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Puchany AJ, Hilmi I. Post-reperfusion syndrome in liver transplant recipients: What is new in prevention and management? World J Crit Care Med 2025; 14:101777. [PMID: 40491878 PMCID: PMC11891853 DOI: 10.5492/wjccm.v14.i2.101777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/22/2024] [Accepted: 12/19/2024] [Indexed: 02/27/2025] Open
Abstract
Post-reperfusion syndrome (PRS) in liver transplant recipients remains one of the most dreaded complications in liver transplant surgery. PRS can impact the short-term and long-term patient and graft outcomes. The definition of PRS has evolved over the years, from changes in arterial blood pressures and heart and/or decreases in the systemic vascular resistance and cardiac output to including the fibrinolysis and grading the severity of PRS. However, all that did not reflect on the management of PRS or its impact on the outcomes. In recent years, new scientific techniques and new technology have been in the pipeline to better understand, manage and maybe prevent PRS. These new methods and techniques are still in the infancy, and they have to be proven not in prevention and management of PRS but their effects in the patient and graft outcomes. In this article, we will review the long history of PRS, its definition, etiology, management and most importantly the new advances in science and technology to prevent and properly manage PRS.
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Affiliation(s)
- Austin James Puchany
- Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Ibtesam Hilmi
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Department of Anesthesiology and Perioperative Medicine, Clinical and Translational Science Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, United States
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2
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Vervoorn MT, van Tuijl S, Ballan EM, Kaffka Genaamd Dengler SE, de Jager SCA, Sluijter JPG, Doevendans PA, van der Kaaij NP. A novel cardioprotective perfusion protocol prevents functional decline during extended normothermic ex situ heart perfusion of marginal porcine hearts. J Heart Lung Transplant 2025; 44:961-971. [PMID: 39490458 DOI: 10.1016/j.healun.2024.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 09/20/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND A common limitation to normothermic ex situ heart perfusion (ESHP) is functional decline. We previously designed a cardioprotective normothermic perfusion protocol, incorporating adenosine-lidocaine cardioplegia, subnormothermic reperfusion, pyruvate and methylprednisolone supplementation, and hemofiltration to prevent myocardial functional decline over 4 hours. In this study, we added continuous catecholamine infusion and protective loading conditions to assess the effectiveness of this enhanced cardioprotective perfusion protocol in preventing functional decline during extended normothermic perfusion in marginal porcine hearts. METHODS Six slaughterhouse pig hearts underwent 9 hours of normothermic ESHP using the enhanced cardioprotective protocol. Cardiac function was assessed at 90, 120, 240, 360, 480 and 540 minutes of ESHP. Subsequently, a preload-challenge was conducted after 9 hours to assess preload-responsiveness (mimicking the Frank-Starling principle) and suitability for transplantation. RESULTS During perfusion, myocardial function remained stable, indicated by consistent mean cardiac index (9.2liter/min/kg at 90; 9.3liter/min/kg at 540 minutes of ESHP), left ventricular stroke work index (6,258mmHg*ml/kg at 90; 6,707mmHg*ml/kg at 540 minutes) and rate of ventricular pressure change over time. In response to a preload-challenge, there was a notable increase of 34% in mean cardiac index and 58% in mean stroke work. CONCLUSIONS Our study demonstrates that the implementation of a cardioprotective protocol enables (very) marginal porcine slaughterhouse hearts, subjected to both a warm and cold ischemic insult prior to ESHP, to sustain satisfactory cardiac function without notable decline during 9 hours of normothermic ESHP, while also preserving their preload-responsiveness. The latter finding might indicate suitability for transplantation. This study provides a groundwork for further extending normothermic ESHP, unlocking the full potential of this promising technology.
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Affiliation(s)
- Mats T Vervoorn
- University Medical Center Utrecht, Department of Cardiothoracic Surgery, Division of Heart and Lungs, Utrecht, The Netherlands
| | | | - Elisa M Ballan
- University Medical Center Utrecht, Department of Cardiothoracic Surgery, Division of Heart and Lungs, Utrecht, The Netherlands; University Medical Center Utrecht, Department of Cardiology, Laboratory of Experimental Cardiology, Division Heart and Lungs, Utrecht, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands
| | - Selma E Kaffka Genaamd Dengler
- University Medical Center Utrecht, Department of Cardiothoracic Surgery, Division of Heart and Lungs, Utrecht, The Netherlands
| | - Saskia C A de Jager
- University Medical Center Utrecht, Department of Cardiology, Laboratory of Experimental Cardiology, Division Heart and Lungs, Utrecht, The Netherlands
| | - Joost P G Sluijter
- University Medical Center Utrecht, Department of Cardiology, Laboratory of Experimental Cardiology, Division Heart and Lungs, Utrecht, The Netherlands; Regenerative Medicine Utrecht, Circulatory Health Research Center, Utrecht University, Utrecht, The Netherlands
| | - Pieter A Doevendans
- Netherlands Heart Institute, Utrecht, The Netherlands; University Medical Center Utrecht, Department of Cardiology, Division Heart and Lungs, Utrecht, The Netherlands
| | - Niels P van der Kaaij
- University Medical Center Utrecht, Department of Cardiothoracic Surgery, Division of Heart and Lungs, Utrecht, The Netherlands.
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3
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Hessheimer AJ, Hartog H, Marcon F, Schlegel A, Adam R, Alwayn I, Angelico R, Antoine C, Berlakovich G, Bruggenwirth I, Calatayud D, Cardini B, Cillo U, Clavien PA, Czigany Z, De Carlis R, de Jonge J, De Meijer VE, Dondossola D, Domínguez-Gil B, Dutkowski P, Eden J, Eshmuminov D, Fundora Y, Gastaca M, Ghinolfi D, Justo I, Lesurtel M, Leuvenink H, Line PD, Lladó L, López López V, Lurje G, Marín LM, Monbaliu D, Muller X, Nadalin S, Nasralla D, Oniscu G, Patrono D, Pirenne J, Selzner M, Toso C, Troisi R, Van Beekum C, Watson C, Weissenbacher A, Zieniewicz K, Schneeberger S, Polak WG, Porte RJ, Fondevila C. Deceased donor liver utilisation and assessment: Consensus guidelines from the European Liver and Intestine Transplant Association. J Hepatol 2025; 82:1089-1109. [PMID: 40189968 DOI: 10.1016/j.jhep.2025.01.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/11/2025] [Accepted: 01/23/2025] [Indexed: 05/03/2025]
Abstract
Over the past two decades, the application of machine perfusion (MP) in human liver transplantation has moved from the realm of clinical exploration to routine clinical practice. Both in situ and ex situ perfusion strategies are feasible, safe, and may offer improvements in relevant post-transplant outcomes. An important utility of these strategies is the ability to transplant grafts traditionally considered too risky to transplant using conventional cold storage alone. While dynamic assessment and ultimately transplantation of such livers is an important goal for the international liver transplant community, its clinical application is inconsistent. To this end, ELITA (the European Liver and Intestine Transplant Association) gathered a panel of experts to create consensus guidelines regarding selection, approach, and criteria for deceased donor liver assessment in the MP era. An eight-member steering committee (SC) convened a panel of 44 professionals working in 14 countries in Europe and North America. The SC identified topics related to liver utilisation and assessment for transplantation. For each topic, subtopics were created to answer specific clinical questions. A systematic literature review was performed, and the panel graded relevant evidence. The SC drafted initial statements addressing each clinical question. Statements were presented at the in-person Consensus Meeting on Liver Discard and Viability Assessment during the ELITA Summit held from April 19-20, 2024, in Madrid, Spain. Online voting was held to approve statements according to a modified Delphi method; statements reaching ≥85% agreement were approved. Statements addressing liver utilisation, the definition of high-risk livers, and strategies and criteria for dynamic liver assessment are presented.
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Affiliation(s)
- Amelia J Hessheimer
- General & Digestive Surgery Service, Hospital Universitario La Paz, IdiPAZ, CIBERehd, Madrid, Spain
| | - Hermien Hartog
- University of Groningen & University Medical Center Groningen, UMCG Comprehensive Transplant Center, Department of Surgery, Groningen, the Netherlands; European Liver & Intestine Transplant Association Board
| | - Francesca Marcon
- General & Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Andrea Schlegel
- Transplantation Center, Department of General Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - René Adam
- Department of Hepatobiliary Surgery & Transplantation, AP-HP Hôpital Paul-Brousse, University of Paris-Saclay, Villejuif, France
| | - Ian Alwayn
- Department of Surgery & LUMC Transplant Center, Leiden University Medical Center, Leiden, the Netherlands
| | - Roberta Angelico
- Hepatobiliary & Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, Rome, Italy
| | | | | | | | - David Calatayud
- Hepatobiliary Surgery & Transplantation Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Benno Cardini
- Department of Visceral, Transplant, & Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Umberto Cillo
- Department of Surgery, Oncology, & Gastroenterology, Hepatobiliary & Liver Transplantation Unit, Padua University Hospital, Padua, Italy
| | - Pierre-Alain Clavien
- Wyss Translational Center, ETH Zurich & University of Zurich, Zurich, Switzerland
| | - Zoltan Czigany
- Department of Surgery & Transplantation, University Hospital Heidelberg, Medical Faculty Ruprecht Karl University Heidelberg, Heidelberg, Germany
| | - Riccardo De Carlis
- Department of General Surgery & Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, & PhD Course in Clinical and Experimental Sciences, University of Padua, Padua, Italy
| | - Jeroen de Jonge
- Division of HPB & Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Vincent E De Meijer
- University of Groningen & University Medical Center Groningen, UMCG Comprehensive Transplant Center, Department of Surgery, Groningen, the Netherlands
| | - Daniele Dondossola
- General & Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Philipp Dutkowski
- Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland
| | - Janina Eden
- University of Groningen & University Medical Center Groningen, UMCG Comprehensive Transplant Center, Department of Surgery, Groningen, the Netherlands
| | - Dilmurodjon Eshmuminov
- Department of Surgery & Transplantation, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Yiliam Fundora
- General & Digestive Surgery Service, Hospital Clínic, Barcelona, Spain
| | - Mikel Gastaca
- Hepatobiliary Surgery & Liver Transplantation Unit, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Bilbao, Spain
| | - Davide Ghinolfi
- Division of Hepatic Surgery & Liver Transplantation, New Santa Chiara Hospital, Pisa, Italy
| | | | - Mickael Lesurtel
- Department of HPB & Transplantation, Beaujon Hospital, APHP, University of Paris Cité, Paris, France
| | - Henri Leuvenink
- University of Groningen & University Medical Center Groningen, UMCG Comprehensive Transplant Center, Department of Surgery, Groningen, the Netherlands
| | - Pal-Dag Line
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; European Liver & Intestine Transplant Association Board
| | - Laura Lladó
- Department of Hepatobiliary Surgery & Liver Transplantation, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Víctor López López
- Department of Surgery & Transplantation, Hospital Clínico Universitario Virgen de la Arrixaca, Murcian Institute of Biosanitary Research, Murcia, Spain
| | - Georg Lurje
- Department of Surgery & Transplantation, University Hospital Heidelberg, Medical Faculty Ruprecht Karl University Heidelberg, Heidelberg, Germany
| | | | | | - Xavier Muller
- Department of Hepato-Pancreato-Biliary Surgery & Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Silvio Nadalin
- University of Tübingen, Tübingen, Germany; European Liver & Intestine Transplant Association Board
| | - David Nasralla
- Department of HPB and Liver Transplant Surgery, Royal Free Hospital, London, United Kingdom
| | - Gabriel Oniscu
- Transplantation Division, Department of Clinical Science, Intervention, & Technology, Karolinska Institutet, Stockholm, Sweden
| | - Damiano Patrono
- General Surgery 2U - Liver Transplant Centre, AOU Città della Salute e della Scienza di Torino, Torino, Italy
| | - Jacques Pirenne
- Abdominal Transplant Surgery, UZ Leuven, KUL, Leuven, Belgium
| | - Markus Selzner
- Department of Abdominal Transplant & Hepatopancreatobiliary Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Christian Toso
- Division of Abdominal Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Roberto Troisi
- Division HPB, Minimally Invasive and Robotic Surgery, Transplantation Center, Federico II University Hospital, Naples, Italy
| | - Cornelius Van Beekum
- Department of General, Visceral, & Transplant Surgery, Transplant Center Hannover, Hannover Medical School, Hannover, Germany
| | - Christopher Watson
- University of Cambridge Department of Surgery, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Annemarie Weissenbacher
- Department of Visceral, Transplant, & Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Krzysztof Zieniewicz
- Department of General, Transplant, & Liver Surgery, Medical University of Warsaw, Warsaw, Poland; European Liver & Intestine Transplant Association Board
| | - Stefan Schneeberger
- Department of Visceral, Transplant, & Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Wojciech G Polak
- Division of HPB & Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands; European Liver & Intestine Transplant Association Board
| | - Robert J Porte
- Division of HPB & Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Constantino Fondevila
- General & Digestive Surgery Service, Hospital Universitario La Paz, IdiPAZ, CIBERehd, Madrid, Spain; Universidad Autónoma de Madrid, Madrid, Spain; European Liver & Intestine Transplant Association Board.
