outcomes were collected for all grafts. The first 20 recipients were allocated into the early group, considered the learning curve population for the center. The subsequent 30 were allocated into the late group. Recipients were also stratified into cohorts depending on MPT, i.e., short (< 8 hours), medium (8-16 hours) and long (> 16 hours).
RESULTS NMPP operational parameters were not predictive of EAD, L-GrAFT7 or 90-day outcomes. The early group had significantly less MPT and cold ischemia time than the late group (553 minutes vs 850 minutes, P < 0.001) and (127.5 minutes vs 154 minutes, P = 0.025), respectively. MPT had no impact in either group.
CONCLUSION Increased MPT of DCD liver grafts had no adverse recipient results for the times utilized in this population, indicating its upper limits, likely beyond 24 hours, are not demonstrated within this study. Future studies are necessary to determine whether longer MPT is beneficial or detrimental to graft function and, if the latter, what is the maximum safe duration. Further studies of the effect of normothermic machine perfusion pump duration on long-term outcomes are also needed.
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Affiliation(s)
- William H Archie
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Maria Baimas-George
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Nathanael Haynes
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Souma Kundu
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Katheryn Peterson
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Chase J Wehrle
- Department of Hepato-Pancreato-Biliary/Liver Transplant Surgery, Cleveland Clinic Transplant Research Center, Cleveland, OH 44195, United States
| | - Damien Huckleberry
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Lon Eskind
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - David Levi
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Jose R Soto
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Roger Denny
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Vincent Casingal
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Allyson Cochran
- Department of Surgery, Carolinas Center for Surgical Outcomes Science, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Erin H Rein
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Dionisios Vrochides
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
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2
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Cruz RJ, Galvao FF, Benicio A. An innovative model of en bloc liver-pancreas-kidney preservation via ex vivo hypothermic acellular machine perfusion. Int J Artif Organs 2025:3913988251330084. [PMID: 40411217 DOI: 10.1177/03913988251330084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2025]
Abstract
BACKGROUND Liver machine perfusion (MP) has emerged as a promising organ preservation modality. Recent studies have shown that the addition of the kidneys to the circuit improves the biochemical environment and could benefit liver preservation. The aim of this study was to explore the technical and anatomical feasibility of en bloc liver-pancreas-kidney MP. We also examined the safety of ex vivo perfusion with a nonoxygen carrier solution and its effects on acid-base and metabolic parameters using this novel multivisceral perfusion platform. METHODS Five multivisceral allografts, including liver, pancreas, duodenum, and kidney, were perfused for 4 h with acellular perfusate. Hemodynamic and laboratory data were evaluated throughout the experiment. RESULTS No system failure was reported. There were minimal changes in the acid-base parameters during the experiment. Lactate and glucose levels were stable throughout hypothermic perfusion. There was a mild increase in liver function parameters in the last hour of hypothermic perfusion. No changes in creatinine levels were observed throughout the study. The urine output increased steadily during the experiment, with an average of 155.6 mL/h. CONCLUSION We described an innovative multivisceral MP technique that could be further used as a platform for physiological studies and targeted therapeutic interventions. Further investigations are necessary to evaluate this ex vivo perfusion technique and provide insights into the feasibility of hypothermic acellular multivisceral MP in clinical scenarios.
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Affiliation(s)
- Ruy J Cruz
- Department of Surgery, Gastrointestinal Rehabilitation and Transplant Center, Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Flavio Fh Galvao
- Research Division, University of São Paulo Medical School, São Paulo, SP, Brazil
| | - Anderson Benicio
- Research Division, University of São Paulo Medical School, São Paulo, SP, Brazil
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3
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Ran Q, Zhang J, Zhong J, Lin J, Zhang S, Li G, You B. Organ preservation: current limitations and optimization approaches. Front Med (Lausanne) 2025; 12:1566080. [PMID: 40206471 PMCID: PMC11980443 DOI: 10.3389/fmed.2025.1566080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 02/28/2025] [Indexed: 04/11/2025] Open
Abstract
Despite the annual rise in patients with end-stage diseases necessitating organ transplantation, the scarcity of high-quality grafts constrains the further development of transplantation. The primary causes of the graft shortage are the scarcity of standard criteria donors, unsatisfactory organ preservation strategies, and mismatching issues. Organ preservation strategies are intimately related to pre-transplant graft viability and the incidence of adverse clinical outcomes. Static cold storage (SCS) is the current standard practice of organ preservation, characterized by its cost-effectiveness, ease of transport, and excellent clinical outcomes. However, cold-induced injury during static cold preservation, toxicity of organ preservation solution components, and post-transplantation reperfusion injury could further exacerbate graft damage. Long-term ex vivo dynamic machine perfusion (MP) preserves grafts in a near-physiological condition, evaluates graft viability, and cures damage to grafts, hence enhancing the usage and survival rates of marginal organs. With the increased use of extended criteria donors (ECD) and advancements in machine perfusion technology, static cold storage is being gradually replaced by machine perfusion. This review encapsulates the latest developments in cryopreservation, subzero non-freezing storage, static cold storage, and machine perfusion. The emphasis is on the injury mechanisms linked to static cold storage and optimization strategies, which may serve as references for the optimization of machine perfusion techniques.
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Affiliation(s)
- Qiulin Ran
- Department of Cardiovascular Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jiayi Zhang
- Translational Medicine Center, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Jisheng Zhong
- Department of Cardiovascular Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Ji Lin
- Department of Cardiovascular Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Shuai Zhang
- Department of Cardiovascular Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Guang Li
- Department of Cardiovascular Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Bin You
- Department of Cardiovascular Surgery, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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4
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Ruppelt A, Pijnenburg I, Pappers C, Samsom RA, Kock L, Grinwis GCM, Spee B, Rasponi M, Stijnen M. Are slaughterhouse-obtained livers suitable for use in ex vivo perfusion research? J Int Med Res 2023; 51:3000605231189651. [PMID: 37565647 PMCID: PMC10422909 DOI: 10.1177/03000605231189651] [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: 03/17/2023] [Accepted: 07/06/2023] [Indexed: 08/12/2023] Open
Abstract
OBJECTIVES The success of the ex vivo machine perfusion of pig livers used for preclinical research depends on organ quality and availability. In this study, we investigated whether livers obtained from slaughterhouses are suitable and equivalent to livers obtained from laboratory pigs. METHODS Livers were obtained from slaughterhouse pigs stunned by electrocution or CO2 inhalation and from laboratory pigs. For the latter group, 45 minutes of warm ischemia was mimicked for a subgroup, ensuring a valid comparison with slaughterhouse-derived livers. RESULTS Livers from CO2-stunned pigs showed lower indocyanine green clearance and bile production, higher blood lactate and potassium concentrations, and higher alanine aminotransferase activities than electrically stunned pigs. Furthermore, livers from electrically stunned pigs, and livers from laboratory pigs, subjected or not to warm ischemia, showed similar performance in terms of perfusion and metabolism. CONCLUSION For an ex vivo liver model generated using slaughterhouse pigs, electrical stunning is preferable to CO2 stunning. Livers from electrically stunned slaughterhouse pigs performed similarly to laboratory pig livers. These findings support the use of livers from electrically stunned slaughterhouse pigs, which may therefore provide an alternative to livers obtained from laboratory pigs, consistent with the principle of the 3Rs.
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Affiliation(s)
- Alicia Ruppelt
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
- LifeTec Group, Eindhoven, The Netherlands
| | | | | | - Roos-Anne Samsom
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Linda Kock
- LifeTec Group, Eindhoven, The Netherlands
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Guy C. M. Grinwis
- Veterinary Pathology Diagnostic Centre, Department of Biomedical Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Marco Rasponi
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
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5
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Schuler MJ, Becker D, Mueller M, Bautista Borrego L, Mancina L, Huwyler F, Binz J, Hagedorn C, Schär B, Gygax E, Weisskopf M, Sousa Da Silva RX, Antunes Crisóstomo JM, Dutkowski P, Rudolf von Rohr P, Clavien PA, Tibbitt MW, Eshmuminov D, Hefti M. Observations and findings during the development of a subnormothermic/normothermic long-term ex vivo liver perfusion machine. Artif Organs 2023; 47:317-329. [PMID: 36106378 DOI: 10.1111/aor.14403] [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: 04/03/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND Ex situliver machine perfusion at subnormothermic/normothermic temperature isincreasingly applied in the field of transplantation to store and evaluateorgans on the machine prior transplantation. Currently, various perfusionconcepts are in clinical and preclinical applications. Over the last 6 years ina multidisciplinary team, a novel blood based perfusion technology wasdeveloped to keep a liver alive and metabolically active outside of the bodyfor at least one week. METHODS Within thismanuscript, we present and compare three scenarios (Group 1, 2 and 3) we werefacing during our research and development (R&D) process, mainly linked tothe measurement of free hemoglobin and lactate in the blood based perfusate. Apartfrom their proven value in liver viability assessment (ex situ), these twoparameters are also helpful in R&D of a long-term liver perfusion machine and moreover supportive in the biomedical engineering process. RESULTS Group 1 ("good" liver on the perfusion machine) represents the best liver clearance capacity for lactate and free hemoglobin wehave observed. In contrast to Group 2 ("poor" liver on the perfusion machine), that has shown the worst clearance capacity for free hemoglobin. Astonishingly,also for Group 2, lactate is cleared till the first day of perfusion andafterwards, rising lactate values are detected due to the poor quality of theliver. These two perfusate parametersclearly highlight the impact of the organ quality/viability on the perfusion process. Whereas Group 3 is a perfusion utilizing a blood loop only (without a liver). CONCLUSION Knowing the feasible ranges (upper- and lower bound) and the courseover time of free hemoglobin and lactate is helpful to evaluate the quality ofthe organ perfusion itself and the maturity of the developed perfusion device. Freehemoglobin in the perfusate is linked to the rate of hemolysis that indicates how optimizing (gentle blood handling, minimizing hemolysis) the perfusion machine actually is. Generally, a reduced lactate clearancecapacity can be an indication for technical problems linked to the blood supplyof the liver and therefore helps to monitor the perfusion experiments.Moreover, the possibility is given to compare, evaluate and optimize developed liverperfusion systems based on the given ranges for these two parameters. Otherresearch groups can compare/quantify their perfusate (blood) parameters withthe ones in this manuscript. The presented data, findings and recommendations willfinally support other researchers in developing their own perfusion machine ormodifying commercially availableperfusion devices according to their needs.