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den Dekker AMP, Franssen A, Steyerberg EW, Lam H, Doppenberg JB, Alwayn IPJ. Donor-Related Risk Factors for Normothermic Machine Perfusion in Liver Transplantation: A Meta-Analysis. Liver Int 2025; 45:e70116. [PMID: 40298438 PMCID: PMC12039471 DOI: 10.1111/liv.70116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/26/2025] [Accepted: 04/20/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND AND AIMS During normothermic machine perfusion (NMP), a variety of criteria are used to gauge the suitability of an organ for transplantation. However, the relations between donor factors and these criteria are poorly understood. The aim of this meta-analysis was to investigate the association between donor-related risk factors and the decision to transplant a liver subjected to NMP. METHODS A comprehensive literature search was performed for articles published up to March 2025 in four databases, reporting livers subjected to NMP for viability assessment prior to transplantation. Effect size (ES) was calculated using Cohen's D and log odds ratio. RESULTS Out of 806 unique articles, 18 were included in this meta-analysis, encompassing 690 liver grafts that underwent NMP. Following viability assessment during NMP, utilisation rate was 82% from donors after brain death and 68% from donors after circulatory death (ES: 0.08, p = 0.88). Transplanted livers had shorter cold ischemia time (ES: -0.34, p = 0.003) and lower liver weight (ES: -0.53, p < 0.001). Donor age, BMI and donor warm ischemia time did not differentiate between transplanted and unused groups. Differences were observed in viability assessment for lactate clearance (ES: 2.0, p = 0.005), glucose metabolism (ES: 2.2, p < 0.001), bile production (ES: 1.0, p = 0.003) and pH (ES: 1.9, p < 0.001). Excellent outcomes, including 10% non-anastomotic strictures, 89% graft survival and 93% patient survival, were achieved in a large cohort of high-risk livers. CONCLUSION Cold ischemia time and liver weight were identified as donor-related risk factors, whereas donor type, age and donor warm ischemia time appear not to impact the decision to transplant during NMP.
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Affiliation(s)
- Abraham M. P. den Dekker
- LUMC Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
- Department of SurgeryLeiden University Medical CenterLeidenthe Netherlands
| | - Alexander Franssen
- LUMC Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Ewout W. Steyerberg
- Department of Biomedical Data SciencesLeiden University Medical CenterLeidenthe Netherlands
- Julius Center for Health Sciences and Primary CareUniversity Medical Center UtrechtUtrechtthe Netherlands
| | - Hwai‐Ding Lam
- LUMC Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
- Department of SurgeryLeiden University Medical CenterLeidenthe Netherlands
| | | | - Ian P. J. Alwayn
- LUMC Transplant CenterLeiden University Medical CenterLeidenthe Netherlands
- Department of SurgeryLeiden University Medical CenterLeidenthe Netherlands
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5
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Tamaki Y, Hatayama N, Fujii Y, Naito M. A compact machine perfusion device for whole blood perfusion in isolated rat liver. J Artif Organs 2025; 28:244-251. [PMID: 39363050 DOI: 10.1007/s10047-024-01474-8] [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: 05/06/2024] [Accepted: 09/19/2024] [Indexed: 10/05/2024]
Abstract
We established a compact machine perfusion system for whole blood perfusion of rat liver by making use of oxygenation filters as an artificial lung. Livers removed from rats were divided into Krebs-Henseleit (control), 50% blood (hemoglobin: 7 g/dL), and whole blood (hemoglobin: 14 g/dL) groups, then perfused (total perfusate volume: 25 ml) with a small oxygenation filter at 37 °C for 120 min. Blood or perfusate was collected over time, and blood gas and blood cell were measured. In addition, bile volume and portal venous pressure measurements were taken. In all groups, the partial pressure of oxygen was controlled to approximately 400 mmHg. Flow rates were maintained at approximately about 20-30 ml/min according to liver size. Portal venous pressure was normal in the 50% blood and whole blood groups, while lower than the reference value in the Krebs-Henseleit group. Twice as much bile was produced in the 50% blood and whole blood groups relative with the Krebs-Henseleit group. We observed no differences in hemoglobin and red blood cell levels. Lactate levels were normal in the 50% blood and whole blood groups, but were elevated in the Krebs-Henseleit group. Our compact perfusion system using oxygenation filters was able to maintain rat liver function by perfusing a small amount of extracorporeal blood. This system is simple and stable, and may contribute to the future development of machine perfusion systems.
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Affiliation(s)
- Yuki Tamaki
- Department of Anatomy, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan.
| | - Naoyuki Hatayama
- Department of Anatomy, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan
| | - Yutaka Fujii
- Department of Clinical Engineering and Medical Technology, Niigata University of Health and Welfare, Niigata, Japan
| | - Munekazu Naito
- Department of Anatomy, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan.
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Zhao Y, Lyu X, Sun Z, Zhang X, Cen J, Yang T, Xu X, Xing W, Zhao S, Wang B, Luo G. Continuous Blood Gas Control Based on Active Disturbance Rejection Control During Ex Vivo Porcine Liver Perfusion. Artif Organs 2025; 49:967-976. [PMID: 39868805 DOI: 10.1111/aor.14955] [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: 09/11/2024] [Revised: 12/20/2024] [Accepted: 01/10/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND Membrane oxygenators facilitate extracorporeal gas exchange, necessitating the monitoring of blood gas. Recent advances in normothermic machine perfusion (NMP) for ex vivo liver offer solutions to the shortage of donor liver. However, maintaining physiological blood gas levels during prolonged NMP is complex and costly. METHODS We introduce a noninvasive and economical approach for regulating the blood gas during NMP of ex vivo porcine livers. By monitoring gas fractions at the outlet of oxygenator, real-time adjustments of blood gas can be made without the online blood gas analyzer. The method involves constructing multivariate linear regression (MLR) models, aligning target setpoints of gas, and employing active disturbance rejection control (ADRC) to achieve closed-loop regulation. RESULTS Ex vivo porcine liver perfusion experiments demonstrated the effectiveness of the method, maintaining blood gas within physiological levels over 24 h (oxygen partial pressure: 150.36 ± 3.33 mmHg, carbon dioxide partial pressure: 41.34 ± 0.91 mmHg). CONCLUSION ADRC-based continuous regulation of gas fraction at the outlet of oxygenator is a feasible and effective approach for managing blood gas during ex vivo porcine liver perfusion.
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Affiliation(s)
- Yilong Zhao
- School of Biomedical Engineering (Suzhou), Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Xin Lyu
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Zhen Sun
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiaoliang Zhang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Jin Cen
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tianhang Yang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Xiaoliang Xu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Wenhui Xing
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Sihan Zhao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Bidou Wang
- School of Biomedical Engineering (Suzhou), Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Gangyin Luo
- School of Biomedical Engineering (Suzhou), Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
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Subbiahanadar Chelladurai K, Selvan Christyraj JD, Rajagopalan K, Vadivelu K, Chandrasekar M, Das P, Kalimuthu K, Balamurugan N, Subramanian V, Selvan Christyraj JRS. Ex vivo functional whole organ in biomedical research: a review. J Artif Organs 2025; 28:131-145. [PMID: 39592544 DOI: 10.1007/s10047-024-01478-4] [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: 02/07/2024] [Accepted: 07/29/2024] [Indexed: 11/28/2024]
Abstract
Model systems are critical in biomedical and preclinical research. Animal and in vitro models serve an important role in our current understanding of human physiology, disease pathophysiology, and therapy development. However, if the system is between cell culture and animal models, it may be able to overcome the knowledge gap that exists in the current system. Studies employing ex vivo organs as models have not been thoroughly investigated. Though the integration of other organs and systems has an impact on many biological mechanisms and disorders, it can add a new dimension to modeling and aid in the identification of new possible therapeutic targets. Here, we have discussed why the ex vivo organ model is desirable and the importance of the inclusion of organs from diverse species, described its historical aspects, studied organs as models in scientific research, and its ex vivo stability. We also discussed, how an ex vivo organ model might help researchers better understand organ physiology, as well as organ-specific diseases and therapeutic targets. We emphasized how this ex vivo organ dynamics will be more competent than existing models, as well as what tissues or organs would have potentially viable longevity for ex vivo modeling including human tissues, organs, and/or at least biopsies and its possible advantage in clinical medicine including organ transplantation procedure and precision medicine.
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Affiliation(s)
- Karthikeyan Subbiahanadar Chelladurai
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
- School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN, 47907, USA
| | - Jackson Durairaj Selvan Christyraj
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India.
| | - Kamarajan Rajagopalan
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Kayalvizhi Vadivelu
- Department of Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Meikandan Chandrasekar
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Puja Das
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Kalishwaralal Kalimuthu
- Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Thiruvananthapuram, Kerala, India
| | - Nivedha Balamurugan
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Vijayalakshmi Subramanian
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Johnson Retnaraj Samuel Selvan Christyraj
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India.
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Ly M, Babekuhl D, Niu A, Yousif P, Wang C, Lau NS, Gorrell MD, McCaughan GW, Crawford M, Pulitano C. Development of a Protocol for Long-Term Ex Vivo Normothermic Machine Perfusion of Rodent Livers. Artif Organs 2025. [PMID: 40386942 DOI: 10.1111/aor.15024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 03/02/2025] [Accepted: 04/30/2025] [Indexed: 05/20/2025]
Abstract
INTRODUCTION Long-term normothermic machine perfusion (LT-NMP) enables the assessment and optimization of livers for days and, potentially, weeks. However, models of LT-NMP have only been described for human and pig livers, which are resource intensive and impractical for laboratory research. Cost-effective small animal models of LT-NMP are needed for future research. This study aimed to develop a system for LT-NMP of rat livers for up to 72 h. METHODS This study was performed in two stages: the development phase (n = 20) and validation phase (n = 5). The perfusion system included an organ reservoir, pump, heat exchanger, long-term oxygenator, and dialysis. Hormonal and nutritional support were continuously infused. During the validation phase, five consecutive grafts were perfused using our protocol. At 72 h postreperfusion, grafts were assessed for viability, which was based on hemodynamic stability, mitochondrial function, bile production, and metabolic activity. RESULTS Rodent livers were supported up to 107 h using our LT-NMP protocol. All grafts in the validation phase remained viable at 72 h (n = 5/5). The median oxygen consumption and bile production at 72 h were 0.079 mLO2/min/g-liver and 8.6 uL/h/g-liver, respectively. All grafts had a systemic vascular resistance less than 0.25 mmHg/mL/min. Metabolic activity, defined as lactate clearance, glucose production, or response to glucagon, was observed in all grafts (5/5). CONCLUSIONS This is the first study to report LT-NMP of rodent livers up to 5 days. Using our protocol, rat livers could reliably be supported until 72 h. This model provides a greater opportunity to investigate novel therapeutics to assess, optimize, and regenerate liver grafts for transplantation.
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Affiliation(s)
- Mark Ly
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Daniel Babekuhl
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Engineering, The University of Sydney, Sydney, New South Wales, Australia
| | - Anita Niu
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Paul Yousif
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Chuanmin Wang
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Ngee-Soon Lau
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Mark D Gorrell
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Geoffrey W McCaughan
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Michael Crawford
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Carlo Pulitano
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
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9
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Ortuño-Costela MC, Pinzani M, Vallier L. Cell therapy for liver disorders: past, present and future. Nat Rev Gastroenterol Hepatol 2025; 22:329-342. [PMID: 40102584 DOI: 10.1038/s41575-025-01050-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/11/2025] [Indexed: 03/20/2025]
Abstract
The liver fulfils a plethora of vital functions and, due to their importance, liver dysfunction has life-threatening consequences. Liver disorders currently account for more than two million deaths annually worldwide and can be classified broadly into three groups, considering their onset and aetiology, as acute liver diseases, inherited metabolic disorders and chronic liver diseases. In the most advanced and severe forms leading to liver failure, liver transplantation is the only treatment available, which has many associated drawbacks, including a shortage of organ donors. Cell therapy via fully mature cell transplantation is an advantageous alternative that may be able to restore a damaged organ's functionality or serve as a bridge until regeneration can occur. Pioneering work has shown that transplanting adult hepatocytes can support liver recovery. However, primary hepatocytes cannot be grown extensively in vitro as they rapidly lose their metabolic activity. Therefore, different cell sources are currently being tested as alternatives to primary cells. Human pluripotent stem cell-derived cells, chemically induced liver progenitors, or 'liver' organoids, hold great promise for developing new cell therapies for acute and chronic liver diseases. This Review focuses on the advantages and drawbacks of distinct cell sources and the relative strategies to address different therapeutic needs in distinct liver diseases.
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Affiliation(s)
- M Carmen Ortuño-Costela
- Berlin Institute of Health, BIH Centre for Regenerative Therapies, Charité-Universitätsmedizin, Berlin, Germany
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Massimo Pinzani
- University College London Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, London, UK
- University of Pittsburgh Medical Center-Mediterranean Institute for Transplantation and Highly Specialized Therapies (UPMC-ISMETT), Palermo, Italy
| | - Ludovic Vallier
- Berlin Institute of Health, BIH Centre for Regenerative Therapies, Charité-Universitätsmedizin, Berlin, Germany.
- Max Planck Institute for Molecular Genetics, Berlin, Germany.
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10
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Spence PJ, Nahrendorf W, Bach FA. Moving beyond discovery science to a mechanistic understanding of human malaria. Curr Opin Microbiol 2025; 85:102610. [PMID: 40288157 DOI: 10.1016/j.mib.2025.102610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 04/02/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025]
Abstract
We've had more than a hundred years of discovery-based human malaria research that has made steady progress in observing disease processes (such as sequestration and vascular occlusion) as well as potential mechanisms of immunity. These observations now take centre stage as we enter an era of mass vaccination that will alter the natural history and epidemiology of malaria. We will need to understand how to protect individuals from breakthrough infections and populations from a shift in the mean age of exposure. It is therefore paramount that we start to directly test our long-standing hypotheses about the causes of disease and the pathways to protection. This is now made possible by improvements to complex cellular model systems as well as a sea-change in our attitude towards human intervention studies. Mechanistic insight is therefore no longer limited to animal models, which are always imperfect, but can be achieved in people and in vivo.
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Affiliation(s)
- Philip J Spence
- Institute of Immunology and Infection Research, University of Edinburgh, UK.
| | - Wiebke Nahrendorf
- Institute of Immunology and Infection Research, University of Edinburgh, UK
| | - Florian A Bach
- Department of Microbiology and Immunology, Stanford University, USA
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11
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Filz von Reiterdank I, Mojoudi M, Bento R, Taggart MS, Dinicu AT, Wojtkiewicz G, Coert JH, Mink van der Molen AB, Weissleder R, Parekkadan B, Uygun K. Ex vivo machine perfusion as a platform for lentiviral gene delivery in rat livers. Gene Ther 2025:10.1038/s41434-025-00536-7. [PMID: 40263629 DOI: 10.1038/s41434-025-00536-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 03/28/2025] [Accepted: 04/08/2025] [Indexed: 04/24/2025]
Abstract
Developing new strategies for local monitoring and delivery of immunosuppression is critical to making allografts safer and more accessible. Ex vivo genetic modification of grafts using machine perfusion presents a promising approach to improve graft function and modulate immune responses while minimizing risks of off-target effects and systemic immunogenicity in vivo. This proof-of-concept study demonstrates the feasibility of using normothermic machine perfusion (NMP) to mimic in vitro conditions for effective gene delivery. In this study, lentiviral vectors encoding the secreted biomarker Gaussia Luciferase (GLuc) and red fluorescent protein (RFP) were introduced ex vivo to rodent livers during a 72-h machine perfusion protocol. After an initial 24-h exposure to viral vectors, the organs were maintained in perfusion for an additional 48 h to monitor gene expression, aligning with in vitro benchmarks. Control livers were perfused in similar fashion, but without viral injections. Virally perfused livers exhibited nearly a 10-fold increase in luminescence compared to controls (p < 0.0001), indicating successful genetic modification of the organs. These findings validate the use of machine perfusion systems and viral vectors to genetically engineer whole organs ex vivo, laying the groundwork for a broad range of applications in transplantation through genetic manipulation of organ systems. Future studies will focus on refining this technology to enhance precision in gene expression and explore its implications for clinical translation.
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Affiliation(s)
- Irina Filz von Reiterdank
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mohammadreza Mojoudi
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Raphaela Bento
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - McLean S Taggart
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Antonia T Dinicu
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Gregory Wojtkiewicz
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - J H Coert
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Aebele B Mink van der Molen
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ralph Weissleder
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
| | - Korkut Uygun
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Shriners Children's Boston, Boston, MA, USA.
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12
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Harkins L, Vilarinho S, Saltzman WM. Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver. Biochemistry 2025; 64:1685-1697. [PMID: 40127248 DOI: 10.1021/acs.biochem.4c00712] [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] [Indexed: 03/26/2025]
Abstract
Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.
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Affiliation(s)
- Lauren Harkins
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, United States
| | - Silvia Vilarinho
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, United States
- Department of Genetics and Pathology, Yale School of Medicine, New Haven, Connecticut 06520, United States
| | - W Mark Saltzman
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, United States
- Department of Chemical & Environmental Engineering, Yale University, New Haven, Connecticut 06520, United States
- Department of Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06520, United States
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut 06520, United States
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13
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Vengohechea J, Vaquero-Rey A, Fondevila C, Hessheimer AJ. The role of renal replacement therapy in improving normothermic machine perfusion of liver grafts. GASTROENTEROLOGIA Y HEPATOLOGIA 2025; 48:502336. [PMID: 39761725 DOI: 10.1016/j.gastrohep.2025.502336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/11/2024] [Accepted: 12/20/2024] [Indexed: 01/24/2025]
Affiliation(s)
- Jordi Vengohechea
- General & Digestive Surgery Service, Hospital Universitario La Paz, IdiPAZ, CIBERehd, Madrid, Spain. https://x.com/@jordivengo
| | - Aida Vaquero-Rey
- General & Digestive Surgery Service, Hospital Universitario La Paz, IdiPAZ, CIBERehd, Madrid, Spain. https://x.com/@HULPSurgery
| | - Constantino Fondevila
- General & Digestive Surgery Service, Hospital Universitario La Paz, IdiPAZ, CIBERehd, Madrid, Spain. https://x.com/@CFondevila
| | - Amelia J Hessheimer
- General & Digestive Surgery Service, Hospital Universitario La Paz, IdiPAZ, CIBERehd, Madrid, Spain.
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14
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Huwyler F, Pfister M, Binz J, Tibbitt MW, Clavien PA. Benefits of multi-day ex situ perfusion include dampened ischemia reperfusion injury in liver transplantation. J Hepatol 2025:S0168-8278(25)00208-9. [PMID: 40147789 DOI: 10.1016/j.jhep.2025.03.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 03/29/2025]
Affiliation(s)
- Florian Huwyler
- Hub for Translational Research and Liver/GI Health, Zurich, Switzerland; Macromolecular Engineering Lab, ETH Zurich, Zurich, Switzerland
| | - Matthias Pfister
- Hub for Translational Research and Liver/GI Health, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Jonas Binz
- Hub for Translational Research and Liver/GI Health, Zurich, Switzerland; Macromolecular Engineering Lab, ETH Zurich, Zurich, Switzerland
| | - Mark W Tibbitt
- Hub for Translational Research and Liver/GI Health, Zurich, Switzerland; Macromolecular Engineering Lab, ETH Zurich, Zurich, Switzerland
| | - Pierre-Alain Clavien
- Hub for Translational Research and Liver/GI Health, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland.
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15
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Hagenbuch B, Stieger B, Locher KP. Organic anion transporting polypeptides: Pharmacology, toxicology, structure, and transport mechanisms. Pharmacol Rev 2025; 77:100023. [PMID: 40148036 DOI: 10.1016/j.pharmr.2024.100023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 11/12/2024] [Indexed: 03/29/2025] Open
Abstract
Organic anion transporting polypeptides (OATPs) are membrane proteins that mediate the uptake of a wide range of substrates across the plasma membrane of various cells and tissues. They are classified into 6 subfamilies, OATP1 through OATP6. Humans contain 12 OATPs encoded by 11 solute carrier of organic anion transporting polypeptide (SLCO) genes: OATP1A2, OATP1B1, OATP1B3, the splice variant OATP1B3-1B7, OATP1C1, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OATP4C1, OATP5A1, and OATP6A1. Most of these proteins are expressed in epithelial cells, where they mediate the uptake of structurally unrelated organic anions, cations, and even neutral compounds into the cytoplasm. The best-characterized members are OATP1B1 and OATP1B3, which have an important role in drug metabolism by mediating drug uptake into the liver and are involved in drug-drug interactions. In this review, we aimed to (1) provide a historical perspective on the identification of OATPs and their nomenclature and discuss their phylogenic relationships and molecular characteristics; (2) review the current knowledge of the broad substrate specificity and their role in drug disposition and drug-drug interactions, with a special emphasis on human hepatic OATPs; (3) summarize the different experimental systems that are used to study the function of OATPs and discuss their advantages and disadvantages; (4) review the available experimental 3-dimensional structures and examine how they can help elucidate the transport mechanisms of OATPs; and (5) finally, summarize the current knowledge of the regulation of OATP expression, discuss clinically important single-nucleotide polymorphisms, and outline challenges of physiologically based pharmacokinetic modeling and in vitro to in vivo extrapolation. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (OATPs) are a family of 12 uptake transporters in the solute carrier superfamily. Several members, particularly the liver-expressed OATP1B1 and OATP1B3, are important drug transporters. They mediate the uptake of several endobiotics and xenobiotics, including statins and numerous other drugs, into hepatocytes, and their inhibition by other drugs or reduced expression due to single-nucleotide polymorphisms can lead to adverse drug effects. Their recently solved 3-dimensional structures should help to elucidate their transport mechanisms and broad substrate specificities.
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Affiliation(s)
- Bruno Hagenbuch
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas.
| | - Bruno Stieger
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Kaspar P Locher
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
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16
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Pavan-Guimaraes J, Devos L, Lascaris B, de Meijer VE, Monbaliu D, Jochmans I, Pulitano C, Porte RJ, Martins PN. Long-Term Liver Machine Perfusion Preservation: A Review of Recent Advances, Benefits and Logistics. Artif Organs 2025; 49:339-352. [PMID: 39895504 DOI: 10.1111/aor.14941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 12/23/2024] [Indexed: 02/04/2025]
Abstract
BACKGROUND The global shortage of suitable donor livers for transplantation has prompted efforts to expand the donor pool by using extended criteria donors. Machine preservation technology has shown promise in optimizing graft preservation and improving logistics. Additionally, it holds potential for organ repair, regeneration, therapeutic applications during extended preservation periods, and enhancing organ allocation. METHODS We conducted a comprehensive literature review using PubMed, Embase, and Web of Science databases. All studies published between January 1, 2022, and February 7, 2024, that described machine perfusion preservation of livers for more than 24 h were eligible for inclusion. The findings were synthesized in a narrative review format to highlight key benefits and advancements. RESULTS We identified eleven studies from multiple research groups, employing various techniques, devices, and preservation durations. Perfusion durations ranged from 1 to 13 days, with notable variations in protocols for long-term preservation beyond 24 h. Viability was assessed during perfusion only. No livers were transplanted. Among the reviewed studies, the introduction of a dialysis system emerged as the most effective strategy for managing waste accumulation during long-term liver perfusion. Differences were also observed in hemodynamics, oxygenation, organ chambers, supplemental regimens, and glycemic control. CONCLUSION Over the past two years, substantial progress has been made in refining protocols for long-term liver machine perfusion, with significant advancements in waste management, enabling successful multi-day perfusions. While these developments are promising, further research is necessary to standardize and optimize long-term perfusion protocols, establishing a reliable platform for both organ preservation and therapeutic applications.
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Affiliation(s)
| | - Lene Devos
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
| | - Bianca Lascaris
- Section of HPB Surgery and Liver Transplantation, UMCG Comprehensive Transplant Center, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Section of HPB Surgery and Liver Transplantation, UMCG Comprehensive Transplant Center, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Diethard Monbaliu
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Ina Jochmans
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Carlo Pulitano
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Robert J Porte
- Division of HPB and Transplant Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Paulo N Martins
- Department of Surgery, Transplant Institute, University of Oklahoma, Oklahoma City, Oklahoma, USA
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17
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Safarikia S, Cirelli R, Spagnoletti G, Martinelli D, Bravetti G, Francalanci P, D'Alessandro A, Di Felice G, Maistri M, Baldissone E, Fratti AM, Simeoli R, Sacchetti E, Cairoli S, Rizzo C, Pariante R, Vacca M, Cappoli A, Albano C, Pietrobattista A, Spada M, Vici CD. Normothermic Machine Perfusion of Explanted Human Metabolic Livers: A Proof of Concept for Studying Inborn Errors of Metabolism. J Inherit Metab Dis 2025; 48:e70010. [PMID: 40026238 PMCID: PMC11874047 DOI: 10.1002/jimd.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/13/2025] [Accepted: 02/04/2025] [Indexed: 03/05/2025]
Abstract
The human liver plays a central metabolic role; however, its physiology may become imbalanced in inborn errors of metabolism (IEM), a broad category of monogenic disorders. Liver transplantation has been increasingly used to improve patient metabolic control, especially in diseases related to amino acid metabolism, such as urea cycle disorders and organic acidurias, to provide enzyme replacement. Ex vivo liver normothermic machine perfusion (NMP) techniques have recently been developed to increase the number of transplantable grafts and improve transplantation outcomes. This study used seven NMP of explanted livers from patients with IEM undergoing transplantation as models to investigate disease-related liver metabolism and function. The perfused livers demonstrated positive viability indicators and disease-specific targeted metabolomics providing the proof-of-principle that our ex vivo model expresses the biochemical disease characteristics and responds to therapeutical intervention in a unique "physiological" milieu, offering an ideal tool to study novel treatments, in a setting closely mirroring human disease.