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Affiliation(s)
- Martin J Schuler
- Wyss Zurich - ETH Zurich/University of Zurich, Zurich, Switzerland
| | - Dustin Becker
- Wyss Zurich - ETH Zurich/University of Zurich, Zurich, Switzerland
| | - Matteo Mueller
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - Lucia Bautista Borrego
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - Leandro Mancina
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - Florian Huwyler
- Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland
| | - Jonas Binz
- Wyss Zurich - ETH Zurich/University of Zurich, Zurich, Switzerland
| | - Catherine Hagedorn
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - Beatrice Schär
- Entwicklung biomedizinische Anwendungen, Securecell AG, Urdorf, Switzerland
| | - Erich Gygax
- Forschung und Entwicklung, Fumedica AG, Muri, Switzerland
| | - Miriam Weisskopf
- Center of Surgical Research, University Hospital Zürich, University of Zürich, Zurich, Switzerland
| | - Richard Xavier Sousa Da Silva
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | | | - Philipp Dutkowski
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Rudolf von Rohr
- Transport Processes and Reactions Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland
| | - Pierre-Alain Clavien
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - Mark W Tibbitt
- Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland
| | - Dilmurodjon Eshmuminov
- Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
| | - Max Hefti
- Wyss Zurich - ETH Zurich/University of Zurich, Zurich, Switzerland
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6
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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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7
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Krüger M, Ruppelt A, Kappler B, Van Soest E, Samsom RA, Grinwis GCM, Geijsen N, Helms JB, Stijnen M, Kock LM, Rasponi M, Kooistra HS, Spee B. Normothermic Ex Vivo Liver Platform Using Porcine Slaughterhouse Livers for Disease Modeling. Bioengineering (Basel) 2022; 9:bioengineering9090471. [PMID: 36135018 PMCID: PMC9495507 DOI: 10.3390/bioengineering9090471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/25/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
Metabolic and toxic liver disorders, such as fatty liver disease (steatosis) and drug-induced liver injury, are highly prevalent and potentially life-threatening. To allow for the study of these disorders from the early stages onward, without using experimental animals, we collected porcine livers in a slaughterhouse and perfused these livers normothermically. With our simplified protocol, the perfused slaughterhouse livers remained viable and functional over five hours of perfusion, as shown by hemodynamics, bile production, indocyanine green clearance, ammonia metabolism, gene expression and histology. As a proof-of-concept to study liver disorders, we show that an infusion of free fatty acids and acetaminophen results in early biochemical signs of liver damage, including reduced functionality. In conclusion, the present platform offers an accessible system to perform research in a functional, relevant large animal model while avoiding using experimental animals. With further improvements to the model, prolonged exposure could make this model a versatile tool for studying liver diseases and potential treatments.
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Affiliation(s)
- Melanie Krüger
- LifeTec Group BV, 5611 ZS Eindhoven, The Netherlands
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Alicia Ruppelt
- LifeTec Group BV, 5611 ZS Eindhoven, The Netherlands
- Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, 20133 Milan, Italy
- Correspondence:
| | | | | | - Roos Anne Samsom
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Guy C. M. Grinwis
- Veterinary Pathology Diagnostic Centre, Department of Biomedical Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, The Netherlands
| | - Niels Geijsen
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - J. Bernd Helms
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands
| | - Marco Stijnen
- LifeTec Group BV, 5611 ZS Eindhoven, The Netherlands
| | - Linda M. Kock
- LifeTec Group BV, 5611 ZS Eindhoven, The Netherlands
- Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
| | - Marco Rasponi
- Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, 20133 Milan, Italy
| | - Hans S. Kooistra
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
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8
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Tessier SN, de Vries RJ, Pendexter CA, Cronin SEJ, Ozer S, Hafiz EOA, Raigani S, Oliveira-Costa JP, Wilks BT, Lopera Higuita M, van Gulik TM, Usta OB, Stott SL, Yeh H, Yarmush ML, Uygun K, Toner M. Partial freezing of rat livers extends preservation time by 5-fold. Nat Commun 2022; 13:4008. [PMID: 35840553 PMCID: PMC9287450 DOI: 10.1038/s41467-022-31490-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 06/20/2022] [Indexed: 02/04/2023] Open
Abstract
The limited preservation duration of organs has contributed to the shortage of organs for transplantation. Recently, a tripling of the storage duration was achieved with supercooling, which relies on temperatures between -4 and -6 °C. However, to achieve deeper metabolic stasis, lower temperatures are required. Inspired by freeze-tolerant animals, we entered high-subzero temperatures (-10 to -15 °C) using ice nucleators to control ice and cryoprotective agents (CPAs) to maintain an unfrozen liquid fraction. We present this approach, termed partial freezing, by testing gradual (un)loading and different CPAs, holding temperatures, and storage durations. Results indicate that propylene glycol outperforms glycerol and injury is largely influenced by storage temperatures. Subsequently, we demonstrate that machine perfusion enhancements improve the recovery of livers after freezing. Ultimately, livers that were partially frozen for 5-fold longer showed favorable outcomes as compared to viable controls, although frozen livers had lower cumulative bile and higher liver enzymes.
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Affiliation(s)
- Shannon N. Tessier
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Reinier J. de Vries
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,grid.7177.60000000084992262Department of Surgery, Amsterdam University Medical Centers – location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Casie A. Pendexter
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,Present Address: Sylvatica Biotech Inc., North Charleston, SC USA
| | - Stephanie E. J. Cronin
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Sinan Ozer
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Ehab O. A. Hafiz
- grid.420091.e0000 0001 0165 571XDepartment of Electron Microscopy Research, Theodor Bilharz Research Institute, Giza, Egypt
| | - Siavash Raigani
- grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,grid.32224.350000 0004 0386 9924Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA USA
| | - Joao Paulo Oliveira-Costa
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.38142.3c000000041936754XDepartment of Medicine and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA USA
| | - Benjamin T. Wilks
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Manuela Lopera Higuita
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Thomas M. van Gulik
- grid.7177.60000000084992262Department of Surgery, Amsterdam University Medical Centers – location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Osman Berk Usta
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Shannon L. Stott
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.38142.3c000000041936754XDepartment of Medicine and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA USA
| | - Heidi Yeh
- grid.32224.350000 0004 0386 9924Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA USA
| | - Martin L. Yarmush
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,grid.430387.b0000 0004 1936 8796Department of Biomedical Engineering, Rutgers University, Piscataway, NJ USA
| | - Korkut Uygun
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Mehmet Toner
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
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9
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Lascaris B, Thorne AM, Lisman T, Nijsten MWN, Porte RJ, de Meijer VE. Long-term normothermic machine preservation of human livers: what is needed to succeed? Am J Physiol Gastrointest Liver Physiol 2022; 322:G183-G200. [PMID: 34756122 DOI: 10.1152/ajpgi.00257.2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although short-term machine perfusion (≤24 h) allows for resuscitation and viability assessment of high-risk donor livers, the donor organ shortage might be further remedied by long-term perfusion machines. Extended preservation of injured donor livers may allow reconditioning, repairing, and regeneration. This review summarizes the necessary requirements and challenges for long-term liver machine preservation, which requires integrating multiple core physiological functions to mimic the physiological environment inside the body. A pump simulates the heart in the perfusion system, including automatically controlled adjustment of flow and pressure settings. Oxygenation and ventilation are required to account for the absence of the lungs combined with continuous blood gas analysis. To avoid pressure necrosis and achieve heterogenic tissue perfusion during preservation, diaphragm movement should be simulated. An artificial kidney is required to remove waste products and control the perfusion solution's composition. The perfusate requires an oxygen carrier, but will also be challenged by coagulation and activation of the immune system. The role of the pancreas can be mimicked through closed-loop control of glucose concentrations by automatic injection of insulin or glucagon. Nutrients and bile salts, generally transported from the intestine to the liver, have to be supplemented when preserving livers long term. Especially for long-term perfusion, the container should allow maintenance of sterility. In summary, the main challenge to develop a long-term perfusion machine is to maintain the liver's homeostasis in a sterile, carefully controlled environment. Long-term machine preservation of human livers may allow organ regeneration and repair, thereby ultimately solving the shortage of donor livers.
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Affiliation(s)
- Bianca Lascaris
- Section of Hepatopancreatobiliary Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Adam M Thorne
- Section of Hepatopancreatobiliary Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Maarten W N Nijsten
- Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatopancreatobiliary Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Section of Hepatopancreatobiliary Surgery & Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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10
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Markmann JF, Abouljoud MS, Ghobrial RM, Bhati CS, Pelletier SJ, Lu AD, Ottmann S, Klair T, Eymard C, Roll GR, Magliocca J, Pruett TL, Reyes J, Black SM, Marsh CL, Schnickel G, Kinkhabwala M, Florman SS, Merani S, Demetris AJ, Kimura S, Rizzari M, Saharia A, Levy M, Agarwal A, Cigarroa FG, Eason JD, Syed S, Washburn WK, Parekh J, Moon J, Maskin A, Yeh H, Vagefi PA, MacConmara MP. Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial. JAMA Surg 2022; 157:189-198. [PMID: 34985503 PMCID: PMC8733869 DOI: 10.1001/jamasurg.2021.6781] [Citation(s) in RCA: 244] [Impact Index Per Article: 81.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Question Can oxygenated portable normothermic perfusion of deceased donor livers for transplant improve outcomes compared with the current standard of care using ischemic cold storage? Findings In this multicenter randomized clinical trial of 300 recipients of liver transplants with the donor liver preserved by either normothermic perfusion or conventional ischemic cold storage, normothermic machine perfusion resulted in decreased early liver graft injury and ischemic biliary complications and greater organ utilization. Meaning In this study, portable normothermic oxygenated machine perfusion of donor liver grafts resulted in improved outcomes after liver transplant and in more livers being transplanted. Importance Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts. Objective To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs). Design, Setting, and Participants This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list. Interventions Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital. Main Outcomes and Measures The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft–related severe adverse events within 30 days after transplant. Results Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant. Conclusions and Relevance This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use. Trial Registration ClinicalTrials.gov Identifier: NCT02522871
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Affiliation(s)
| | | | | | | | | | | | | | | | - Corey Eymard
- University of Tennessee Health Science Center, Memphis
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - James D Eason
- University of Tennessee Health Science Center, Memphis
| | | | | | | | - Jang Moon
- Mount Sinai Health System, New York, New York
| | | | - Heidi Yeh
- Massachusetts General Hospital, Boston
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11
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Lan Q, Li Y, Robertson J, Jin R. Modeling of pre-transplantation liver viability with spatial-temporal smooth variable selection. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2021; 208:106264. [PMID: 34256248 DOI: 10.1016/j.cmpb.2021.106264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/28/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND AND OBJECTIVE Liver viability assessment plays a critical role in liver transplantation, and the accuracy of the assessment directly determines the success of the transplantation surgery and patient's outcomes. With various factors that affect liver viability, including pre-existing medical conditions of donors, the procurement process, and preservation conditions, liver viability assessment is typically subjective, invasive or inconsistent in results among different surgeons and pathologists. Motivated by these challenges, we aimed to create a non-invasive statistical model utilizing spatial-temporal infrared image (IR) data to predict the binary liver viability (acceptable/unacceptable) during the preservation. METHODS The spatial-temporal features of liver surface temperature, monitored by IR thermography, are significantly correlated with the liver viability. A spatial-temporal smooth variable selection (STSVS) method is proposed to define the smoothness of model parameters corresponding to different liver surface regions at different times. RESULTS A case study, using porcine livers, has been performed to validate the efficacy of the STSVS method. The comparison results show that STSVS has the better overall prediction performance compared to the past state-of-the-art predictive models, including generalized linear model (GLM), support vector machine (SVM), LASSO, and Fused LASSO. Moreover, the significant predictors identified by the STSVS method indicate the importance of edges of lobes in predicting liver viability during the pre-transplantation preservation. CONCLUSIONS The proposed method has the best performance in predicting liver viability. This 'real-time' prediction method may increase the utilization of donors' livers without damaging tissues and time-consuming, yet imprecise feature assessment.
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Affiliation(s)
- Qing Lan
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA.
| | - Yifu Li
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA
| | - John Robertson
- Department of Biomedical Engineering and Mechanics, Virginia Tech, VA 24061, USA
| | - Ran Jin
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA
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12
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Masior Ł, Grąt M. Methods of Attenuating Ischemia-Reperfusion Injury in Liver Transplantation for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:8229. [PMID: 34360995 PMCID: PMC8347959 DOI: 10.3390/ijms22158229] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent indications for liver transplantation. However, the transplantation is ultimately associated with the occurrence of ischemia-reperfusion injury (IRI). It affects not only the function of the graft but also significantly worsens the oncological results. Various methods have been used so far to manage IRI. These include the non-invasive approach (pharmacotherapy) and more advanced options encompassing various types of liver conditioning and machine perfusion. Strategies aimed at shortening ischemic times and better organ allocation pathways are still under development as well. This article presents the mechanisms responsible for IRI, its impact on treatment outcomes, and strategies to mitigate it. An extensive review of the relevant literature using MEDLINE (PubMed) and Scopus databases until September 2020 was conducted. Only full-text articles written in English were included. The following search terms were used: "ischemia reperfusion injury", "liver transplantation", "hepatocellular carcinoma", "preconditioning", "machine perfusion".
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Affiliation(s)
- Łukasz Masior
- Department of General, Vascular and Oncological Surgery, Medical University of Warsaw, Stępińska Street 19/25, 00-739 Warsaw, Poland
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha Street 1A, 02-097 Warsaw, Poland;
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13
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Haque O, Raigani S, Rosales I, Carroll C, Coe TM, Baptista S, Yeh H, Uygun K, Delmonico FL, Markmann JF. Thrombolytic Therapy During ex-vivo Normothermic Machine Perfusion of Human Livers Reduces Peribiliary Vascular Plexus Injury. Front Surg 2021; 8:644859. [PMID: 34222314 PMCID: PMC8245781 DOI: 10.3389/fsurg.2021.644859] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 05/24/2021] [Indexed: 12/29/2022] Open
Abstract
Background: A major limitation in expanding the use of donation after circulatory death (DCD) livers in transplantation is the increased risk of graft failure secondary to ischemic cholangiopathy. Warm ischemia causes thrombosis and injury to the peribiliary vascular plexus (PVP), which is supplied by branches of the hepatic artery, causing higher rates of biliary complications in DCD allografts. Aims/Objectives: We aimed to recondition discarded DCD livers with tissue plasminogen activator (tPA) while on normothermic machine perfusion (NMP) to improve PVP blood flow and reduce biliary injury. Methods: Five discarded DCD human livers underwent 12 h of NMP. Plasminogen was circulated in the base perfusate prior to initiation of perfusion and 1 mg/kg of tPA was administered through the hepatic artery at T = 0.5 h. Two livers were split prior to perfusion (S1, S2), with tPA administered in one lobe, while the other served as a control. The remaining three whole livers (W1-W3) were compared to seven DCD control liver perfusions (C1-C7) with similar hepatocellular and biliary viability criteria. D-dimer levels were measured at T = 1 h to verify efficacy of tPA. Lactate, total bile production, bile pH, and difference in biliary injury scores before and after perfusion were compared between tPA and non-tPA groups using unpaired, Mann-Whitney tests. Results: Average weight-adjusted D-dimer levels were higher in tPA livers in the split and whole-liver model, verifying drug function. There were no differences in perfusion hepatic artery resistance, portal vein resistance, and arterial lactate between tPA livers and non-tPA livers in both the split and whole-liver model. However, when comparing biliary injury between hepatocellular and biliary non-viable whole livers, tPA livers had significantly lower PVP injury scores (0.67 vs. 2.0) and mural stroma (MS) injury scores (1.3 vs. 2.7). Conclusion: This study demonstrates that administration of tPA into DCD livers during NMP can reduce PVP and MS injury. Further studies are necessary to assess the effect of tPA administration on long term biliary complications.
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Affiliation(s)
- Omar Haque
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Siavash Raigani
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Ivy Rosales
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Cailah Carroll
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States
| | - Taylor M Coe
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Sofia Baptista
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States
| | - Heidi Yeh
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Korkut Uygun
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Francis L Delmonico
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States.,New England Donor Services (NEDS), Waltham, MA, United States
| | - James F Markmann
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
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14
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Haque OJ, Roth EM, Fleishman A, Eckhoff DE, Khwaja K. Long-Term Outcomes of Early Experience in Donation After Circulatory Death Liver Transplantation: Outcomes at 10 Years. Ann Transplant 2021; 26:e930243. [PMID: 33875633 PMCID: PMC8067669 DOI: 10.12659/aot.930243] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Donation after circulatory death (DCD) livers remain an underutilized pool of transplantable organs due to concerns of inferior long-term patient survival (PS) and graft survival (GS), which factors greatly into clinician decision-making and patient expectations. MATERIAL AND METHODS This retrospective study used SRTR data to assess 33 429 deceased-donor liver transplants (LT) and compared outcomes between DCD and donation after brain death (DBD) LT recipients in the United States. Data were collected from 2002 to 2008 to obtain 10 years of follow-up (2012-2018) in the era of MELD implementation. Propensity scores for donor type (DCD vs DBD) were estimated using logistic regression, and the association of donor type with 10-year outcomes was evaluated after adjustment using stabilized inverse probability of treatment weights. RESULTS After adjusting for confounders, patient survival for DBD recipients at 10 years was 60.7% versus 57.5% for DCD recipients (P=0.24). Incorporating retransplants, 10-year adjusted patient survival was 60.2% for DBD recipients versus 55.5% for DCD recipients (P=0.07). Adjusted 10-year graft survival for DBD recipients was 56.4% versus 45.4% for DCD recipients (P<0.001). Surprisingly, however, 1 year after LT, DBD and DCD graft failure rates converged to 7.5% over the remaining 9 years. CONCLUSIONS These data reveal inferior 10-year DCD graft survival, but only in the first year after LT, and similar 10-year patient survival in DCD LT recipients compared to DBD recipients. Our results show the stability and longevity of DCD grafts, which should encourage the increased utilization of these livers for transplantation.
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Affiliation(s)
- Omar J Haque
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Eve M Roth
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Aaron Fleishman
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Devin E Eckhoff
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Khalid Khwaja
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
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15
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Hamed MO, Barlow AD, Dolezalova N, Khosla S, Sagar A, Gribble FM, Davies S, Murphy MP, Hosgood SA, Nicholson ML, Saeb-Parsy K. Ex vivo normothermic perfusion of isolated segmental porcine bowel: a novel functional model of the small intestine. BJS Open 2021; 5:6220254. [PMID: 33839750 PMCID: PMC8038264 DOI: 10.1093/bjsopen/zrab009] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/26/2021] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND There is an unmet need for suitable ex vivo large animal models in experimental gastroenterology and intestinal transplantation. This study details a reliable and effective technique for ex vivo normothermic perfusion (EVNP) of segmental porcine small intestine. METHODS Segments of small intestine, 1.5-3.0 m in length, were retrieved from terminally anaesthetized pigs. After a period of cold ischaemia, EVNP was performed for 2 h at 37°C with a mean pressure of 80 mmHg using oxygenated autologous blood diluted with Ringer's solution. The duration of EVNP was extended to 4 h for a second set of experiments in which two segments of proximal to mid-ileum (1.5-3.0 m) were retrieved from each animal and reperfused with whole blood (control) or leucocyte-depleted blood to examine the impact of leucocyte depletion on reperfusion injury. RESULTS After a mean cold ischaemia time of 5 h and 20 min, EVNP was performed in an initial group of four pigs. In the second set of experiments, five pigs were used in each group. In all experiments bowel segments were well perfused and exhibited peristalsis during EVNP. Venous glucose levels significantly increased following luminal glucose stimulation (mean(s.e.m.) basal level 1.8(0.6) mmol/l versus peak 15.5(5.8) mmol/l; P < 0.001) and glucagon-like peptide 1 (GLP-1) levels increased in all experiments, demonstrating intact absorptive and secretory intestinal functions. There were no significant differences between control and leucocyte-depleted animals regarding blood flow, venous glucose, GLP-1 levels or histopathology at the end of 4 h of EVNP. CONCLUSIONS This novel model is suitable for the investigation of gastrointestinal physiology, pathology and ischaemia reperfusion injury, along with evaluation of potential therapeutic interventions.
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Affiliation(s)
- M O Hamed
- Correspondence to: Department of Surgery, Addenbrookes Hospital, Hills Road, Cambridge, CB2 0QQ, UK (e-mail:)
| | - A D Barlow
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Campus, Cambridge, UK
| | - N Dolezalova
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Campus, Cambridge, UK
| | - S Khosla
- Wellcome Trust – MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - A Sagar
- Wellcome Trust – MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - F M Gribble
- Department of Histopathology, University of Cambridge, Cambridge, UK
| | - S Davies
- Department of Histopathology, University of Cambridge, Cambridge, UK
| | - M P Murphy
- MRC Mitochondrial Biology Unit, Cambridge, UK
| | - S A Hosgood
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Campus, Cambridge, UK
| | - M L Nicholson
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Campus, Cambridge, UK
| | - K Saeb-Parsy
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Campus, Cambridge, UK
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16
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Ishihara Y, Bochimoto H, Kondoh D, Obara H, Matsuno N. The ultrastructural characteristics of bile canaliculus in porcine liver donated after cardiac death and machine perfusion preservation. PLoS One 2020; 15:e0233917. [PMID: 32470051 PMCID: PMC7259665 DOI: 10.1371/journal.pone.0233917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 05/14/2020] [Indexed: 12/16/2022] Open
Abstract
The effects of each type of machine perfusion preservation (MP) of liver grafts donated after cardiac death on the bile canaliculi of hepatocytes remain unclear. We analyzed the intracellular three-dimensional ultrastructure of the bile canaliculi and hepatocyte endomembrane systems in porcine liver grafts after warm ischemia followed by successive MP with modified University of Wisconsin gluconate solution. Transmission and osmium-maceration scanning electron microscopy revealed that lumen volume of the bile canaliculi decreased after warm ischemia. In liver grafts preserved by hypothermic MP condition, bile canaliculi tended to recover in terms of lumen volume, while their microvilli regressed. In contrast, midthermic MP condition preserved the functional form of the microvilli of the bile canaliculi. Machine perfusion preservation potentially restored the bile canaliculus lumen and alleviated the cessation of cellular endocrine processes due to warm ischemia. In addition, midthermic MP condition prevented the retraction of the microvilli of bile canaliculi, suggesting further mitigation of the damage of the bile canaliculi.