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Affiliation(s)
- Samira Safarikia
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Riccardo Cirelli
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
- Division of Hepatobiliopancreatic Surgery, Liver and Kidney Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Gionata Spagnoletti
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
- Division of Hepatobiliopancreatic Surgery, Liver and Kidney Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Diego Martinelli
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Giulia Bravetti
- Cardiac Surgery Unit, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Paola Francalanci
- Division of Pathology, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | | | - Giovina Di Felice
- Clinical Analysis Laboratory, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Marta Maistri
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
- Division of Hepatobiliopancreatic Surgery, Liver and Kidney Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Elena Baldissone
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Alberto M. Fratti
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
- Division of Hepatobiliopancreatic Surgery, Liver and Kidney Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Raffaele Simeoli
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Elisa Sacchetti
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Sara Cairoli
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Cristiano Rizzo
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Rosanna Pariante
- Division of Anesthesiology and Intensive Care, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Michele Vacca
- Division of Transfusion Medicine, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Andrea Cappoli
- Division of Nephrology, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Christian Albano
- B Cell Research Unit, Immunology Research Area, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Andrea Pietrobattista
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
- Unit of Hepatology and Transplant Clinic, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Marco Spada
- Research Unit of Clinical Hepatogastroenterology and Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
- Division of Hepatobiliopancreatic Surgery, Liver and Kidney Transplantation, Bambino Gesù Children's HospitalIRCCSRomeItaly
| | - Carlo Dionisi Vici
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's HospitalIRCCSRomeItaly
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18
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Todd R, van Leeuwen LL, Holzner M, Kim-Schluger L, Fiel MI, Puleston D, Florman SS, Akhtar MZ. Normothermic machine perfusion of explanted livers: Exploratory study of an alternative translational model for end-stage liver disease. Artif Organs 2025; 49:431-440. [PMID: 39578939 DOI: 10.1111/aor.14905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/08/2024] [Accepted: 11/01/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) is a technique for donor liver preservation and assessment in transplantation. NMP has gained momentum recently by enabling safer use of higher risk organs via organ viability assessment. It also offers a platform for investigating ex vivo organ biology. METHODS In this exploratory study, we completed a complex vascular reconstruction of explanted, diseased livers from patients undergoing transplantation and then perfused them normothermically on a closed perfusion circuit. We compared these livers to non-diseased donor livers via perfusate samples collected during perfusion. RESULTS Five hepatectomized grafts and eight donor livers were perfused for 1 h or longer. Four hepatectomized livers cleared lactate, and all consumed glucose; all control livers cleared lactate, and seven utilized glucose. Significantly higher portal vein flows were achieved in the control group. CONCLUSIONS Our findings illustrate the feasibility of using closed-circuit NMP as a platform to study hepatectomized organs, which could reshape the research landscape in mechanisms of disease and applied therapeutics for patients with end-stage liver disease.
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Affiliation(s)
- Rachel Todd
- Recanati/Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - L Leonie van Leeuwen
- Recanati/Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, USA
| | - Matthew Holzner
- Recanati/Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, USA
| | - Leona Kim-Schluger
- Recanati/Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, USA
| | - Maria Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Daniel Puleston
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sander S Florman
- Recanati/Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, USA
| | - M Zeeshan Akhtar
- Recanati/Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, USA
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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19
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Zarei S, Ghalichi F, Ahmadlouydarab M. Computational exploration of injection strategies for improving medicine distribution in the liver. Comput Biol Med 2025; 185:109585. [PMID: 39729858 DOI: 10.1016/j.compbiomed.2024.109585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 11/24/2024] [Accepted: 12/13/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND AND OBJECTIVES The liver, a vital metabolic organ, is always susceptible to various diseases that ultimately lead to fibrosis, cirrhosis, acute liver failure, chronic liver failure, and even cancer. Optimal and specific medicine delivery in various diseases, hepatectomy, shunt placement, and other surgical interventions to reduce liver damage, transplantation, optimal preservation, and revival of the donated organ all rely on a complete understanding of perfusion and mass transfer in the liver. This study aims to simulate the computational fluid dynamics of perfusion and the temporal-spatial distribution of a medicine in a healthy liver to evaluate the hemodynamic characteristics of flow and medicine transport with the purpose of more effective liver treatment. METHODS Patient-specific geometries of parenchyma and hepatic artery, portal vein, and hepatic vein vessels of a healthy liver were segmented and reconstructed from the abdominal computed tomography scan images. Mesh was generated for the comprehensive combined model using unstructured tetrahedral elements. Transient pressure values were applied as boundary conditions at the portal vein and hepatic artery inlets, and pressure outlet boundary condition was assumed at the hepatic vein outlet. Medicine injection was done through the portal vein. The liver parenchyma was assumed to be a porous medium. Finally, computational fluid dynamics (CFD) simulation was performed to investigate blood perfusion, medicine distribution, and saturation time. RESULTS The velocity parameter values calculated for the hepatic artery, portal vein, and hepatic vein vessels were consistent with the physiological ranges. The mass flow rate was higher in the portal vein than in the hepatic artery, which was consistent with high perfusion through the portal vein. The portal pressure gradient was 8.53 mmHg. From a pharmacokinetic viewpoint, medicine distribution in porous tissue was a heterogeneous process. Medicine distribution was higher at end-diastolic pressure than at peak-systolic pressure which showed the influence of hepatic artery flow. The tissue was saturated faster at first 40 s and with decreasing porosity, saturation time decreased, and distribution improved. CONCLUSION The right lobe included a higher number of vascular terminals due to its larger volume, and the flow rate was higher in this lobe compared to the left lobe. This showed the significant effect of the right lobe on the overall function of the body. Recirculation flow zones along hepatic artery and portal vein branches emphasized the sensitivity of downstream vessels. Rotational flow and potential vortex formation at the hepatic vein outlet may indicate a risk of plaque and clot formation in this region. The heterogeneous distribution of medicine indicated the importance of injection time in treating liver diseases. The percentage of tissue porosity affected the saturation time, so adjusting the medicine dose and injection time could be challenging in treatments.
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Affiliation(s)
- Sevda Zarei
- Department of Biomedical Engineering, Division of Biomechanics, Sahand University of Technology, Tabriz, Iran
| | - Farzan Ghalichi
- Department of Biomedical Engineering, Division of Biomechanics, Sahand University of Technology, Tabriz, Iran
| | - Majid Ahmadlouydarab
- Faculty of Chemical & Petroleum Engineering, University of Tabriz, Tabriz, Iran.
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20
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Jeddou H, Tzedakis S, Chaouch MA, Sulpice L, Samson M, Boudjema K. Viability Assessment During Normothermic Machine Liver Perfusion: A Literature Review. Liver Int 2025; 45:e16244. [PMID: 39821671 PMCID: PMC11740183 DOI: 10.1111/liv.16244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 12/25/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
BACKGROUND AND OBJECTIVE The discrepancy between donor organ availability and demand leads to a significant waiting-list dropout rate and mortality. Although quantitative tools such as the Donor Risk Index (DRI) help assess organ suitability, many potentially viable organs are still discarded due to the lack of universally accepted markers to predict post-transplant outcomes. Normothermic machine perfusion (NMP) offers a platform to assess viability before transplantation. Thus, livers considered unsuitable for transplantation based on the DRI can be evaluated and potentially transplanted. During NMP, various viability criteria have been proposed. These criteria are neither homogeneous nor consensual. In this review, we aimed to describe the viability criteria during NMP and evaluate their ability to predict hepatic graft function following transplantation. We conducted a PubMed search using the terms 'liver transplantation', 'normothermic machine perfusion' and 'assessment', including only English publications up to February 2024. Viability assessment during NMP includes multiple hepatocellular and cholangiocellular criteria. Lactate clearance and bile production are commonly used indicators, but their ability to predict post-transplant outcomes varies significantly. The predictive value of cholangiocellular criteria such as bile pH, bicarbonate and glucose levels remains under investigation. Novel markers, such as microRNAs and proteomic profiles, offer the potential to enhance graft evaluation accuracy and provide insights into the molecular mechanisms underlying liver viability. Combining perfusion parameters with biomarkers may improve the prediction of long-term graft survival. Future research should focus on standardising viability assessment protocols and exploring real-time biomarker evaluations, which could enhance transplantation outcomes and expand the donor pool.
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Affiliation(s)
- Heithem Jeddou
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Stylianos Tzedakis
- Department of Hepato‐Biliary, Digestive and Endocrine SurgeryCochin Hospital, APHPParisFrance
- Université Paris CitéParisFrance
| | - Mohamed Ali Chaouch
- Department of Visceral and Digestive SurgeryMonastir University HospitalMonastirTunisia
| | - Laurent Sulpice
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- INSERM OSS U1242, University Hospital, Rennes 1 UniversityRennesFrance
| | - Michel Samson
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Karim Boudjema
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
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21
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Kim JJ, Kurial SNT, Choksi PK, Nunez M, Lunow-Luke T, Bartel J, Driscoll J, Her CL, Dhillon S, Yue W, Murti A, Mao T, Ramos JN, Tiyaboonchai A, Grompe M, Mattis AN, Syed SM, Wang BM, Maher JJ, Roll GR, Willenbring H. AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion. Nat Biotechnol 2025:10.1038/s41587-024-02523-6. [PMID: 39881029 DOI: 10.1038/s41587-024-02523-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 12/02/2024] [Indexed: 01/31/2025]
Abstract
Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV capsid performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently and specifically than AAV5, AAV8 and AAV6, which are most commonly used clinically, and AAV-NP59, which is better at transducing human hepatocytes engrafted in immune-deficient mice. AAV-LK03 preferentially transduced periportal hepatocytes in normal liver, whereas AAV5 targeted pericentral hepatocytes in steatotic liver. AAV5 and AAV8 transduced liver sinusoidal endothelial cells as efficiently as hepatocytes. AAV capsid and steatosis influenced vector episome formation, which determines gene therapy durability, with AAV5 delaying concatemerization. Our findings inform capsid choice in clinical AAV liver gene therapy, including consideration of disease-relevant hepatocyte zonation and effects of steatosis, and facilitate the development of AAV capsids that transduce hepatocytes or other therapeutically relevant cell types in the human liver with maximum efficiency and specificity.
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Affiliation(s)
- Jae-Jun Kim
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Simone N T Kurial
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
| | - Pervinder K Choksi
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA, USA
| | - Miguel Nunez
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Tyler Lunow-Luke
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Jan Bartel
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Julia Driscoll
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Chris L Her
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Simaron Dhillon
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Stone Research Foundation, San Francisco, CA, USA
| | - William Yue
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Abhishek Murti
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Tin Mao
- Ambys Medicines, South San Francisco, CA, USA
- Genentech, South San Francisco, CA, USA
| | - Julian N Ramos
- Ambys Medicines, South San Francisco, CA, USA
- Adverum Biotechnologies, Redwood City, CA, USA
| | - Amita Tiyaboonchai
- Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
| | - Markus Grompe
- Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | - Aras N Mattis
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Shareef M Syed
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Bruce M Wang
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jacquelyn J Maher
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Garrett R Roll
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Holger Willenbring
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
- Liver Center, University of California, San Francisco, San Francisco, CA, USA.
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22
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Cillo U, Lonati C, Bertacco A, Magnini L, Battistin M, Borsetto L, Dazzi F, Al-Adra D, Gringeri E, Bacci ML, Schlegel A, Dondossola D. A proof-of-concept study in small and large animal models for coupling liver normothermic machine perfusion with mesenchymal stromal cell bioreactors. Nat Commun 2025; 16:283. [PMID: 39746966 PMCID: PMC11697227 DOI: 10.1038/s41467-024-55217-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 12/03/2024] [Indexed: 01/04/2025] Open
Abstract
To fully harness mesenchymal-stromal-cells (MSCs)' benefits during Normothermic Machine Perfusion (NMP), we developed an advanced NMP platform coupled with a MSC-bioreactor and investigated its bio-molecular effects and clinical feasibility using rat and porcine models. The study involved three work packages: 1) Development (n = 5): MSC-bioreactors were subjected to 4 h-liverless perfusion; 2) Rat model (n = 10): livers were perfused for 4 h on the MSC-bioreactor-circuit or with the standard platform; 3) Porcine model (n = 6): livers were perfused using a clinical device integrated with a MSC-bioreactor or in its standard setup. MSCs showed intact stem-core properties after liverless-NMP. Liver NMP induced specific, liver-tailored, changes in MSCs' secretome. Rat livers exposed to bioreactor-based perfusion produced more bile, released less damage and pro-inflammatory biomarkers, and showed improved mithocondrial function than those subjected to standard NMP. MSC-bioreactor integration into a clinical device resulted in no machine failure and perfusion-related injury. This proof-of-concept study presents a novel MSC-based liver NMP platform that could reduce the deleterious effects of ischemia/reperfusion before transplantation.