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Affiliation(s)
- Yo Ishihara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Bochimoto
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Japan
- Division of Aerospace Medicine, Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku, Japan
- * E-mail:
| | - Daisuke Kondoh
- Laboratory of Veterinary Anatomy, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Hiromichi Obara
- Department of Mechanical Engineering, Tokyo Metropolitan University, Hachioji, Japan
| | - Naoto Matsuno
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Japan
- Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
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17
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Zhang Z, Ju W, Tang Y, Wang L, Zhu C, Gao N, Zhao Q, Huang S, Wang D, Yang L, Han M, Xiong W, Wu L, Chen M, Zhang Y, Zhu Y, Sun C, Zhu X, Guo Z, He X. First Preliminary Experience with Preservation of Liver Grafts from Extended-Criteria Donors by Normothermic Machine Perfusion in Asia. Ann Transplant 2020; 25:e921529. [PMID: 32312947 PMCID: PMC7193227 DOI: 10.12659/aot.921529] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/24/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Normothermic machine perfusion (NMP) can provide access to evaluate and resuscitate high-risk donor livers before transplantation. The purpose of this study was to determine the efficacy of NMP in preservation and assessment of extended-criteria donor (ECD) livers in China. CASE REPORT From September 2018 to March 2019, 4 liver grafts from 3 transplant center defined as ECD were subjected to NMP, and then were transplanted successfully. During perfusion, perfusion parameters such as vascular flow, glucose level, lactate clearance, and bile production/composition were recorded to assess graft viability. All recipients were followed up 6 months after transplantation. CONCLUSIONS NMP provides a potential tool for preservation and assessment of ECD livers in China.
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Affiliation(s)
- Zhiheng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Linhe Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Caihui Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Ningxin Gao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Shanzhou Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Dongping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Lu Yang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Ming Han
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Wei Xiong
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Linwei Wu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Yixi Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Yanling Zhu
- Department of Cardiopulmonary Bypass, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Chengjun Sun
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, P.R. China
- Organ Transplant Center, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, Guangdong, P.R. China
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Grant AA, Bhakta S, Brozzi N, Talon A, Klima A, Duenas A, Galbut D, Loebe M, Ghodsizad A. DCD and DBD lung transplantation optimized by ex vivo perfusion: What to do when the pump fails. J Card Surg 2019; 35:191-194. [PMID: 31899833 DOI: 10.1111/jocs.14273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Ex vivo perfusion is a safe and feasible method of assessing and using high-risk donor organs. AIM We describe a case of successfully ex vivo treated and transplanted human lung allografts. METHODS Donor human lungs were assessed using ex vivo, our trouble shooting protocol allowed safe recovery. RESULTS We successfully implanted our ex vivo treated organs.
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Affiliation(s)
- April A Grant
- Division of Trauma and Surgical Critical Care, Department of Surgery, University of Miami School of Medicine, Miami, Florida.,Heart and Lung Transplant and Mechanical Circulatory Support, Miami Transplant Institute, Miami, Florida
| | - Shivang Bhakta
- Heart and Lung Transplant and Mechanical Circulatory Support, Miami Transplant Institute, Miami, Florida
| | - Nicholas Brozzi
- Heart and Lung Transplant and Mechanical Circulatory Support, Miami Transplant Institute, Miami, Florida.,Division Heart and Lung Transplant and Mechanical Circulatory Support, Department of Surgery, University of Miami School of Medicine, Miami, Florida
| | - Andrew Talon
- Heart and Lung Transplant and Mechanical Circulatory Support, Miami Transplant Institute, Miami, Florida
| | - Alan Klima
- Comprehensive Care Services, Inc, Livonia, Michigan
| | | | - David Galbut
- Division of Cardiothoracic Surgery, Department of Surgery, Jackson Hospital System, Miami, Florida
| | - Matthias Loebe
- Heart and Lung Transplant and Mechanical Circulatory Support, Miami Transplant Institute, Miami, Florida.,Division Heart and Lung Transplant and Mechanical Circulatory Support, Department of Surgery, University of Miami School of Medicine, Miami, Florida
| | - Ali Ghodsizad
- Heart and Lung Transplant and Mechanical Circulatory Support, Miami Transplant Institute, Miami, Florida.,Division Heart and Lung Transplant and Mechanical Circulatory Support, Department of Surgery, University of Miami School of Medicine, Miami, Florida
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19
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Linares-Cervantes I, Echeverri J, Cleland S, Kaths JM, Rosales R, Goto T, Kollmann D, Hamar M, Urbanellis P, Mazilescu L, Ganesh S, Adeyi OA, Yip P, Goryńska P, Bojko B, Goryński K, Grant DR, Selzner N, Wąsowicz M, Selzner M. Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts. Am J Transplant 2019; 19:2991-3005. [PMID: 31012532 DOI: 10.1111/ajt.15395] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 04/03/2019] [Accepted: 04/18/2019] [Indexed: 01/25/2023]
Abstract
Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart-beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30'), 70 minutes (DCD70'), and 120 minutes (DCD120') of warm ischemia were studied. The HBD, DCD30', and DCD70'-groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120'-group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120'-group (>2 mmol/L) at 4 hours of perfusion (P = .04). The fold-urea increase was significantly lower in the DCD120'-group (≤0.4) compared to the other groups (≥0.65) (P = .01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120'-group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120'-group (≤1) (P < .01). Three hours after transplantation, the DCD120'-group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P = .02). Rocuronium levels were higher at all the time-points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.
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Affiliation(s)
- Ivan Linares-Cervantes
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.,National Council for Science and Technology, Mexico City, Mexico
| | - Juan Echeverri
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada.,Doctoral Program in Surgery and Morphological Sciences, Autonomous University of Barcelona, Barcelona, Spain
| | - Stuart Cleland
- Department of Anesthesiology and Pain Management, Toronto General Hospital, Toronto, Ontario, Canada.,Department of Anaesthesia, University Hospitals, Plymouth, UK
| | - Johann Moritz Kaths
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Roizar Rosales
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Toru Goto
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Dagmar Kollmann
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada.,Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Matyas Hamar
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Peter Urbanellis
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Laura Mazilescu
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Sujani Ganesh
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Oyedele A Adeyi
- Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada
| | - Paul Yip
- Department of Clinical Biochemistry, Toronto General Hospital, Toronto, Ontario, Canada
| | - Paulina Goryńska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland
| | - Krzysztof Goryński
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland
| | - David R Grant
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Nazia Selzner
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
| | - Marcin Wąsowicz
- Department of Anesthesiology and Pain Management, Toronto General Hospital, Toronto, Ontario, Canada
| | - Markus Selzner
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada
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20
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Bral M, Aboelnazar N, Hatami S, Thiesen A, Bigam DL, Freed DH, Shapiro AMJ. Clearance of transaminases during normothermic ex situ liver perfusion. PLoS One 2019; 14:e0215619. [PMID: 31017974 PMCID: PMC6481840 DOI: 10.1371/journal.pone.0215619] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 04/04/2019] [Indexed: 01/02/2023] Open
Abstract
Background One of the most promising applications of liver normothermic machine perfusion (NMP) is the potential to directly assess graft viability and injury. In most NMP studies, perfusate transaminases are utilized as markers of graft injury. Our aim was to further elucidate the metabolism of transaminases by healthy porcine livers during NMP, specifically whether such livers could clear circuit perfusate transaminases. Methods A highly concentrated transaminase solution was prepared from homogenized liver, with an aspartate aminotransferase (AST) level of 107,427 U/L. Three livers in the treatment group were compared to three controls, during 48 hours of NMP. In the treatment group, the circuit perfusate was injected with the transaminase solution to artificially raise the AST level to a target of 7,500 U/L. Perfusate samples were taken at two-hour intervals and analyzed for biochemistry until NMP end. Graft oxygen consumption and vascular parameters were monitored. Results Compared to controls, treated perfusions demonstrated abrupt elevations in transaminase levels (p>0.0001) and lactate dehydrogenase (LDH) (p>0.0001), which decreased over time, but never to control baseline. Liver function, as demonstrated by lactate clearance and oxygen consumption was not different between groups. The treatment group demonstrated a higher portal vein resistance (p = 0.0003), however hepatic artery resistance was similar. Treated livers had higher bile production overall (p<0.0001). Conclusions Addition of high levels of transaminases and LDH to a healthy porcine liver during ex situ perfusion results in progressive clearance of these enzymes, suggesting preserved liver metabolism. Such tolerance tests may provide valuable indicators of prospective graft function.
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Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | | - Sanaz Hatami
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Aducio Thiesen
- Department of Pathology, University of Alberta, Edmonton, Canada
| | - David L. Bigam
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Darren H. Freed
- Department of Surgery, University of Alberta, Edmonton, Canada
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21
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Tchilikidi KY. Liver graft preservation methods during cold ischemia phase and normothermic machine perfusion. World J Gastrointest Surg 2019; 11:126-142. [PMID: 31057698 PMCID: PMC6478595 DOI: 10.4240/wjgs.v11.i3.126] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/21/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023] Open
Abstract
The growing demand for donor organs requires measures to expand donor pool. Those include extended criteria donors, such as elderly people, steatotic livers, donation after cardiac death, etc. Static cold storage to reduce metabolic requirements developed by Collins in late 1960s is the mainstay and the golden standard for donated organ protection. Hypothermic machine perfusion provides dynamic organ preservation at 4°C with protracted infusion of metabolic substrates to the graft during the ex vivo period. It has been used instead of static cold storage or after it as short perfusion in transplant center. Normothermic machine perfusion (NMP) delivers oxygen, and nutrition at physiological temperature mimicking regular environment in order to support cellular function. This would minimize effects of ischemia/reperfusion injury. Potentially, NMP may help to estimate graft functionality before implantation into a recipient. Clinical studies demonstrated at least its non-inferiority or better outcomes vs static cold storage. Regular grafts donated after brain death could be safely preserved with convenient static cold storage. Except for prolonged ischemia time where hypothermic machine perfusion started in transplant center could be estimated to provide possible positive reconditioning effect. Use of hypothermic machine perfusion in regular donation instead of static cold storage or in extended criteria donors requires further investigation. Multicenter randomized clinical trial supposed to be completed in December 2021. Extended criteria donors need additional measures for graft storage and assessment until its implantation. NMP is actively evaluating promising method for this purpose. Future studies are necessary for precise estimation and confirmation to issue clinical practice recommendations.
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22
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Bral M, Gala-Lopez B, Thiesen A, Hatami S, Bigam DL, Freed DM, James Shapiro AM. Determination of Minimal Hemoglobin Level Necessary for Normothermic Porcine Ex Situ Liver Perfusion. Transplantation 2019; 102:1284-1292. [PMID: 29757899 DOI: 10.1097/tp.0000000000002272] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND In current studies of ex situ liver perfusion there exists considerable variability in perfusate composition, including the type of oxygen carrier. Herein, we aim to clarify the minimal hemoglobin level necessary during normothermic porcine ex situ liver perfusion. METHODS Livers procured from 35 to 45 kg domestic pigs were connected to our experimental ex situ circuit (n = 10). In the treatment group, perfusate was sequentially diluted hourly to predetermined hemoglobin levels. At the end of each hemoglobin dilution, perfusate samples were analyzed for liver transaminases, lactate dehydrogenase (LD), total bilirubin, and lactate levels. Liver oxygen consumption was measured. In the control group, livers were perfused continually for a duration of 24 hours at target hemoglobin levels of 30 and 20 g/L. RESULTS Rising liver transaminases, significantly higher lactate (P < 0.001), and LD levels (P < 0.001) were noted at lower perfusate hemoglobin levels in the treatment group. Liver oxygen utilization (P < 0.001) and hepatic artery oxygen delivery (P < 0.001) were significantly lower at lower hemoglobin levels, whereas liver vessel resistance remained relatively constant. Histology demonstrated increasing parenchymal damage at lower hemoglobin levels. In control livers, higher perfusate transaminases, higher lactate, and LD levels were noted at a perfusion hemoglobin level of 20 g/L. CONCLUSIONS Ex situ liver function decompensated during perfusion between a mean hemoglobin level of 30 to 20 g/L, as evidenced by notably rising lactate and LD levels. This study demonstrates optimal hemoglobin concentration during normothermic ex situ liver perfusion to ensure a fully metabolically functioning graft.
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Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - Boris Gala-Lopez
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - Aducio Thiesen
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Sanaz Hatami
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - David L Bigam
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Darren M Freed
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, Canada.,Members of the Canadian National Transplant Research Project (CNTRP)
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23
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Impact of Different Clinical Perfusates During Normothermic Ex Situ Liver Perfusion on Pig Liver Transplant Outcomes in a DCD Model. Transplant Direct 2019; 5:e437. [PMID: 30993191 PMCID: PMC6445654 DOI: 10.1097/txd.0000000000000876] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 01/09/2019] [Indexed: 11/26/2022] Open
Abstract
Supplemental digital content is available in the text. Background Human albumin/dextran (HA-D), bovine-gelatin (BG), and packed red blood cells plus plasma have been used in European and North-American clinical trials of normothermic ex situ liver perfusion (NEsLP). We compared the effects of these perfusates in a porcine model during NEsLP and after transplantation. Methods Porcine livers were retrieved 30 minutes after circulatory death. After 5 hours of NEsLP, grafts were transplanted. Three groups (n = 6) were assessed (HA-D vs BG vs whole blood [WB]). One group of static cold storage (SCS) was evaluated for comparison with the perfusion groups. Hemodynamic variables, liver and endothelial injury, and function were assessed during NEsLP and posttransplantation. Results Hepatic artery flow was higher since the beginning of NEsLP in the HA-D group (HA-D, 238 ± 90 mL/min vs BG, 97 ± 33 mL/min vs WB, 148 ± 49 mL/min; P = 0.01). Hyaluronic acid was lower in the HA-D at the end of perfusion (HA-D, 16.28 ± 7.59 ng/μL vs BG, 76.05 ± 15.30 ng/μL vs WB, 114 ± 46 ng/μL; P < 0.001). After transplant, aspartate aminotransferase was decreased in the HA-D group when compared with the rest of the groups (HA-D, 444 ± 226 IU/L vs BG, 1033 ± 694 IU/L vs WB, 616 ± 444 IU/L vs SCS, 2235 ± 1878 IU/L). At 5 hours after transplant, lactate was lower in the HA-D group (HA-D, 3.88 ± 1.49 mmol/L vs BG, 7.79 ± 2.68 mmol/L vs WB, 8.16 ± 3.86 mmol/L vs SCS, 9.06 ± 3.54 mmol/L; P = 0.04). International Normalized Ratio was improved in HA-D group compared to the rest of the groups (HA-D, 1.23 ± 0.30 vs BG, 1.63 ± 0.20 vs WB, 1.50 ± 0.31 vs SCS, 1.97 ± 1.55; P = 0.03) after transplantation. In contrast, BG displayed lower aspartate aminotransferase levels during NEsLP (HA-D, 183 ± 53 IU/L vs BG, 142 ± 52 IU/L vs WB, 285 ± 74 IU/L; P = 0.01) and less cleaved-caspase-3 staining (HA-D, 2.05 ± 0.73% vs BG, 0.95 ± 1.14% vs WB, 1.74 ± 0.54% vs SCS, 7.95 ± 2.38%) compared with the other groups. On the other hand, the bile from the WB showed higher pH (HA-D, 7.54 ± 0.11 vs BG, 7.34 ± 0.37 vs WB, 7.59 ± 0.18) and lower glucose levels (HA-D, 0.38 ± 0.75 mmol/L vs BG, 1.42 ± 1.75 mmol/L vs WB, 0 ± 0 mmol/L) by the end of perfusion. Conclusions Overall HA-D displayed more physiologic conditions during NEsLP that were reflected in less graft injury and improved liver function and survival after transplantation. Optimization of the perfusates based on the beneficial effects found with these different solutions would potentially improve further the outcomes through the use of NEsLP in marginal grafts.
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24
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Nassar A, Liu Q, Walsh M, Quintini C. Normothermic Ex Vivo Perfusion of Discarded Human Pancreas. Artif Organs 2019. [PMID: 29516579 DOI: 10.1111/aor.12985] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Ahmed Nassar
- Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA
| | - Qiang Liu
- Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA
| | - Matthew Walsh
- Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA
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25
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Porcine Isolated Liver Perfusion for the Study of Ischemia Reperfusion Injury: A Systematic Review. Transplantation 2019; 102:1039-1049. [PMID: 29509572 DOI: 10.1097/tp.0000000000002156] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Understanding ischemia reperfusion injury (IRI) is essential to further improve outcomes after liver transplantation (LT). Porcine isolated liver perfusion (ILP) is increasingly used to reproduce LT-associated IRI in a strictly controlled environment. However, whether ILP is a reliable substitute of LT was never validated. METHODS We systematically reviewed the current experimental setups for ILP and parameters of interest reflecting IRI. RESULTS Isolated liver perfusion was never compared with transplantation in animals. Considerable variability exists between setups, and comparative data are unavailable. Experience so far suggests that centrifugal pump(s) with continuous flow are preferred to reduce the risk of embolism. Hepatic outflow can be established by cannulation of the inferior vena cava or freely drained in an open bath. Whole blood at approximately 38°C, hematocrit of 20% or greater, and the presence of leukocytes to trigger inflammation is considered the optimal perfusate. A number of parameters related to the 4 liver compartments (hepatocyte, cholangiocyte, endothelium, immune cells) are available; however, their significance and relation to clinical outcomes is not well described. CONCLUSIONS Porcine ILP provides a reproducible model to study early IRI events. As all models, it has its limitations. A standardization of the setup would allow comparison of data and progress in the field.
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Comparison of BQ123, Epoprostenol, and Verapamil as Vasodilators During Normothermic Ex Vivo Liver Machine Perfusion. Transplantation 2018; 102:601-608. [PMID: 29189484 DOI: 10.1097/tp.0000000000002021] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The optimal vasodilator to avoid hepatic artery vasospasm during normothermic ex vivo liver perfusion (NEVLP) is yet to be determined. We compared safety and efficacy of BQ123 (endothelin1 antagonist), epoprostenol (prostacyclin analogue), and verapamil (calcium channel antagonist). METHODS Livers from porcine heart beating donors were perfused for 3 hours and transplanted into recipient pigs. Four groups were compared: group 1, livers perfused with a dose of 1.25 mg of BQ123 at baseline and at 2 hours of perfusion; group 2, epoprostenol at a continuous infusion of 4 mg/h; group 3, verapamil 2.5 mg at baseline and at 2 hours of perfusion; group 4, no vasodilator used during ex vivo perfusion. Liver injury and function were assessed during perfusion, and daily posttransplantation until postoperative day (POD) 3. All groups were compared with a cold storage group for postoperative graft function. RESULTS Hepatic artery flow during NEVLP was significantly higher in BQ123 compared with verapamil, epoprostenol, and no vasodilator-treated livers. Aspartate aminotransferase levels were significantly lower with BQ123 and verapamil compared with epoprostenol and control group during perfusion. Peak aspartate aminotransferase levels were lower in pigs receiving BQ123 and verapamil perfused grafts compared with epoprostenol and control group. International Normalized Ratio, alkaline phosphatase, and total bilirubin levels were lower in the BQ123 and verapamil groups compared to epoprostenol group. Cold storage group had increased markers of ischemia reperfusion injury and slower graft function recovery compared to machine perfused grafts. CONCLUSION The use of BQ123, epoprostenol, and verapamil during NEVLP is safe. Livers perfused with BQ123 and verapamil have higher hepatic artery flow and reduced hepatocyte injury during perfusion compared with epoprostenol. Hepatic artery flow is significantly reduced in the absence of vasodilators during NEVLP.
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27
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Jayant K, Reccia I, Shapiro AMJ. Normothermic ex-vivo liver perfusion: where do we stand and where to reach? Expert Rev Gastroenterol Hepatol 2018; 12:1045-1058. [PMID: 30064278 DOI: 10.1080/17474124.2018.1505499] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nowadays liver transplantation is considered as the treatment of choice, however, the scarcity of suitable donor organs limits the delivery of care to the end-stage liver disease patients leading to the death while on the waiting list. The advent of ex-situ normothermic machine perfusion (NMP) has emerged as an alternative to the standard organ preservation technique, static cold storage (SCS). The newer technique promises to not only restore the normal metabolic activity but also attempt to recondition the marginal livers back to the pristine state, which are otherwise more susceptible to ischemic injury and foster the poor post-transplant outcomes. Areas covered: An extensive search of all the published literature describing the role of NMP based device in liver transplantation as an alternative to SCS was made on MEDLINE, EMBASE, Cochrane, BIOSIS, Crossref, Scopus databases and clinical trial registry on 10 May 2018. Expert commentary: The main tenet of NMP is the establishment of the physiological milieu, which permits aerobic metabolism to continue through out the period of preservation and limits the effects of ischemia-reperfusion (I/R) injury. In addition, by assessing the various metabolic and synthetic parameters the viability and suitability of donor livers for transplantation can be determined. This important technological advancement has scored satisfactorily on the safety and efficacy parameters in preliminary clinical studies. The present review suggests that NMP can offer the opportunity to assess and safely utilize the marginal donor livers if deemed appropriate for the transplantation. However, ongoing trials will determine its full potential and further adoption.