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Affiliation(s)
- Umberto Cillo
- Hepato-Biliary-Pancreatic Surgery and Liver Transplant Unit, General Surgery 2, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Caterina Lonati
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy.
| | - Alessandra Bertacco
- Hepato-Biliary-Pancreatic Surgery and Liver Transplant Unit, General Surgery 2, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Lucrezia Magnini
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy
| | - Michele Battistin
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy
| | - Lara Borsetto
- Hepato-Biliary-Pancreatic Surgery and Liver Transplant Unit, General Surgery 2, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Francesco Dazzi
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
| | - David Al-Adra
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Enrico Gringeri
- Hepato-Biliary-Pancreatic Surgery and Liver Transplant Unit, General Surgery 2, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Maria Laura Bacci
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Schlegel
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy
- Transplantation Center, Digestive Disease and Surgery Institute, Department of Immunity and Inflammation, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44106, USA
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100, Milan, Italy
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23
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Ly M, Lau NS, Dennis C, Chen J, Risbey C, Tan S, Chen R, Wang C, Gorrell MD, McKenzie C, Kench JG, Liu K, McCaughan GW, Crawford M, Pulitano C. Long-term ex situ normothermic machine perfusion allows regeneration of human livers with severe bile duct injury. Am J Transplant 2025; 25:60-71. [PMID: 39059585 DOI: 10.1016/j.ajt.2024.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/28/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024]
Abstract
Bile duct regeneration is hypothesized to prevent biliary strictures, a leading cause of morbidity after liver transplantation. Assessing the capacity for biliary regeneration may identify grafts as suitable for transplantation that are currently declined, but this has been unfeasible until now. This study used long-term ex situ normothermic machine perfusion (LT-NMP) to assess biliary regeneration. Human livers that were declined for transplantation were perfused at 36 °C for up to 13.5 days. Bile duct biopsies, bile, and perfusate were collected throughout perfusion, which were examined for features of injury and regeneration. Biliary regeneration was defined as new Ki-67-positive biliary epithelium following severe injury. Ten livers were perfused for a median duration of 7.5 days. Severe bile duct injury occurred in all grafts, and biliary regeneration occurred in 70% of grafts. Traditional biomarkers of biliary viability such as bile glucose improved during perfusion but this was not associated with biliary regeneration (P > .05). In contrast, the maintenance of interleukin-6 and vascular endothelial growth factor-A levels in bile was associated with biliary regeneration (P = .017 for both cytokines). This is the first study to demonstrate biliary regeneration during LT-NMP and identify a cytokine signature in bile as a novel biomarker for biliary regeneration during LT-NMP.
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Affiliation(s)
- Mark Ly
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia; Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Centenary Institute, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Ngee-Soon Lau
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia; Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Claude Dennis
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Jinbiao Chen
- Centenary Institute, The University of Sydney, Sydney, Australia
| | - Charles Risbey
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia; Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Sarah Tan
- Central Sydney Immunology Laboratory, Royal Prince Alfred Hospital, NSW, Australia
| | - Renfen Chen
- Central Sydney Immunology Laboratory, Royal Prince Alfred Hospital, NSW, Australia
| | - Chuanmin Wang
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia; Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Mark D Gorrell
- Centenary Institute, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Catriona McKenzie
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - James G Kench
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Ken Liu
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Centenary Institute, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Geoffrey W McCaughan
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Centenary Institute, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Michael Crawford
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia; Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Carlo Pulitano
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia; Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
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24
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Lan T, Yu M, Ming T, Wang H, Deng J, Cheng S, Shen Z, Kong D. A novel cytoprotective organ perfusion platform for reconstructing homeostasis of DCD liver while alleviating IRI injury. Bioeng Transl Med 2025; 10:e10724. [PMID: 39801755 PMCID: PMC11711209 DOI: 10.1002/btm2.10724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 07/21/2024] [Accepted: 09/06/2024] [Indexed: 01/16/2025] Open
Abstract
Pump is a vital component for expelling the perfusate in small animal isolated organ normothermic machine perfusion (NMP) systems whose flexible structure and rhythmic contraction play a crucial role in maintaining perfusion system homeostasis. However, the continuous extrusion forming with the rigid stationary shaft of the peristaltic pumps can damage cells, leading to metabolic disorders and eventual dysfunction of transplanted organs. Here, we developed a novel biomimetic blood-gas system (BBGs) for preventing cell damage. This system mimics the cardiac cycle and features an adjustable inspiratory-to-expiratory (IE) ratio to mitigate acidosis caused by continuous oxygen inhalation. In our study, adipose stem cells (ADSCs) were cultured within the circulatory system for 10 min, 2, and 4 h. Compared to the peristaltic pump, the BBGs significantly reduced cell apoptosis and morphological injury while enhancing cell proliferation and adhesion. Additionally, when the supernatant from ADSCs was introduced to LPS-induced macrophages for 24 h, the BBGs group demonstrated a more pronounced anti-inflammatory effect, characterized by reduced M1 macrophage expression. Besides, with isolated rat livers from donation after circulatory death (DCD) perfusion with ADSCs for 6 h by the BBGs, we detected fewer apoptotic cells and a reduced inflammatory response, evidenced by down-regulated TNF-α expression. The development of BBGs demonstrates the feasibility of recreating physiological liquid-gas circulation in vitro, offering an alternative platform for isolated organ perfusion, especially for applications involving cell therapy.
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Affiliation(s)
- Tingting Lan
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, School of Medicine, Nankai UniversityTianjinChina
| | - Mingxing Yu
- State Key Laboratory of Medicinal Chemical BiologyCollege of Life Science, Nankai UniversityTianjinChina
| | - Tao Ming
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, School of Medicine, Nankai UniversityTianjinChina
| | - Hong Wang
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
| | - Juan Deng
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
| | - Shuhan Cheng
- State Key Laboratory of Medicinal Chemical BiologyCollege of Life Science, Nankai UniversityTianjinChina
| | - Zhongyang Shen
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, School of Medicine, Nankai UniversityTianjinChina
| | - Deling Kong
- Research Institute of Transplant Medicine, Tianjin First Central Hospital, School of Medicine, Nankai UniversityTianjinChina
- State Key Laboratory of Medicinal Chemical BiologyCollege of Life Science, Nankai UniversityTianjinChina
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25
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De Carlis R, Lauterio A, Schlegel A, Gringeri E, Patrono D, Camagni S, Dondossola D, Pezzati D, Olivieri T, Pagano D, Bongini M, Montanelli P, Ravaioli M, Bernasconi D, Valsecchi MG, Baccarani U, Cescon M, Andorno E, Mazzaferro V, Gruttadauria S, Di Benedetto F, Ghinolfi D, Caccamo L, Pinelli D, Romagnoli R, Cillo U, De Carlis L. Are there any benefits of prolonged hypothermic oxygenated perfusion?: Results from a national retrospective study. Liver Transpl 2025; 31:70-84. [PMID: 39287560 DOI: 10.1097/lvt.0000000000000476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 08/11/2024] [Indexed: 09/19/2024]
Abstract
Dual hypothermic oxygenated perfusion (DHOPE) is increasingly being used to extend liver preservation to improve transplant logistics. However, little is known about its benefits in high-risk liver grafts. This study aimed to investigate whether prolonged DHOPE provides benefits other than improved logistics in all liver types. We performed a national retrospective cohort study of 177 liver transplants from 12 Italian centers preserved with DHOPE for ≥4 hours between 2015 and 2022. A control group of 177 DHOPEs of <4 hours during the same period was created using 1:1 propensity score matching. The impact of risk profiles and preservation times on the outcomes was assessed using univariable and multivariable regression models. No significant differences in posttransplant outcomes were found between prolonged and short DHOPEs. However, the prolonged group had a significantly lower incidence of posttransplant acute kidney injury (AKI) compared to the short group (30.5% vs. 44.6%, p = 0.008). Among prolonged DHOPEs, no differences in transplant outcomes were observed according to donor risk index, Eurotransplant definition for marginal grafts, and balance of risk score. DHOPE duration was associated with a lower risk of AKI in multivariable models adjusted for donor risk index, Eutrotransplant marginal grafts, and balance of risk score. Prolonged hypothermic oxygenated perfusion confirmed its protective effect against AKI in a multivariable model adjusted for donor and recipient risk factors [OR: 0.412, 95% CI: 0.200-0.850, p = 0.016]. Prolonged DHOPE is widely used to improve transplant logistics, provides good results with high-risk grafts, and appears to be associated with a lower risk of posttransplant AKI. These results provide further insight into the important role of DHOPE in preventing posttransplant complications.
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Affiliation(s)
- Riccardo De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Ph.D. Course in Clinical and Experimental Sciences, University of Padua, Padua, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Andrea Schlegel
- Transplantation Center at Digestive Disease and Surgery Institute and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Enrico Gringeri
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
| | - Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino University of Turin, Turin, Italy
| | - Stefania Camagni
- Department of Organ Failure and Transplantation, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Daniele Pezzati
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Hospital, Pisa, Italy
| | - Tiziana Olivieri
- Hepato-pancreato-biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Duilio Pagano
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, University of Pittsburgh Medical Center, Palermo, Italy
| | - Marco Bongini
- Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Paolo Montanelli
- Liver Transplantation Unit, San Martino Polyclinic Hospital, Genoa, Italy
| | - Matteo Ravaioli
- General Surgery and Transplant Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Davide Bernasconi
- Bicocca Bioinformatics Biostatistics and Bioimaging Centre, School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
- Department of Clinical Research and Innovation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Maria Grazia Valsecchi
- Bicocca Bioinformatics Biostatistics and Bioimaging Centre, School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Umberto Baccarani
- General Surgery Clinic and Liver Transplant Center, University-Hospital of Udine, Udine, Italy
| | - Matteo Cescon
- General Surgery and Transplant Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Enzo Andorno
- Liver Transplantation Unit, San Martino Polyclinic Hospital, Genoa, Italy
| | - Vincenzo Mazzaferro
- Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Department of Oncology, University of Milan, Milan, Italy
| | - Salvatore Gruttadauria
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, University of Pittsburgh Medical Center, Palermo, Italy
- Department of Surgery and Medical and Surgical Specialties, University of Catania, Catania, Italy
| | - Fabrizio Di Benedetto
- Hepato-pancreato-biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Davide Ghinolfi
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Hospital, Pisa, Italy
| | - Lucio Caccamo
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Domenico Pinelli
- Department of Organ Failure and Transplantation, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino University of Turin, Turin, Italy
| | - Umberto Cillo
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
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Shishido Y, Tracy KM, Petrovic M, Adesanya T, Fortier AK, Raietparvar K, Glomp GA, Simonds E, Harris TR, Simon V, Tucker WD, Petree B, Cortelli M, Cardwell NL, Crannell C, Liang J, Murphy AC, Fields BL, McReynolds M, Demarest CT, Ukita R, Rizzari M, Montenovo M, Magliocca JF, Karp SJ, Rauf MA, Shah AS, Bacchetta M. Novel Dynamic Organ Storage System Enhances Liver Graft Function in a Porcine Donation After Circulatory Death Model. ASAIO J 2024:00002480-990000000-00611. [PMID: 39693205 DOI: 10.1097/mat.0000000000002365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Donation after circulatory death (DCD) livers face increased risks of critical complications when preserved with static cold storage (SCS). Although machine perfusion (MP) may mitigate these risks, its cost and logistical complexity limit widespread application. We developed the Dynamic Organ Storage System (DOSS), which delivers oxygenated perfusate at 10°C with minimal electrical power requirement and allows real-time effluent sampling in a portable cooler. In a porcine DCD model, livers were preserved using DOSS or SCS for 10 hours and evaluated with 4 hours of normothermic MP, with n = 5 per group. After 4 hours of normothermic MP, the DOSS group demonstrated significantly lower perfusate lactate (p = 0.023), increased perfusate fibrinogen (p = 0.005), higher oxygen consumption (p = 0.018), greater bile production (p = 0.013), higher bile bicarbonate levels (p = 0.035) and bile/perfusate sodium ratio (p = 0.002), and lower hepatic arterial resistance after phenylephrine administration (p = 0.018). Histological analysis showed lower apoptotic markers in DOSS-preserved livers, with fewer cleaved caspase-3 (p = 0.039) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL; p = 0.009) positive cells. These findings suggest that DOSS can enhance DCD allograft function during transport, offering potential clinical benefits and contributing to the expansion of the donor pool.
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Affiliation(s)
- Yutaka Shishido
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kaitlyn M Tracy
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mark Petrovic
- Vanderbilt University Medical School , Nashville, Tennessee
| | | | | | | | | | | | - Timothy R Harris
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Victoria Simon
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - William D Tucker
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Brandon Petree
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Michael Cortelli
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Nancy L Cardwell
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Christian Crannell
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jiancong Liang
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Alexandria C Murphy
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Blanche L Fields
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Melanie McReynolds
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Caitlin T Demarest
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rei Ukita
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Michael Rizzari
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Martin Montenovo
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Joseph F Magliocca
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Seth J Karp
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - M Ameen Rauf
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ashish S Shah
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew Bacchetta
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
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Lascaris B, Nijsten MWN, de Meijer VE. No need for complex blood purification systems for renal replacement therapy during long-term liver normothermic machine perfusion. J Hepatol 2024; 81:e287-e289. [PMID: 38879171 DOI: 10.1016/j.jhep.2024.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/06/2024] [Accepted: 06/06/2024] [Indexed: 11/19/2024]
Affiliation(s)
- Bianca Lascaris
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, 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
| | - Vincent E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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28
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Risbey CWG, Lau NS, Pulitano C. The importance of developing viability criteria to assess liver grafts undergoing multi-week normothermic perfusion. J Hepatol 2024; 81:e290-e291. [PMID: 39038549 DOI: 10.1016/j.jhep.2024.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 07/24/2024]
Affiliation(s)
- Charles W G Risbey
- Department of Transplant Surgery, Royal Prince Alfred Hospital. 50 Missenden Rd, Camperdown, 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO). 145 Missenden Rd, Camperdown, 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI). 145 Missenden Rd, Camperdown, 2050, NSW, Australia; Central Clinical School, The University of Sydney. John Hopkins Dr, Camperdown, 2050, NSW, Australia
| | - Ngee-Soon Lau
- Centre for Organ Assessment, Repair, & Optimization (COARO). 145 Missenden Rd, Camperdown, 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI). 145 Missenden Rd, Camperdown, 2050, NSW, Australia; Central Clinical School, The University of Sydney. John Hopkins Dr, Camperdown, 2050, NSW, Australia
| | - Carlo Pulitano
- Department of Transplant Surgery, Royal Prince Alfred Hospital. 50 Missenden Rd, Camperdown, 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO). 145 Missenden Rd, Camperdown, 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI). 145 Missenden Rd, Camperdown, 2050, NSW, Australia; Central Clinical School, The University of Sydney. John Hopkins Dr, Camperdown, 2050, NSW, Australia.