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Affiliation(s)
- Kumar Jayant
- a Department of Surgery and Cancer , Imperial College London , London , UK
| | - Isabella Reccia
- a Department of Surgery and Cancer , Imperial College London , London , UK
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Kim J, Zimmerman M, Hong J. Emerging Innovations in Liver Preservation and Resuscitation. Transplant Proc 2018; 50:2308-2316. [DOI: 10.1016/j.transproceed.2018.03.080] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 03/02/2018] [Indexed: 12/18/2022]
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Akateh C, Beal EW, Whitson BA, Black SM. Normothermic Ex-vivo Liver Perfusion and the Clinical Implications for Liver Transplantation. J Clin Transl Hepatol 2018; 6:276-282. [PMID: 30271739 PMCID: PMC6160298 DOI: 10.14218/jcth.2017.00048] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 02/07/2018] [Accepted: 03/01/2018] [Indexed: 12/13/2022] Open
Abstract
Despite significant improvements in outcomes after liver transplantation, many patients continue to die on the waiting list, while awaiting an available organ for transplantation. Organ shortage is not only due to an inadequate number of available organs, but also the inability to adequately assess and evaluate these organs prior to transplantation. Over the last few decades, ex-vivo perfusion of the liver has emerged as a useful technique for both improved organ preservation and assessment of organs prior to transplantation. Large animal studies have shown the superiority of ex-vivo perfusion over cold static storage. However, these studies have not, necessarily, been translatable to human livers. Small animal studies have been essential in understanding and improving this technology. Similarly, these results have yet to be translated into clinical use. A few Phase 1 clinical trials have shown promise and confirmed the viability of this technology. However, more robust studies are needed before ex-vivo liver perfusion can be widely accepted as the new clinical standard of organ preservation. Here, we aimed to review all relevant large and small animal research, as well as human liver studies on normothermic ex-vivo perfusion, and to identify areas of deficiency and opportunities for future research endeavors.
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Affiliation(s)
- Clifford Akateh
- General and Gastrointestinal Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- *Correspondence to: Clifford Akateh, General and Gastrointestinal Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, 395 W 12th Ave, Room 654, Columbus, OH-43210-1267, USA. Tel: +1-614-293-8704, Fax: +1-614-293-4063, E-mail:
| | - Eliza W. Beal
- General and Gastrointestinal Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Bryan A. Whitson
- Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sylvester M. Black
- Division of Transplant Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Optimizing Livers for Transplantation Using Machine Perfusion versus Cold Storage in Large Animal Studies and Human Studies: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9180757. [PMID: 30255101 PMCID: PMC6145150 DOI: 10.1155/2018/9180757] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/01/2018] [Accepted: 08/16/2018] [Indexed: 12/25/2022]
Abstract
Background Liver allograft preservation frequently involves static cold storage (CS) and machine perfusion (MP). With its increasing popularity, we investigated whether MP was superior to CS in terms of beneficial outcomes. Methods Human studies and large animal studies that optimized livers for transplantation using MP versus CS were assessed (PubMed/Medline/EMBASE). Meta-analyses were conducted for comparisons. Study quality was assessed according to the Newcastle-Ottawa quality assessment scale and SYRCLE's risk of bias tool. Results Nineteen studies were included. Among the large animal studies, lower levels of lactate dehydrogenase (SMD -3.16, 95% CI -5.14 to -1.18), alanine transferase (SMD -2.46, 95% CI -4.03 to -0.90), and hyaluronic acid (SMD -2.48, 95% CI -4.21 to -0.74) were observed in SNMP-preserved compared to CS-preserved livers. NMP-preserved livers showing lower level of hyaluronic acid (SMD -3.97, 95% CI -5.46 to -2.47) compared to CS-preserved livers. Biliary complications (RR 0.45, 95% CI 0.28 to 0.73) and early graft dysfunction (RR 0.56, 95% CI 0.34 to 0.92) also significantly reduced with HMP preservation in human studies. No evidence of publication bias was found. Conclusions MP preservation could improve short-term outcomes after transplantation compared to CS preservation. Additional randomized controlled trials (RCTs) are needed to develop clinical applications of MP preservation.
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Gullón L, Gutiérrez-Gutiérrez J, Sánchez del Arco RT, Rivera A, Fernández I, Del Cañizo JF. Development of an automated liver perfusion system: The benefit of a hemofilter. Int J Artif Organs 2018; 41:723-729. [DOI: 10.1177/0391398818783851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Introduction: Liver perfusion machines are close to becoming a reality in the transplantation field. However, depending on the techniques used and the goals pursued, their application is limited in the research field. Here, we present the entire development of a perfusion system with self-made engineering, completely autonomous controls, and a high degree of versatility that allows the design of different studies on liver functionality. Methods: A user-friendly interface permits real-time monitoring and remote control by the devices within the circuit. Centrifugal pumps allow the perfusate enter the organ with controlled pressures and flows at both hepatic artery and portal vein. The implementation of a hemofilter as a novel tool permits to control and maintain homeostasis. Peristaltic pumps adjust pH, extraction rate, and total volume by means of sensors. Results: Real-time monitoring facilitates liver functionality assessment. The controlled system shows rapid stabilization and quick responses to changes during 6 h of perfusion experiments. Furthermore, the integration of a hemofilter helps the system to eliminate toxic waste and maintain homeostasis. Discussion: The machine provides the basis of a perfusion system with autonomous controls and the implementation of a hemofilter that enables a more efficient control of hemostasis. Moreover, the developed hardware and software are subjected to further tuning for additional purposes such as pathophysiologic studies, suboptimal grafts recovery, or recellularization of decellularized scaffolds among others.
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Affiliation(s)
- Lucía Gullón
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - Judit Gutiérrez-Gutiérrez
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Fundación para la Investigación Biomédica del Hospital Gregorio Marañón (FIBHGM), Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Robert T Sánchez del Arco
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Fundación para la Investigación Biomédica del Hospital Gregorio Marañón (FIBHGM), Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Andrés Rivera
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Ignacio Fernández
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Juan F Del Cañizo
- Laboratorio de Circulación Artificial (LCA), Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Fundación para la Investigación Biomédica del Hospital Gregorio Marañón (FIBHGM), Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Pabellón de Medicina y Cirugía Experimental, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
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Kumar R, Chung WY, Runau F, Isherwood JD, Kuan KG, West K, Garcea G, Dennison AR. Ex vivo normothermic porcine pancreas: A physiological model for preservation and transplant study. Int J Surg 2018; 54:206-215. [PMID: 29730077 DOI: 10.1016/j.ijsu.2018.04.057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 04/04/2018] [Accepted: 04/29/2018] [Indexed: 10/17/2022]
Abstract
INTRODUCTION An ex vivo normothermic porcine pancreas perfusion (ENPPP) model was established to investigate effects of machine perfusion pressures on graft preservation. METHODOLOGY Nine porcine pancreata were perfused with autologous blood at 50 mmHg (control) pressure. Graft viability was compared against four ex-vivo porcine pancreata perfused at 20 mmHg ('low') pressure. Arterio-venous oxygen gas differentials, biochemistry, and graft insulin responses to glucose stimulation were compared. Immunohistochemistry stains compared the cellular viability. RESULTS Control pancreata were perfused for a median of 3 h (range 2-4 h) with a mean pressure 50 mmHg and graft flow 141 mL min-1. In comparison, all of the 'low' pressure models were perfused for 4 h, with mean perfusion pressure 20 mmHg and graft flow 40 mL.min-1. All pancreata demonstrated cellular viability with evidence of oxygen consumption with preserved endocrine and exocrine function. However, following statistical analysis, the 'low' pressure perfusion of porcine pancreata compared favourably in important biochemical and immunohistochemistry cellular profiles; potentially arguing for an improved method for graft preservation. CONCLUSION ENPPP will facilitate whole organ preservation to be studied in further detail and avoids use of expensive live animals. ENPPP is reproducible and mimics a "donation after circulatory death" scenario.
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Affiliation(s)
- Rohan Kumar
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom.
| | - Wen Yuan Chung
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom
| | - Franscois Runau
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom
| | - John David Isherwood
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom
| | - Kean Guan Kuan
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom
| | - Kevin West
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom
| | - Giuseppe Garcea
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom
| | - Ashley Robert Dennison
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, LE5 4PW, United Kingdom
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Normothermic Ex Vivo Machine Perfusion for Liver Grafts Recovered from Donors after Circulatory Death: A Systematic Review and Meta-Analysis. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2018; 2018:6867986. [PMID: 29849531 PMCID: PMC5937385 DOI: 10.1155/2018/6867986] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 03/15/2018] [Indexed: 12/20/2022]
Abstract
As a result of donation after circulatory death liver grafts' poor tolerance to cold storage, there has been increasing research interest in normothermic machine perfusion. This study aims to systematically review the current literature comparing normothermic perfusion to cold storage in donation after circulatory death liver grafts and complete a meta-analysis of published large animal and human studies. A total of nine porcine studies comparing cold storage to normothermic machine perfusion for donation after circulatory death grafts were included for analysis. There was a significant reduction in AST (mean difference −2291 U/L, CI (−3019, −1563); P ≤ 0.00001) and ALT (mean difference −175 U/L, CI (−266, −85); P = 0.0001), for normothermic perfusion relative to static cold storage, with moderate (I2 = 61%) and high (I2 = 96%) heterogeneity, respectively. Total bile production was also significantly higher (mean difference = 174 ml, CI (155, 193); P ≤ 0.00001). Further research focusing on standardization, performance of this technology following periods of cold storage, economic implications, and clinical trial data focused on donation after circulatory death grafts will be helpful to advance this technology toward routine clinical utilization for these grafts.
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Ceresa CDL, Nasralla D, Jassem W. Normothermic Machine Preservation of the Liver: State of the Art. CURRENT TRANSPLANTATION REPORTS 2018; 5:104-110. [PMID: 29564207 PMCID: PMC5843699 DOI: 10.1007/s40472-018-0186-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Purpose of Review This review aims to introduce the concept of normothermic machine perfusion (NMP) and its role in liver transplantation. By discussing results from recent clinical studies and highlighting the potential opportunities provided by this technology, we aim to provide a greater insight into NMP and the role it can play to enhance liver transplantation. Recent Findings NMP has recently been shown to be both safe and feasible in liver transplantation and has also demonstrated its superiority to traditional cold storage in terms of early biochemical liver function. Through the ability to perform a viability assessment during preservation and extend preservation times, it is likely that an increase in organ utilisation will follow. NMP may facilitate the enhanced preservation with improved outcomes from donors after cardiac death and steatotic livers. Furthermore, it provides the exciting potential for liver-directed therapeutic interventions. Summary Evidence to date suggests that NMP facilitates the enhanced preservation of liver grafts with improved early post-transplant outcomes. The key role for this technology is to increase the number and quality of liver grafts available for transplantation and to reduce waiting list deaths.
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Affiliation(s)
- Carlo D L Ceresa
- 1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - David Nasralla
- 1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Wayel Jassem
- 2Institute of Liver Studies, King's College Hospital, London, UK
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Ceresa CDL, Nasralla D, Coussios CC, Friend PJ. The case for normothermic machine perfusion in liver transplantation. Liver Transpl 2018; 24:269-275. [PMID: 29272051 DOI: 10.1002/lt.25000] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 12/19/2017] [Indexed: 12/22/2022]
Abstract
In recent years, there has been growing interest in normothermic machine perfusion (NMP) as a preservation method in liver transplantation. In most countries, because of a donor organ shortage, an unacceptable number of patients die while awaiting transplantation. In an attempt to increase the number of donor organs available, transplant teams are implanting a greater number of high-risk livers, including those from donation after circulatory death, older donors, and donors with steatosis. NMP maintains the liver ex vivo on a circuit by providing oxygen and nutrition at 37°C. This permits extended preservation times, the ability to perform liver viability assessment, and the potential for liver-directed therapeutic interventions during preservation. It is hoped that this technology may facilitate the enhanced preservation of marginal livers with improved posttransplant outcomes by reducing ischemia/reperfusion injury. Clinical trials have demonstrated its short-term superiority over cold storage in terms of early biochemical liver function, and it is anticipated that it may result in increased organ utilization, helping to reduce the number of wait-list deaths. However, further studies are required to demonstrate longer-term efficacy and the impact on biliary complications as well as further knowledge to exploit and maximize the potential of this exciting new technology. Liver Transplantation 24 269-275 2018 AASLD.
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Affiliation(s)
- Carlo D L Ceresa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - David Nasralla
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | | | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Liu Q, Nassar A, Buccini L, Iuppa G, Soliman B, Pezzati D, Hassan A, Blum M, Baldwin W, Bennett A, Chavin K, Okamoto T, Uso TD, Fung J, Abu-Elmagd K, Miller C, Quintini C. Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 hours of normothermic machine perfusion. Liver Transpl 2018; 24:233-245. [PMID: 29125712 DOI: 10.1002/lt.24972] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/18/2017] [Accepted: 11/05/2017] [Indexed: 02/07/2023]
Abstract
Normothermic machine perfusion (NMP) is an emerging technology to preserve liver allografts more effectively than cold storage (CS). However, little is known about the effect of NMP on steatosis and the markers indicative of hepatic quality during NMP. To address these points, we perfused 10 discarded human livers with oxygenated NMP for 24 hours after 4-6 hours of CS. All livers had a variable degree of steatosis at baseline. The perfusate consisted of packed red blood cells and fresh frozen plasma. Perfusate analysis showed an increase in triglyceride levels from the 1st hour (median, 127 mg/dL; interquartile range [IQR], 95-149 mg/dL) to 24th hour of perfusion (median, 203 mg/dL; IQR, 171-304 mg/dL; P = 0.004), but tissue steatosis did not decrease. Five livers produced a significant amount of bile (≥5 mL/hour) consistently throughout 24 hours of NMP. Lactate in the perfusate cleared to <3 mmol/L in most livers within 4-8 hours of NMP, which was independent of bile production rate. This is the first study to characterize the lipid profile and functional assessment of discarded human livers at 24 hours of NMP. Liver Transplantation 24 233-245 2018 AASLD.
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Affiliation(s)
- Qiang Liu
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Ahmed Nassar
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Laura Buccini
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | - Basem Soliman
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | - Ahmed Hassan
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Matthew Blum
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | - Ana Bennett
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | - Kenneth Chavin
- University Hospital, Case Western Reserve University, Cleveland, OH
| | | | | | - John Fung
- Transplantation Center, Cleveland Clinic, Cleveland, OH
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Watson CJE, Jochmans I. From "Gut Feeling" to Objectivity: Machine Preservation of the Liver as a Tool to Assess Organ Viability. CURRENT TRANSPLANTATION REPORTS 2018; 5:72-81. [PMID: 29564205 PMCID: PMC5843692 DOI: 10.1007/s40472-018-0178-9] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Purpose of Review The purpose of this review was to summarise how machine perfusion could contribute to viability assessment of donor livers. Recent Findings In both hypothermic and normothermic machine perfusion, perfusate transaminase measurement has allowed pretransplant assessment of hepatocellular damage. Hypothermic perfusion permits transplantation of marginal grafts but as yet has not permitted formal viability assessment. Livers undergoing normothermic perfusion have been investigated using parameters similar to those used to evaluate the liver in vivo. Lactate clearance, glucose evolution and pH regulation during normothermic perfusion seem promising measures of viability. In addition, bile chemistry might inform on cholangiocyte viability and the likelihood of post-transplant cholangiopathy. Summary While the use of machine perfusion technology has the potential to reduce and even remove uncertainty regarding liver graft viability, analysis of large datasets, such as those derived from large multicenter trials of machine perfusion, are needed to provide sufficient information to enable viability parameters to be defined and validated .
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Affiliation(s)
- Christopher J E Watson
- 1Department of Surgery, University of Cambridge School of Clinical Medicine, Cambridge, UK.,2The National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), Cambridge, UK
| | - Ina Jochmans
- 3Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.,4Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
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He X, Ji F, Zhang Z, Tang Y, Yang L, Huang S, Li W, Su Q, Xiong W, Zhu Z, Wang L, Lv L, Yao J, Zhang L, Zhang L, Guo Z. Combined liver-kidney perfusion enhances protective effects of normothermic perfusion on liver grafts from donation after cardiac death. Liver Transpl 2018; 24:67-79. [PMID: 29024427 DOI: 10.1002/lt.24954] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 09/18/2017] [Accepted: 09/26/2017] [Indexed: 12/31/2022]
Abstract
It has been shown that combined liver-kidney normothermic machine perfusion (NMP) is able to better maintain the circuit's biochemical milieu. Nevertheless, whether the combined perfusion is superior to liver perfusion alone in protecting livers from donation after circulatory death (DCD) is unclear. We aimed to test the hypothesis and explored the mechanisms. Livers from 15 DCD pig donors were subjected to either static cold storage (group A), liver-alone NMP (group B), or combined liver-kidney NMP (group C). Livers were preserved for 6 hours and reperfused ex vivo for 2 hours to simulate transplantation or were transplanted in situ. During perfusion, group C showed an improved acid-base and biochemical environment in the circuit over group B. After reperfusion, the architecture of the liver grafts was best preserved in group C, followed by group B, then group A, as shown by the histology and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining of both hepatocytes and biliary epithelium. Ki-67 staining showed substantial hepatocyte proliferation and biliary epithelial regeneration after perfusion in group B and group C. Group C produced more bile in the reperfusion phase than those in group A and group B, with more physiological bile composition and less severe biliary epithelium injury. Von Willebrand factor-positive endothelial cells and E-selectin expression decreased in both group B and group C. Combined liver-kidney NMP not only produced more adenosine triphosphate, protected the nitric oxide signaling pathway, but also diminished oxidative stress (high mobility group box-1 protein and 8-hydroxy-2-deoxy guanosine levels) and inflammatory cytokine (IL6 and IL8) release when compared with liver-alone NMP and CS. In addition, the 7-day survival rate of liver transplant recipients was higher in group C than that in groups A and B. In conclusion, combined liver-kidney NMP can better protect DCD livers from warm ischemia and reperfusion injury probably by maintaining the stability of the internal environment and by abolishing oxidative stress injury. Liver Transplantation 24 67-79 2018 AASLD.
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Affiliation(s)
- Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Fei Ji
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiheng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Lu Yang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shanzhou Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Wenwen Li
- Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiao Su
- Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Xiong
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zebin Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Linhe Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Lei Lv
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jiyou Yao
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Linan Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Longjuan Zhang
- Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
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Avruch JH, Bruinsma BG, Weeder PD, Sridharan GV, Porte RJ, Yeh H, Markmann JF, Uygun K. A novel model for ex situ reperfusion of the human liver following subnormothermic machine perfusion. TECHNOLOGY 2017; 5:196-200. [PMID: 31106253 PMCID: PMC6524532 DOI: 10.1142/s2339547817500108] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Machine perfusion-based organ preservation techniques are prudently transitioning into clinical practice. Although experimental data is compelling, the outcomes in the highly variable clinical donation-transplantation setting are unpredictable. Here, we offer an intermediate tool for pre-clinical assessment of human donor livers. We present a model for ex situ reperfusion of discarded human livers and report on its application in three human livers that have undergone subnormothermic (21°C) machine perfusion as an experimental preservation method. During reperfusion, the livers macroscopically reperfused in the first 15 minutes, and remained visually well-perfused for 3 hours of ex situ reperfusion. Bile production and oxygen consumption were observed throughout ex situ reperfusion. ATP levels increased 4.25-fold during SNMP. Between the end of SNMP and the end of reperfusion ATP levels dropped 45%. ALT levels in blood increased rapidly in the first 30 minutes and ALT release continued to taper off towards the end of perfusion. Release of CRP, TNF-α, IL-1β, and IL-12, IFN-γ was sustained during reperfusion. These findings support the use of this model for the evaluation of novel human liver preservation techniques.
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Affiliation(s)
- James H Avruch
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Bote G Bruinsma
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Pepijn D Weeder
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gautham V Sridharan
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Heidi Yeh
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - James F Markmann
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Korkut Uygun
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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42
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Cold storage or normothermic perfusion for liver transplantation: probable application and indications. Curr Opin Organ Transplant 2017; 22:300-305. [PMID: 28301388 DOI: 10.1097/mot.0000000000000410] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Preservation of the liver via normothermic machine perfusion (NMP) is rapidly becoming an area of great academic and clinical interest. This review focuses on the benefits and limitations of NMP and where the role for static cold storage may lie. RECENT FINDINGS Clinical studies have recently been published reporting the use of NMP in liver preservation for transplantation. They have described the technology to be well tolerated and feasible with potentially improved posttransplant outcomes. NMP facilitates extended preservation times as well as the potential to increase organ utilization through viability assessment and regeneration. However, this technology is considerably more costly than cold storage and carries significant logistical challenges. Cold storage remains the gold standard preservation for standard criteria livers with good long-term patient and graft survival. SUMMARY NMP is an exciting new technological advancement in liver preservation, which is likely to have a positive impact in liver transplantation. However, randomized controlled trials are required to justify its inclusion into standard practice and provide evidence to support its efficacy.
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Bochimoto H, Matsuno N, Ishihara Y, Shonaka T, Koga D, Hira Y, Nishikawa Y, Furukawa H, Watanabe T. The ultrastructural characteristics of porcine hepatocytes donated after cardiac death and preserved with warm machine perfusion preservation. PLoS One 2017; 12:e0186352. [PMID: 29023512 PMCID: PMC5638504 DOI: 10.1371/journal.pone.0186352] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 10/01/2017] [Indexed: 12/15/2022] Open
Abstract
The effects of warm machine perfusion preservation of liver grafts donated after cardiac death on the intracellular three-dimensional ultrastructure of the organelles in hepatocytes remain unclear. Here we analyzed comparatively the ultrastructure of the endomembrane systems in porcine hepatocytes under warm ischemia and successive hypothermic and midthermic machine perfusion preservation, a type of the warm machine perfusion. Porcine liver grafts which had a warm ischemia time of 60 minutes were perfused for 4 hours with modified University of Wisconsin gluconate solution. Group A grafts were preserved with hypothermic machine perfusion preservation at 8°C constantly for 4 hours. Group B grafts were preserved with rewarming up to 22°C by warm machine perfusion preservation for 4 hours. An analysis of hepatocytes after 60 minutes of warm ischemia by scanning electron microscope revealed the appearance of abnormal vacuoles and invagination of mitochondria. In the hepatocytes preserved by subsequent hypothermic machine perfusion preservation, strongly swollen mitochondria were observed. In contrast, the warm machine perfusion preservation could preserve the functional appearance of mitochondria in hepatocytes. Furthermore, abundant vacuoles and membranous structures sequestrating cellular organelles like autophagic vacuoles were frequently observed in hepatocytes after warm machine perfusion preservation. In conclusion, the ultrastructure of the endomembrane systems in the hepatocytes of liver grafts changed in accordance with the temperature conditions of machine perfusion preservation. In addition, temperature condition of the machine perfusion preservation may also affect the condition of the hepatic graft attributed to autophagy systems, and consequently alleviate the damage of the hepatocytes.