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29
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Jiao X, Li Y, Chen Z, Zhang Q, He R, Huang Y, Zuo Z. Targeting the PDE3B-cAMP-autophagy axis prevents liver injury in long-term supercooling liver preservation. Sci Transl Med 2024; 16:eadk0636. [PMID: 39602509 DOI: 10.1126/scitranslmed.adk0636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 05/11/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024]
Abstract
In liver transplantation, donor livers are typically stored in a preservation solution at 4°C for up to 12 hours. However, this short preservation duration can lead to various issues, such as suboptimal donor-recipient matching and limited opportunities for organ sharing. Previous studies have developed a long-term preservation method called supercooling liver preservation (SLP) to address these issues. However, in this study using a rat model, we observed that long-term SLP led to more severe liver damage compared with clinically prevalent traditional static cold storage (SCS) for durations less than 8 hours. To understand the potential mechanism of SLP-induced liver injury, we conducted an integrative metabolomic, transcriptomic, and proteomic analysis. We identified the PDE3B-cAMP-autophagy pathway as a key determinant of SLP-induced liver injury. Specifically, we found that PDE3B was elevated during SLP, which promoted a reduction of cAMP metabolites, triggering an AMPK-dependent autophagy process that led to liver injury in rats. We found that blocking the reduction in cAMP using the PDE3B inhibitor cilostamide inhibited autophagy and substantially ameliorated liver injury during 48-hour SLP in rat livers. Furthermore, we validated the effectiveness of cilostamide treatment in preventing liver injury in pig and human liver 48-hour SLP models. In summary, our results reveal that metabolic reprogramming involving the PDE3B-cAMP-autophagy axis is the key determinant of liver injury in long-term SLP and provide an early therapeutic strategy to prevent liver injury in this setting.
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Affiliation(s)
- Xingyuan Jiao
- Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yihu Li
- Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
- Department of Hepatobiliary Surgery, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China
| | - Zhihang Chen
- State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510060, China
| | - Qi Zhang
- Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Rui He
- Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yinbing Huang
- Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhixiang Zuo
- State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510060, China
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30
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Lau NS, McCaughan G, Ly M, Liu K, Crawford M, Pulitano C. Long-term machine perfusion of human split livers: a new model for regenerative and translational research. Nat Commun 2024; 15:9809. [PMID: 39532864 PMCID: PMC11557707 DOI: 10.1038/s41467-024-54024-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Recent advances in machine perfusion have revolutionised the field of transplantation by prolonging preservation, permitting evaluation of viability prior to implant and rescue of discarded organs. Long-term perfusion for days-to-weeks provides time to modify these organs prior to transplantation. By using long-term normothermic machine perfusion to facilitate liver splitting and subsequent perfusion of both partial organs, possibilities even outside the clinical arena become possible. This model remains in its infancy but in the future, could allow for detailed study of liver injury and regeneration, and ex-situ treatment strategies such as defatting, genetic modulation and stem-cell therapies. Here we provide insight into this new model for research and highlight its great potential and current limitations.
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Affiliation(s)
- Ngee-Soon Lau
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Geoffrey McCaughan
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Mark Ly
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Ken Liu
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Michael Crawford
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Carlo Pulitano
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia.
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia.
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
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31
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Li Z, Pfister M, Huwyler F, Hoffmann W, Tibbitt MW, Dutkowski P, Clavien PA. Revolutionizing Liver Transplantation: Transitioning to an Elective Procedure Through Ex Situ Normothermic Machine Perfusion - A Benefit Analysis. Ann Surg 2024; 280:887-895. [PMID: 39077782 DOI: 10.1097/sla.0000000000006462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/31/2024]
Abstract
OBJECTIVE To assess the impact of normothermic machine perfusion (NMP) on patients, medical teams, and costs by gathering global insights and exploring current limitations. BACKGROUND NMP for ex situ liver graft perfusion is gaining increasing attention for its capability to extend graft preservation. It has the potential to transform liver transplantation (LT) from an urgent to a purely elective procedure, which could revolutionize LT logistics, reduce burden on patients and health care providers, and decrease costs. METHODS A 31-item survey was sent to international transplant directors to gather their NMP experiences and vision. In addition, we performed a systematic review on cost-analysis in LT and assessed studies on cost-benefit in converting urgent-to-elective procedures. We compared the costs of available NMPs and conducted a sensitivity analysis of NMP's cost benefits. RESULTS Of 120 transplant programs contacted, 64 (53%) responded, spanning North America (31%), Europe (42%), Asia (22%), and South America (5%). Of the total, 60% had adopted NMP, with larger centers (>100 transplants/year) in North America and Europe more likely to use it. The main NMP systems were OrganOx-metra (39%), XVIVO (36%), and TransMedics-OCS (15%). Despite NMP adoption, 41% of centers still perform >50% of LTs at nights/weekends. Centers recognized NMP's benefits, including improved work satisfaction and patient outcomes, but faced challenges like high costs and machine complexity. 16% would invest $100,000 to 500'000, 33% would invest $50,000 to 100'000, 38% would invest $10,000 to 50'000, and 14% would invest <$10,000 in NMP. These results were strengthened by a cost analysis for NMP in emergency-to-elective LT transition. Accordingly, while liver perfusions with disposables up to $10,000 resulted in overall positive net balances, this effect was lost when disposables' cost amounted to >$40,000/organ. CONCLUSIONS The adoption of NMP is hindered by high costs and operational complexity. Making LT elective through NMP could reduce costs and improve outcomes, but overcoming barriers requires national reimbursements and simplified, automated NMP systems for multiday preservation.
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Affiliation(s)
- Zhihao Li
- Department of Surgery and Transplantation, University of Zurich, Zurich, Switzerland
| | - Matthias Pfister
- Department of Surgery and Transplantation, University of Zurich, Zurich, Switzerland
- Wyss Zurich Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Florian Huwyler
- Wyss Zurich Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland
- Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland
| | - Waldemar Hoffmann
- Wyss Zurich Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Mark W Tibbitt
- Department of Surgery and Transplantation, University of Zurich, Zurich, Switzerland
- Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Visceral Surgery, University Hospital Basel, Switzerland
| | - Pierre-Alain Clavien
- Department of Surgery and Transplantation, University of Zurich, Zurich, Switzerland
- Wyss Zurich Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland
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32
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Cywes C, Banker A, Muñoz N, Levine M, Abu-Gazala S, Bittermann T, Abt P. The Potential Utilization of Machine Perfusion to Increase Transplantation of Macrosteatotic Livers. Transplantation 2024; 108:e370-e375. [PMID: 38773856 DOI: 10.1097/tp.0000000000005057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2024]
Abstract
BACKGROUND The demand for liver transplantation has led to the utilization of marginal grafts including moderately macrosteatotic livers (macrosteatosis ≥30% [Mas30]), which are associated with an elevated risk of graft failure. Machine perfusion (MP) has emerged as a technique for organ preservation and viability testing; however, little is known about MP in Mas30 livers. This study evaluates the utilization and outcomes of Mas30 livers in the era of MP. METHODS The Organ Procurement and Transplantation Network database was queried to identify biopsy-proven Mas30 deceased donor liver grafts between June 1, 2016, and June 23, 2023. Univariable and multivariable models were constructed to study the association between MP and graft utilization and survival. RESULTS The final cohort with 3317 Mas30 livers was identified, of which 72 underwent MP and were compared with 3245 non-MP livers. Among Mas30 livers, 62 (MP) and 1832 (non-MP) were transplanted (utilization of 86.1% versus 56.4%, P < 0.001). Donor and recipient characteristics were comparable between MP and non-MP groups. In adjusted analyses, MP was associated with significantly increased Mas30 graft utilization (odds ratio, 7.89; 95% confidence interval [CI], 3.76-16.58; P < 0.001). In log-rank tests, MP was not associated with 1- and 3-y graft failure (hazard ratio, 0.49; 95% CI, 0.12-1.99; P = 0.319 and hazard ratio 0.43; 95% CI, 0.11-1.73; P = 0.235, respectively). CONCLUSIONS The utilization rate of Mas30 grafts increases with MP without detriment to graft survival. This early experience may have implications for increasing the available donor pool of Mas30 livers.
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Affiliation(s)
- Claire Cywes
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Amay Banker
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Nicolas Muñoz
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Matthew Levine
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Samir Abu-Gazala
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Therese Bittermann
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Peter Abt
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Purssell A, Kumar D. Impact of machine perfusion on transplant infectious diseases: New challenges and opportunities. Transpl Infect Dis 2024; 26 Suppl 1:e14348. [PMID: 39078339 DOI: 10.1111/tid.14348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/30/2024] [Accepted: 07/09/2024] [Indexed: 07/31/2024]
Abstract
Preservation techniques that maintain the viability of an organ graft between retrieval from the donor and implantation into the recipient remain a critical aspect of solid organ transplantation. While traditionally preservation is accomplished with static cold storage, advances in ex vivo dynamic machine perfusion, both hypothermic and normothermic, have allowed for prolongation of organ viability and recovery of marginal organs effectively increasing the usable donor pool. However, the use of these novel machine perfusion technologies likely exposes the recipient to additional infectious risk either through clonal expansion of pathogens derived during organ recovery or de novo exogenous acquisition of pathogens while the organ remains on the machine perfusion circuit. There is a paucity of high-quality studies that have attempted to quantify infection risk, although it appears that prolonging the time on the machine perfusion circuit and normothermic parameters increases the risk of infection. Conversely, the use of ex vivo machine perfusion unlocks new opportunities to detect and treat donor-derived infections before implantation into the recipient. This review seeks to reveal how the use of ex vivo machine perfusion strategies may augment the risk of infection in the organ recipient as well as outline ways that this technology could be leveraged to enhance our ability to manage donor-derived infections.
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Affiliation(s)
- Andrew Purssell
- Ajmera Transplant Centre, University Health Network, Toronto, Canada
| | - Deepali Kumar
- Ajmera Transplant Centre, University Health Network, Toronto, Canada
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Lascaris B, Bodewes SB, Adelmeijer J, Nijsten MWN, Porte RJ, de Meijer VE, Lisman T. Production of physiological amounts of hemostatic proteins by human donor livers during ex situ long-term normothermic machine perfusion for up to 7 days. J Thromb Haemost 2024; 22:3097-3106. [PMID: 39173880 DOI: 10.1016/j.jtha.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/06/2024] [Accepted: 08/01/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) is used for preservation and assessment of human donor livers prior to transplantation. During NMP, the liver is metabolically active, which allows detailed studies on the physiology of human livers. OBJECTIVES To study the production of hemostatic proteins in human donor livers during NMP for up to 7 days. METHODS In this observational study, 9 livers underwent NMP for up to 7 days with a heparinized perfusate based on red blood cells and colloids using a modified Liver Assist device (XVIVO). Perfusate samples were collected before NMP and daily thereafter for measurement of antigen and activity levels of a comprehensive panel of hemostatic proteins after heparin neutralization. RESULTS Within 1 day, perfusate samples displayed the potential for coagulation activation as evidenced by international normalized ratio and activated partial thromboplastin assays. This was accompanied by detection of substantial quantities of functionally active coagulation proteins and inhibitors, although the specific activity of many proteins was decreased, compared with that in normal plasma. Perfusate levels of hemostatic proteins increased in the first days, reaching a stable level after 3 to 4 days of perfusion. CONCLUSION During long-term NMP of human livers, functionally active hemostatic proteins are released into the perfusate in substantial quantities, but some proteins appear to have decreased functional properties compared with proteins in normal human plasma. We propose that NMP may be used as a platform to test efficacy of drugs that stimulate or inhibit the production of coagulation factors or to test liver-mediated clearance of prohemostatic protein therapeutics.