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Affiliation(s)
- Hiroki Bochimoto
- Health Care Administration Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Naoto Matsuno
- Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
- * E-mail:
| | - Yo Ishihara
- Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Tatsuya Shonaka
- Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Daisuke Koga
- Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Yoshiki Hira
- Area of Functional Anatomy, Department of Nursing, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Yuji Nishikawa
- Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Hiroyuki Furukawa
- Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Tsuyoshi Watanabe
- Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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Hobeika MJ, Miller CM, Pruett TL, Gifford KA, Locke JE, Cameron AM, Englesbe MJ, Kuhr CS, Magliocca JF, McCune KR, Mekeel KL, Pelletier SJ, Singer AL, Segev DL. PROviding Better ACcess To ORgans: A comprehensive overview of organ-access initiatives from the ASTS PROACTOR Task Force. Am J Transplant 2017; 17:2546-2558. [PMID: 28742951 DOI: 10.1111/ajt.14441] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 06/25/2017] [Accepted: 07/13/2017] [Indexed: 01/25/2023]
Abstract
The American Society of Transplant Surgeons (ASTS) PROviding better Access To Organs (PROACTOR) Task Force was created to inform ongoing ASTS organ access efforts. Task force members were charged with comprehensively cataloguing current organ access activities and organizing them according to stakeholder type. This white paper summarizes the task force findings and makes recommendations for future ASTS organ access initiatives.
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Affiliation(s)
- M J Hobeika
- Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - C M Miller
- Liver Transplantation Program, Cleveland Clinic, Cleveland, OH, USA
| | - T L Pruett
- Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - K A Gifford
- American Society of Transplant Surgeons, Arlington, VA, USA
| | - J E Locke
- University of Alabama at Birmingham Comprehensive Transplant Institute, Birmingham, AL, USA
| | - A M Cameron
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - M J Englesbe
- Department of Surgery, Section of Transplantation, University of Michigan, Ann Arbor, MI, USA
| | - C S Kuhr
- Virginia Mason Medical Center, Seattle, WA, USA
| | - J F Magliocca
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | - K R McCune
- Department of Surgery, Columbia University, New York, NY, USA
| | - K L Mekeel
- Division of Transplantation and Hepatobiliary Surgery, University of California San Diego, San Diego, CA, USA
| | - S J Pelletier
- Division of Transplant Surgery, Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - A L Singer
- Transplant Center, Mayo Clinic, Phoenix, AZ, USA
| | - D L Segev
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Development of a prolonged warm ex vivo perfusion model for kidneys donated after cardiac death. Int J Artif Organs 2017; 40:265-271. [PMID: 28574105 DOI: 10.5301/ijao.5000586] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2017] [Indexed: 12/19/2022]
Abstract
PURPOSE Ex vivo perfusion of marginal kidney grafts offers the chance to expand the donor pool, but there is no current clinical standard for the prolonged warm perfusion of renal grafts. This exploratory pilot study seeks to identify a stable ex vivo kidney perfusion model that can support low intravascular resistance and preserve histologic architecture in a porcine donation after cardiac death (DCD) model. METHODS 15 kidneys were preserved in 1 of 3 settings: normothermic whole blood (NT-WB), normothermic Steen Solution™ (XVIVO Perfusion) with whole blood (NT-Steen/WB), or subnormothermic Steen Solution™ at 21°C (SNT-Steen). Kidneys were primarily assessed using hemodynamic parameters and histologic analysis. RESULTS NT-WB perfusion resulted in high vascular resistance and glomerular necrosis. NT-Steen/WB and SNT-Steen resistance ranged between 0.18-0.45 mmHg/mL per minute and 0.25-0.53 mmHg/mL per minute, respectively, enabling stable perfusion for up to 24 hours. NT-Steen/WB demonstrated tubular and glomerular necrosis, while the histologic architecture of SNT-Steen was preserved with the exception of numerous proteinaceous casts. CONCLUSIONS Our results suggest that ex vivo kidney perfusion with Steen Solution™ at 21°C supports low and stable vascular resistance and provides adequate histologic preservation during 24-hour perfusion.
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Marecki H, Bozorgzadeh A, Porte RJ, Leuvenink HG, Uygun K, Martins PN. Liver ex situ machine perfusion preservation: A review of the methodology and results of large animal studies and clinical trials. Liver Transpl 2017; 23:679-695. [PMID: 28240817 DOI: 10.1002/lt.24751] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 01/31/2017] [Indexed: 12/11/2022]
Abstract
Ex vivo machine perfusion (MP) is a promising way to better preserve livers prior to transplantation. Currently, no methodology has a verified benefit over simple cold storage. Before becoming clinically feasible, MP requires validation in models that reliably predict human performance. Such a model has been found in porcine liver, whose physiological, anatomical, and immunological characteristics closely resemble the human liver. Since the 1930s, researchers have explored MP as preservation, but only recently have clinical trials been performed. Making this technology clinically available holds the promise of expanding the donor pool through more effective preservation of extended criteria donor (ECD) livers. MP promises to decrease delayed graft function, primary nonfunction, and biliary strictures, which are all common failure modes of transplanted ECD livers. Although hypothermic machine perfusion (HMP) has become the standard for kidney ex vivo preservation, the precise settings and clinical role for liver MP have not yet been established. In research, there are 2 schools of thought: normothermic machine perfusion, closely mimicking physiologic conditions, and HMP, to maximize preservation. Here, we review the literature for porcine ex vivo MP, with an aim to summarize perfusion settings and outcomes pertinent to the clinical establishment of MP. Liver Transplantation 23 679-695 2017 AASLD.
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Affiliation(s)
- Hazel Marecki
- Transplant Division, Department of Surgery, University of Massachusetts, Worcester, MA
| | - Adel Bozorgzadeh
- Transplant Division, Department of Surgery, University of Massachusetts, Worcester, MA
| | - Robert J Porte
- Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Henri G Leuvenink
- Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Korkut Uygun
- Center of Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Paulo N Martins
- Transplant Division, Department of Surgery, University of Massachusetts, Worcester, MA
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Goldaracena N, Spetzler VN, Echeverri J, Kaths JM, Cherepanov V, Persson R, Hodges MR, Janssen HLA, Selzner N, Grant DR, Feld JJ, Selzner M. Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation-A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion. Am J Transplant 2017; 17:970-978. [PMID: 27805315 DOI: 10.1111/ajt.14100] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 10/12/2016] [Accepted: 10/16/2016] [Indexed: 01/25/2023]
Abstract
Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation.
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Affiliation(s)
- N Goldaracena
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - V N Spetzler
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - J Echeverri
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - J M Kaths
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - V Cherepanov
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada
| | - R Persson
- Roche Innovation Center, Copenhagen, Denmark
| | | | - H L A Janssen
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada
| | - N Selzner
- Multi Organ Transplant Program-Department of Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - D R Grant
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - J J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada
| | - M Selzner
- Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada
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Kumar R, Chung WY, Dennison AR, Garcea G. Ex Vivo Porcine Organ Perfusion Models as a Suitable Platform for Translational Transplant Research. Artif Organs 2017; 41:E69-E79. [PMID: 28266040 DOI: 10.1111/aor.12865] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 08/03/2016] [Accepted: 08/24/2016] [Indexed: 12/24/2022]
Abstract
In transplantation surgery, extending the criteria for organ donation to include organs that may have otherwise been previously discarded has provided the impetus to improve organ preservation. The traditional method of cold static storage (CS) has been tried and tested and is suitable for organs meeting standard criteria donation. Ex vivo machine perfusion is, however, associated with evidence suggesting that it may be better than CS alone and may allow for organ donation criteria to be extended. Much of our knowledge of organ preservation is derived from animal studies. We review ex vivo porcine organ perfusion models and discuss the relevance to the field of transplantation surgery. Following a systematic literature search, only articles that reported on experimental studies with focus on any aspect(s) of ex vivo and porcine perfusion of organs yet limited to the context of organ transplantation surgery were included. The database search and inclusion/exclusion criteria identified 22 journal articles. All 22 articles discussed ex vivo porcine organ perfusion within the context of transplant preservation surgery: 8 liver, 3 kidney, 3 lung, 2 pancreas/islet, 4 discussed a combined liver-kidney multiorgan model, 1 small bowel, and 1 cardiac perfusion model systems. The ex vivo porcine perfusion model is a suitable, reliable, and safe translational research model. It has advantages to investigate organ preservation techniques in a reproducible fashion in order to improve our understanding and has implications to extend the criteria for organ donation.
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Affiliation(s)
- Rohan Kumar
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, UK
| | - Wen Yuan Chung
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, UK
| | | | - Giuseppe Garcea
- Department of Hepato-Pancreato-Biliary Surgery, University Hospitals of Leicester, Leicester, UK
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Liu S, Pang Q, Zhang J, Zhai M, Liu S, Liu C. Machine perfusion versus cold storage of livers: a meta-analysis. Front Med 2016; 10:451-464. [PMID: 27837413 DOI: 10.1007/s11684-016-0474-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 07/19/2016] [Indexed: 12/18/2022]
Abstract
Different organ preservation methods are key factors influencing the results of liver transplantation. In this study, the outcomes of experimental models receiving donation after cardiac death (DCD) livers preserved through machine perfusion (MP) or static cold storage (CS) were compared by conducting a meta-analysis. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated to compare pooled data from two animal species. Twenty-four studies involving MP preservation were included in the meta-analysis. Compared with CS preservation, MP can reduce the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and hyaluronic acid (HA) and the changes in liver weight. By contrast, MP can enhance bile production and portal vein flow (PVF). Alkaline phosphatase (ALP) levels and histological changes significantly differed between the two preservation methods. In conclusion, MP of DCD livers is superior to CS in experimental animals.
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Affiliation(s)
- Sushun Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Qing Pang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jingyao Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Mimi Zhai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Sinan Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Chang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China.
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50
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Echeverri J, Selzner M. "In 10 years" debate: Con-machine perfusion will be limited to specific situations (Steatotic, donation after circulatory death). Liver Transpl 2016; 22:29-32. [PMID: 27588758 DOI: 10.1002/lt.24622] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 08/30/2016] [Indexed: 12/31/2022]
Affiliation(s)
- Juan Echeverri
- Department of Surgery, Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | - Markus Selzner
- Department of Surgery, Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.
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