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Affiliation(s)
- Bianca Lascaris
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Silke B Bodewes
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jelle Adelmeijer
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center 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
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Vincent E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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35
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Hosgood SA, Nicholson ML. Current Basic Research in Normothermic Machine Perfusion. Eur Surg Res 2024; 65:137-145. [PMID: 39471796 DOI: 10.1159/000542290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 10/24/2024] [Indexed: 11/01/2024]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) is gradually being introduced into clinical transplantation to improve the quality of organs and increase utilisation. This review details current understanding of the underlying mechanistic effects of NMP in the heart, lung, liver, and kidney. It also considers recent advancements to extend the perfusion interval in these organs and the use of NMP to introduce novel therapeutic interventions, with a focus on organ modulation. SUMMARY The re-establishment of circulation during NMP leads to the upregulation of inflammatory and immune mediators, similar to an ischaemia-reperfusion injury response. The level of injury is determined by the condition of the organ, but inflammation may also be exacerbated by the passenger leucocytes that emerge from the organ during perfusion. There is evidence that damaged organs can recover and that prolonged NMP may be advantageous. In the liver, successful 7-day NMP has been achieved. The delivery of therapeutic agents to an organ can aid repair and be used to modify the organ to reduce immunogenicity or change the structure of the blood group antigens to create a universal donor blood group organ. KEY MESSAGES The application of NMP in organ transplantation is a growing area of research and is increasingly being used in the clinic. In the future, NMP may offer the opportunity to change practice. If organs can be preserved for days on an NMP system, transplantation may become an elective rather than an emergency procedure. The ability to introduce therapies during NMP is an effective way to treat an organ and avoid the complexity of treating the recipient.
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Affiliation(s)
- Sarah A Hosgood
- Department of Surgery, University of Cambridge, Cambridge, UK
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36
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Ozgur OS, Taggart M, Mojoudi M, Pendexter C, Filz von Reiterdank I, Kharga A, Yeh H, Toner M, Longchamp A, Tessier SN, Uygun K. Optimized partial freezing protocol enables 10-day storage of rat livers. Sci Rep 2024; 14:25260. [PMID: 39448774 PMCID: PMC11502795 DOI: 10.1038/s41598-024-76674-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
Preserving organs at subzero temperatures with halted metabolic activity holds the potential to prolong preservation and expand the donor organ pool for transplant. Our group recently introduced partial freezing, a novel approach in high-subzero storage at -15 °C, enabling 5-day storage of rodent livers through precise control over ice nucleation and unfrozen fraction. However, increased vascular resistance and tissue edema suggested a need for improvements to extend viable preservation. Here, we describe an optimized partial freezing protocol with key optimizations, including an increased concentration of polyethylene glycol (PEG) to enhance membrane stability while minimizing shear stress during cryoprotectant unloading with an acclimation period and a maintained osmotic balance through an increase in bovine serum albumin (BSA). These approaches ensured the viability during preservation and recovery processes, promoting liver function and ensuring optimal preservation. This was evidenced by increased oxygen consumption, decreased vascular resistance, and edema. Ultimately, we show that using the optimized protocol, livers can be stored for 10 days with comparable vascular resistance and lactate levels to 5 days, outperforming the viability of time-matched static cold stored (SCS) livers as the current gold standard. This study represents a significant advancement in expanding organ availability through prolonged preservation, thereby revolutionizing transplant medicine.
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Affiliation(s)
- Ozge Sila Ozgur
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
| | - Mclean Taggart
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
| | - Mohammedreza Mojoudi
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
| | - Casie Pendexter
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
| | - Irina Filz von Reiterdank
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
| | - Anil Kharga
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Heidi Yeh
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Mehmet Toner
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
| | - Alban Longchamp
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Hospitals for Children, Boston, MA, USA
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Shannon N Tessier
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Shriners Hospitals for Children, Boston, MA, USA.
| | - Korkut Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Shriners Hospitals for Children, Boston, MA, USA.
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Clarke G, Mao J, Hann A, Fan Y, Gupta A, Nutu A, Buckel Schaffner E, Kayani K, Murphy N, Bangash MN, Casey AL, Wootton I, Lawson AJ, Dasari BVM, Perera MTPR, Mergental H, Afford SC. A reproducible extended ex-vivo normothermic machine liver perfusion protocol utilising improved nutrition and targeted vascular flows. COMMUNICATIONS MEDICINE 2024; 4:214. [PMID: 39448795 PMCID: PMC11502869 DOI: 10.1038/s43856-024-00636-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Normothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers. METHODS Human livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion. RESULTS Perfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120-184 h), with preserved viability throughout. CONCLUSIONS Livers can be reproducibly perfused in excess of 120 (range 121-184) hours with evidence of preserved hepatocyte and cholangiocyte function.
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Affiliation(s)
- George Clarke
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK.
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK.
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK.
| | - Jingwen Mao
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK
| | - Angus Hann
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK
| | - Yiyu Fan
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK
| | | | - Anisa Nutu
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
| | | | - Kayani Kayani
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK
- Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
| | - Nicholas Murphy
- Intensive Care Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TH, UK
| | - Mansoor N Bangash
- Intensive Care Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TH, UK
| | - Anna L Casey
- Microbiology Department, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
| | - Isla Wootton
- Clinical Biochemistry, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
| | - Alexander J Lawson
- Clinical Biochemistry, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
| | - Bobby V M Dasari
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
| | - M Thamara P R Perera
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2TH, UK
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK
| | - Simon C Afford
- Birmingham Biomedical Research Centre, National Institute for Health Research (NIHR), University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TH, UK
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Guo Z, Yin M, Sun C, Xu G, Wang T, Jia Z, Zhang Z, Zhu C, Zheng D, Wang L, Huang S, Liu D, Zhang Y, Xie R, Gao N, Zhan L, He S, Zhu Y, Li Y, Nashan B, Andrea S, Xu J, Zhao Q, He X. Liver protects neuron viability and electrocortical activity in post-cardiac arrest brain injury. EMBO Mol Med 2024; 16:2322-2348. [PMID: 39300235 PMCID: PMC11479250 DOI: 10.1038/s44321-024-00140-z] [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: 02/24/2024] [Revised: 07/18/2024] [Accepted: 08/14/2024] [Indexed: 09/22/2024] Open
Abstract
Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.
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Affiliation(s)
- Zhiyong Guo
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China.
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.
| | - Meixian Yin
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Chengjun Sun
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
- Department of Organ Transplantation, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Guixing Xu
- Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tielong Wang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Zehua Jia
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Zhiheng Zhang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Caihui Zhu
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Donghua Zheng
- Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Linhe Wang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Shanzhou Huang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Di Liu
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Yixi Zhang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Rongxing Xie
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Ningxin Gao
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Liqiang Zhan
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Shujiao He
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Yifan Zhu
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Yuexin Li
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Björn Nashan
- Organ Transplant Center, The First Affiliated Hospital of the University of Science and Technology of China, Hefei, China
| | - Schlegel Andrea
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Jin Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Qiang Zhao
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China.
| | - Xiaoshun He
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China.
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Uygun K, von Reiterdank IF, Mojoudi M, Bento R, Taggart M, Dinicu A, Wojtkiewicz G, Coert J, van der Molen AM, Weissleder R, Parekkadan B. Ex Vivo Machine Perfusion as a Platform for Lentiviral Gene Delivery in Rat Livers. RESEARCH SQUARE 2024:rs.3.rs-4784505. [PMID: 39315250 PMCID: PMC11419271 DOI: 10.21203/rs.3.rs-4784505/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Developing new strategies for local monitoring and delivery of immunosuppression is critical to making allografts safer and more accessible. Ex vivo genetic modification of grafts using machine perfusion presents a promising approach to improve graft function and modulate immune responses while minimizing risks of off-target effects and systemic immunogenicity in vivo. This proof-of-concept study demonstrates the feasibility of using normothermic machine perfusion (NMP) to mimic in vitro conditions for effective gene delivery. In this study, lentiviral vectors carrying biosensor constructs with Gaussia Luciferase (GLuc) were introduced to rodent livers during a 72-hour perfusion period, with a targeted delivery of 3 × 107 infection units (IU). Following the initial 24-hour exposure required for viral transduction, an additional 48 hours was necessary to observe gene expression, analogous to in vitro benchmarks. The perfused livers displayed significantly increased luminescence compared to controls, illustrating successful genetic modification. These findings validate the ex vivo use of lentiviral particles in a rodent liver model and lay the groundwork for a broad range of applications through genetic manipulation of organ systems. Future studies will focus on refining this technology to enhance precision in gene expression and explore its implications for clinical transplantation.
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Affiliation(s)
- Korkut Uygun
- Massachusetts General Hospital, Harvard Medical School
| | | | | | | | | | | | | | - J Coert
- University Medical Center Utrecht
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40
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Zhao Q, Li J, Lin Z, Tang Y, Yang D, Qin M, Ma X, Ji H, Chen H, Wang T, Chen M, Ju W, Wang D, Guo Z, Zhu X, Dan J, Hu A, He X. The First Case of Intra-portal Islet Implantation During Liver Machine Perfusion Allowing Simultaneous Islet-liver Transplantation in A Human: A New and Safe Treatment for End-stage Liver Disease Combined With Diabetes Mellitus. Ann Surg 2024; 281:00000658-990000000-01066. [PMID: 39247951 PMCID: PMC11723485 DOI: 10.1097/sla.0000000000006526] [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: 09/10/2024]
Abstract
OBJECTIVE Evaluating the safety and efficacy of implanting a liver with islet grafts into patients with end-stage liver disease and diabetes mellitus (DM). BACKGROUND DM and end-stage liver diseases are significant health concern worldwide, often coexisting and mutually influencing each other. Addressing both diseases simultaneously is paramount. METHODS We utilized the islet transplantation combined ischemia-free liver transplantation (ITIFLT) technique to treat a patient with hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM). The liver was procured and preserved using the ischemia-free liver transplantation (IFLT) technique, and during normothermic machine perfusion (NMP), isolated and purified islet grafts were transplanted into the liver through the portal vein. Finally, the liver, incorporating with the transplant islet grafts, was implanted into the recipient without interruption of blood supply. RESULTS The patient received both liver and islet graft from the same donor. The patient achieved insulin-independence by post-transplant day (PTD) 9, and both liver and islet function remained robust. The patient was discharged on PTD 18 and experienced no surgical or transplantation-related complications during the follow-up period. Furthermore, islet grafts presence was observed in liver biopsies after islet transplantation. CONCLUSIONS This landmark case marks the inaugural application of ITIFLT in humans, signifying its potential as a promising treatment modality for end-stage liver disease with DM.
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Affiliation(s)
- Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jiahao Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zepeng Lin
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, 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 Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Daopeng Yang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Meiting Qin
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xue Ma
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Haibin Ji
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Honghui Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Tielong Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Dongping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jia Dan
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Anbin Hu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
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Alnagar AM, Hajibandeh S, Hajibandeh S, Hakeem AR, Dasari BV. Impact of Donor Obesity on Graft and Recipient Survival Outcomes After Liver Transplantation: A Systematic Review and Meta-analysis. Transplant Direct 2024; 10:e1656. [PMID: 39220221 PMCID: PMC11365672 DOI: 10.1097/txd.0000000000001656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/17/2024] [Accepted: 03/26/2024] [Indexed: 09/04/2024] Open
Abstract
Background The effect of donor body mass index (BMI) on liver transplantation (LT) outcomes remains unclear. Methods A systematic search of the MEDLINE, CENTRAL, Web of Science, and bibliographic reference lists was conducted. All comparative studies evaluating the outcomes of LT in obese (BMI > 30 kg/m2) and nonobese donors (BMI < 30 kg/m2) were included, and their risk of bias was assessed using the ROBINS-I assessment tool. Patient and graft survival, acute rejection, and graft failure requiring retransplantation were evaluated as outcome parameters. A random-effects model was used for outcome synthesis. Results We included 6 comparative studies reporting a total of 5071 liver transplant recipients from 708 obese and 4363 nonobese donors. There was no significant difference in 1-y (89.1% versus 84.0%, odds ratio [OR] 1.58; 95% CI 0.63-3.94, P = 0.33), 5-y (74.2%% versus 73.5%, OR 1.12; 95% CI 0.45-2.80, P = 0.81) graft survival, and 1-y (87.1% versus 90.3%, OR 0.71; 95% CI 0.43-1.15, P = 0.17) and 5-y (64.5% versus 71.6%, OR 0.71; 95% CI 0.49-1.05, P = 0.08) patient survival between 2 groups. Furthermore, recipients from obese and nonobese donors had a comparable risk of graft failure requiring retransplantation (OR 0.92; 95% CI 0.33-2.60, P = 0.88) or acute graft rejection (OR 0.70; 95% CI 0.45-1.11, P = 0.13). Conclusions A meta-analysis of the best available evidence (level 2a) demonstrates that donor obesity does not seem to have a negative impact on graft or patient outcomes. The available studies might be subject to selection bias as the grafts from obese donors are usually subject to biopsy to exclude steatosis and the recipients usually belong to the low-risk group. Future research is needed to evaluate the impact of donors subgrouped by various higher BMI on graft and patient-related outcomes as well as to capture data of the discarded grafts from obese donors; hence, selection criteria for the grafts that could be used for transplantation from obese donors is identified.
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Affiliation(s)
- Amr M.T. Alnagar
- Hepatobiliary and Pancreatic Surgery and Liver Transplant Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Shahab Hajibandeh
- Department of Hepatobiliary and Pancreatic Surgery, University Hospital of Wales, Cardiff, United Kingdom
| | - Shahin Hajibandeh
- Department of Hepatobiliary and Pancreatic Surgery, University Hospital Coventry, Coventry, United Kingdom
| | - Abdul R. Hakeem
- Department of Hepatobiliary and Liver Transplant Surgery, St James’s University Hospital NHS Trust, Leeds, United Kingdom
| | - Bobby V.M. Dasari
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Department of Liver Transplantation, HPB Surgery, Queen Elizabeth Hospital, Birmingham, United Kingdom
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42
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Cillo U, Nalesso F, Bertacco A, Indraccolo S, Gringeri E. Normothermic perfusion of a human tumoral liver for 17 days with concomitant extracorporeal blood purification therapy: Case description. J Hepatol 2024; 81:e96-e98. [PMID: 38703827 DOI: 10.1016/j.jhep.2024.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 05/06/2024]
Affiliation(s)
- Umberto Cillo
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Federico Nalesso
- Nephrology, Dialysis and Transplant Unit, Department of Medicine, University of Padua, Padova, Italy
| | - Alessandra Bertacco
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy.
| | - Stefano Indraccolo
- Basic and Translational Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, Padova University, Padova, Italy
| | - Enrico Gringeri
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
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43
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Feng S, Roll GR, Rouhani FJ, Sanchez Fueyo A. The future of liver transplantation. Hepatology 2024; 80:674-697. [PMID: 38537154 DOI: 10.1097/hep.0000000000000873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/02/2024] [Indexed: 06/15/2024]
Abstract
Over the last 50 years, liver transplantation has evolved into a procedure routinely performed in many countries worldwide. Those able to access this therapy frequently experience a miraculous risk-benefit ratio, particularly if they face the imminently life-threatening disease. Over the decades, the success of liver transplantation, with dramatic improvements in early posttransplant survival, has aggressively driven demand. However, despite the emergence of living donors to augment deceased donors as a source of organs, supply has lagged far behind demand. As a result, rationing has been an unfortunate focus in recent decades. Recent shifts in the epidemiology of liver disease combined with transformative innovations in liver preservation suggest that the underlying premise of organ shortage may erode in the foreseeable future. The focus will sharpen on improving equitable access while mitigating constraints related to workforce training, infrastructure for organ recovery and rehabilitation, and their associated costs. Research efforts in liver preservation will undoubtedly blossom with the aim of optimizing both the timing and conditions of transplantation. Coupled with advances in genetic engineering, regenerative biology, and cellular therapies, the portfolio of innovation, both broad and deep, offers the promise that, in the future, liver transplantation will not only be broadly available to those in need but also represent a highly durable life-saving therapy.
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Affiliation(s)
- Sandy Feng
- Department of Surgery, Division of Transplant Surgery, University of California, San Francisco, California, USA
| | - Garrett R Roll
- Department of Surgery, Division of Transplant Surgery, University of California, San Francisco, California, USA
| | - Foad J Rouhani
- Tissue Regeneration and Clonal Evolution Laboratory, The Francis Crick Institute, London, UK
- Institute of Liver Studies, King's College London, King's College Hospital, NHS Foundation Trust, London, UK
| | - Alberto Sanchez Fueyo
- Institute of Liver Studies, King's College London, King's College Hospital, NHS Foundation Trust, London, UK
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Zhao Q, Wang X, Liu K, Chen H, Dan J, Zhu Z, Guo L, Chen H, Ju W, Wang D, Tang Y, Guo Z, He X. Activation of farnesoid X receptor enhances the efficacy of normothermic machine perfusion in ameliorating liver ischemia-reperfusion injury. Am J Transplant 2024; 24:1610-1622. [PMID: 38615902 DOI: 10.1016/j.ajt.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 03/11/2024] [Accepted: 04/04/2024] [Indexed: 04/16/2024]
Abstract
The shortage of transplant organs remains a severe global issue. Normothermic machine perfusion (NMP) has the potential to increase organ availability, yet its efficacy is hampered by the inflammatory response during machine perfusion. Mouse liver ischemia-reperfusion injury (IRI) models, discarded human liver models, and porcine marginal liver transplantation models were utilized to investigate whether farnesoid X receptor (FXR) activation could mitigate inflammation-induced liver damage. FXR expression levels before and after reperfusion were measured. Gene editing and coimmunoprecipitation techniques were employed to explore the regulatory mechanism of FXR in inflammation inhibition. The expression of FXR correlates with the extent of liver damage after reperfusion. Activation of FXR significantly suppressed the inflammatory response triggered by IRI, diminished the release of proinflammatory cytokines, and improved liver function recovery during NMP, assisting discarded human livers to reach transplant standards. Mechanistically, FXR disrupts the interaction between p65 and p300, thus inhibiting modulating the nuclear factor kappa-B signaling pathway, a key instigator of inflammation. Our research across multiple species confirms that activating FXR can optimize NMP by attenuating IRI-related liver damage, thereby improving the utilization of marginal livers for transplantation.
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Affiliation(s)
- Qiang Zhao
- 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, Guangzhou, China
| | - Xiaobo 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, Guangzhou, China
| | - Kunpeng Liu
- Guangdong Provincial Key Laboratory of Liver Disease, Cell-Gene Therapy Translational Medicine Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Honghui Chen
- 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, Guangzhou, China
| | - Jia Dan
- 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, Guangzhou, China
| | - Zebin Zhu
- Organ Transplant Center, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Lili 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, Guangzhou, China
| | - Huadi Chen
- 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, Guangzhou, China
| | - Weiqiang Ju
- 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, Guangzhou, China
| | - Dongping 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, 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, 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, Guangzhou, China.
| | - 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, Guangzhou, China.
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Lei C, Li Z, Ma S, Zhang Q, Guo J, Ouyang Q, Lei Q, Zhou L, Yang J, Lin J, Ettlinger R, Wuttke S, Li X, Brinker CJ, Zhu W. Improving normothermic machine perfusion and blood transfusion through biocompatible blood silicification. Proc Natl Acad Sci U S A 2024; 121:e2322418121. [PMID: 39159377 PMCID: PMC11363281 DOI: 10.1073/pnas.2322418121] [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: 12/22/2023] [Accepted: 07/11/2024] [Indexed: 08/21/2024] Open
Abstract
The growing world population and increasing life expectancy are driving the need to improve the quality of blood transfusion, organ transplantation, and preservation. Here, to improve the ability of red blood cells (RBCs) for normothermic machine perfusion, a biocompatible blood silicification approach termed "shielding-augmenting RBC-in-nanoscale amorphous silica (SARNAS)" has been developed. The key to RBC surface engineering and structure augmentation is the precise control of the hydrolysis form of silicic acid to realize stabilization of RBC within conformal nanoscale silica-based exoskeletons. The formed silicified RBCs (Si-RBCs) maintain membrane/structural integrity, normal cellular functions (e.g., metabolism, oxygen-carrying capability), and enhance resistance to external stressors as well as tunable mechanical properties, resulting in nearly 100% RBC cryoprotection. In vivo experiments confirm their excellent biocompatibility. By shielding RBC surface antigens, the Si-RBCs provide universal blood compatibility, the ability for allogeneic mechanical perfusion, and more importantly, the possibility for cross-species transfusion. Being simple, reliable, and easily scalable, the SARNAS strategy holds great promise to revolutionize the use of engineered blood for future clinical applications.
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Affiliation(s)
- Chuanyi Lei
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou510006, People’s Republic of China
| | - Zeyu Li
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou510006, People’s Republic of China
| | - Shuhao Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou310027, People’s Republic of China
| | - Qi Zhang
- The Second Affiliated Hospital of Anhui Medical University, Hefei23060, People’s Republic of China
| | - Jimin Guo
- Center for Micro-Engineered Materials and the Department of Chemical and Biological Engineering, The University of New Mexico, Albuquerque, NM87131
| | - Qing Ouyang
- Department of Hepatobiliary Surgery and Liver Transplant Center, The General Hospital of Southern Theater, Guangzhou510010, People’s Republic of China
| | - Qi Lei
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou510006, People’s Republic of China
| | - Liang Zhou
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou510006, People’s Republic of China
| | - Junxian Yang
- Research Department of Medical Sciences, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou510080, China
| | - Jiangguo Lin
- Research Department of Medical Sciences, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou510080, China
| | - Romy Ettlinger
- EastChem School of Chemistry, University of St Andrews, North Haugh, St. AndrewsKY16 9ST, United Kingdom
| | - Stefan Wuttke
- BCMaterials, Basque Center for Materials, UPV/EHU Science Park, Leioa48950, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao48009, Spain
| | - Xuejin Li
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou310027, People’s Republic of China
| | - C. Jeffrey Brinker
- Center for Micro-Engineered Materials and the Department of Chemical and Biological Engineering, The University of New Mexico, Albuquerque, NM87131
| | - Wei Zhu
- MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou510006, People’s Republic of China
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Zhang IW, Lurje I, Lurje G, Knosalla C, Schoenrath F, Tacke F, Engelmann C. Combined Organ Transplantation in Patients with Advanced Liver Disease. Semin Liver Dis 2024; 44:369-382. [PMID: 39053507 PMCID: PMC11449526 DOI: 10.1055/s-0044-1788674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.
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Affiliation(s)
- Ingrid Wei Zhang
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain
| | - Isabella Lurje
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Knosalla
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Felix Schoenrath
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
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Patrono D, De Stefano N, Vissio E, Gambella A, Romagnoli R. Long-term normothermic machine perfusion of fatty livers: towards transplanting untransplantable livers? Hepatobiliary Surg Nutr 2024; 13:681-685. [PMID: 39175741 PMCID: PMC11336520 DOI: 10.21037/hbsn-24-285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 06/20/2024] [Indexed: 08/24/2024]
Affiliation(s)
- Damiano Patrono
- General Surgery 2U – Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Nicola De Stefano
- General Surgery 2U – Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Elena Vissio
- Pathology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | | | - Renato Romagnoli
- General Surgery 2U – Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
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49
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Groen PC, van Leeuwen OB, de Jonge J, Porte RJ. Viability assessment of the liver during ex-situ machine perfusion prior to transplantation. Curr Opin Organ Transplant 2024; 29:239-247. [PMID: 38764406 PMCID: PMC11224566 DOI: 10.1097/mot.0000000000001152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
PURPOSE OF REVIEW In an attempt to reduce waiting list mortality in liver transplantation, less-than-ideal quality donor livers from extended criteria donors are increasingly accepted. Predicting the outcome of these organs remains a challenge. Machine perfusion provides the unique possibility to assess donor liver viability pretransplantation and predict postreperfusion organ function. RECENT FINDINGS Assessing liver viability during hypothermic machine perfusion remains challenging, as the liver is not metabolically active. Nevertheless, the levels of flavin mononucleotide, transaminases, lactate dehydrogenase, glucose and pH in the perfusate have proven to be predictors of liver viability. During normothermic machine perfusion, the liver is metabolically active and in addition to the perfusate levels of pH, transaminases, glucose and lactate, the production of bile is a crucial criterion for hepatocyte viability. Cholangiocyte viability can be determined by analyzing bile composition. The differences between perfusate and bile levels of pH, bicarbonate and glucose are good predictors of freedom from ischemic cholangiopathy. SUMMARY Although consensus is lacking regarding precise cut-off values during machine perfusion, there is general consensus on the importance of evaluating both hepatocyte and cholangiocyte compartments. The challenge is to reach consensus for increased organ utilization, while at the same time pushing the boundaries by expanding the possibilities for viability testing.
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Affiliation(s)
- Puck C Groen
- Department of Surgery, Division of Hepato-Pancreato- Biliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
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Ozgur OS, Taggart MS, Mojoudi M, Pendexter C, Kharga A, Yeh H, Toner M, Longchamp A, Tessier SN, Uygun K. Optimized Partial Freezing Protocol Enables 10-Day Storage of Rat Livers. RESEARCH SQUARE 2024:rs.3.rs-4584242. [PMID: 39011100 PMCID: PMC11247935 DOI: 10.21203/rs.3.rs-4584242/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Abstract
Preserving organs at subzero temperatures with halted metabolic activity holds the potential to prolong preservation and expand the donor organ pool for transplant. Our group recently introduced partial freezing, a novel approach in high-subzero storage at -15°C, enabling 5 days storage of rodent livers through precise control over ice nucleation and unfrozen fraction. However, increased vascular resistance and tissue edema suggested a need for improvements to extend viable preservation. Here, we describe an optimized partial freezing protocol with key optimizations including increased concentration of propylene glycol to reduce ice recrystallization and maintained osmotic balance through an increase in bovine serum albumin, all while minimizing sheer stress during cryoprotectant unloading with an acclimation period. These approaches ensured the viability during preservation and recovery processes, promoting liver function and ensuring optimal preservation. This was evidenced by increased oxygen consumption, decreased vascular resistance and edema. Ultimately, we show that using the optimized protocol, livers can be stored for 10 days with comparable vascular resistance and lactate levels to 5 days, outperforming the viability of time-matched cold stored livers as the current gold standard. This study represents a significant advancement in expanding organ availability through prolonged preservation and thereby revolutionizing transplant medicine.
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Affiliation(s)
| | | | | | | | - Anil Kharga
- Massachusetts General Hospital, Harvard Medical School
| | - Heidi Yeh
- Massachusetts General Hospital, Harvard Medical School
| | - Mehmet Toner
- Massachusetts General Hospital, Harvard Medical School
| | | | | | - Korkut Uygun
- Massachusetts General Hospital, Harvard Medical School
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