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Baimas-George M, Archie WH, Soltys K, Soto JR, Levi D, Eskind L, Casingal V, Denny R, Attia M, Mazariegos GV, Vrochides D. Optimizing liver utilization for transplantation with partial grafts undergoing normothermic machine perfusion: Two case reports. World J Transplant 2025; 15:104109. [DOI: 10.5500/wjt.v15.i3.104109] [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: 12/09/2024] [Revised: 12/30/2024] [Accepted: 02/10/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Liver transplantation (LT) is the only curative, life-saving option for children and adults with end-stage liver disease. Due to the well-known shortage and heterogeneity of grafts, split LT (SLT) is an attractive strategy to expand the donor pool and reduce waitlist times. Given increased risk of cold ischemia time with SLT, machine perfusion represents a promising option to reduce it and optimize transplant logistics and outcomes. The present communication describes various possible combinations of procurement steps to perform SLT facilitated by placing one or both grafts on a normothermic machine perfusion (NMP) closed circuit device.
CASE SUMMARY A 19-month-old female with biliary atresia after failed Kasai portoenterostomy and a 42-year-old woman with unresectable intrahepatic cholangiocarcinoma were selected as recipients for a SLT from a 17-year-old male donor. The SLT generated a left lateral segment and a right trisectional graft of appropriate volume for both recipients. After a mixed in-situ and ex-situ split, in order to improve logistics, the right trisectional graft was placed on a closed circuit NMP device, following an appropriate vascular reconstruction. Both grafts were implanted with excellent short-term outcomes.
CONCLUSION Use of NMP with SLT for preservation prior to implantation allows not only for graft optimization but also for significant improvement of transplant logistics. We propose various models and standardization of logistic options for combining SLT with NMP to optimize graft availability and outcomes.
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Affiliation(s)
- Maria Baimas-George
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - William H Archie
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Kyle Soltys
- Division of Pediatric Abdominal Transplantation, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Jose R Soto
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - David Levi
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Lon Eskind
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Vincent Casingal
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Roger Denny
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Magdy Attia
- Liver Transplant Unit, Leeds Teaching Hospital, Leeds BD 11, United Kingdom
| | - George V Mazariegos
- Division of Pediatric Abdominal Transplantation, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Dionisios Vrochides
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
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Archie WH, Baimas-George M, Haynes N, Kundu S, Peterson K, Wehrle CJ, Huckleberry D, Eskind L, Levi D, Soto JR, Denny R, Casingal V, Cochran A, Rein EH, Vrochides D. Upper limit of normothermic machine preservation of liver grafts from donation after circulatory death yet to be defined. World J Transplant 2025; 15:99170. [DOI: 10.5500/wjt.v15.i2.99170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 11/07/2024] [Accepted: 12/11/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND The normothermic machine perfusion pump (NMPP) could shape the future of transplantation. Providing ex-vivo optimization, NMPP attenuates ischemic insult while replenishing energy. An understanding of machine perfusion time (MPT) impact and potential clinical benefits is paramount and necessitates exploration.
AIM To investigate the relationship between MPT and post-transplant graft function.
METHODS Retrospective review of the first 50 donation after circulatory death (DCD) grafts preserved using NMPP in a tertiary institution was performed. Essential preservation time points, graft parameters, recipient information, and postoperative outcomes were prospectively recorded. Early allograft dysfunction (EAD), L-Graft7 score and 90-day outcomes were collected for all grafts. The first 20 recipients were allocated into the early group, considered the learning curve population for the center. The subsequent 30 were allocated into the late group. Recipients were also stratified into cohorts depending on MPT, i.e., short (< 8 hours), medium (8-16 hours) and long (> 16 hours).
RESULTS NMPP operational parameters were not predictive of EAD, L-GrAFT7 or 90-day outcomes. The early group had significantly less MPT and cold ischemia time than the late group (553 minutes vs 850 minutes, P < 0.001) and (127.5 minutes vs 154 minutes, P = 0.025), respectively. MPT had no impact in either group.
CONCLUSION Increased MPT of DCD liver grafts had no adverse recipient results for the times utilized in this population, indicating its upper limits, likely beyond 24 hours, are not demonstrated within this study. Future studies are necessary to determine whether longer MPT is beneficial or detrimental to graft function and, if the latter, what is the maximum safe duration. Further studies of the effect of normothermic machine perfusion pump duration on long-term outcomes are also needed.
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Affiliation(s)
- William H Archie
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Maria Baimas-George
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Nathanael Haynes
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Souma Kundu
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Katheryn Peterson
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Chase J Wehrle
- Department of Hepato-Pancreato-Biliary/Liver Transplant Surgery, Cleveland Clinic Transplant Research Center, Cleveland, OH 44195, United States
| | - Damien Huckleberry
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Lon Eskind
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - David Levi
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Jose R Soto
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Roger Denny
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Vincent Casingal
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Allyson Cochran
- Department of Surgery, Carolinas Center for Surgical Outcomes Science, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Erin H Rein
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Dionisios Vrochides
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
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Okumura K, Dhand A, Hasjim BJ, Misawa R, Sogawa H, Veillette G, Nishida S. Liver transplant practices in the era of normothermic machine perfusion in the United States. World J Transplant 2025; 15:100427. [DOI: 10.5500/wjt.v15.i2.100427] [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: 08/17/2024] [Revised: 12/05/2024] [Accepted: 12/27/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Normothermic liver machine perfusion (NMP) is a novel technology used to preserve and evaluate the function of liver allografts.
AIM To assess NMP utilization in liver transplant (LT) practices.
METHODS All adult deceased-donor LT recipients between January 2021 and September 2023 in the United States were analyzed. Outcomes including discard rates, survival, preservation time and timing of surgery were compared between two groups: NMP vs non-NMP.
RESULTS Between 2021 and 2023, NMP was utilized in 1493 (6.3%) of all LTs in the United States. Compared to non-NMP group, NMP group had lower allograft discard rate (6.5% vs 10%, P < 0.001), older recipients’ age (median: 47 vs 42 years, P < 0.001), and higher utilization of donors from donation after circulatory death (DCD) (55% vs 11%, P < 0.001). NMP group also had longer distances between recipient and donor hospitals (median: 156 vs 138 miles, P < 0.001), longer preservation time (median: 12.2 vs 5.8 hours, P < 0.001), and more daytime reperfusion (74% vs 55%, P < 0.001). Post-transplant survival outcomes were comparable between the two groups. In a subgroup analysis of NMP, recipients in the long preservation time (≥ 8 hours) group had higher daytime reperfusion (78% vs 55%, P < 0.001) and similar post-transplant survival when compared to the short preservation time (< 8 hours) group.
CONCLUSION The utilization of NMP is associated with lower discard rates and increased DCD organs for LT. NMP allows for prolonging the preservation time and increased occurrence of daytime LT, without any impact on the survival outcomes.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center, Valhalla, NY 10595, United States
| | - Abhay Dhand
- Department of Surgery, Westchester Medical Center, Valhalla, NY 10595, United States
| | - Bima J Hasjim
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92697, United States
| | - Ryosuke Misawa
- Department of Surgery, Westchester Medical Center, Valhalla, NY 10595, United States
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center, Valhalla, NY 10595, United States
| | - Gregory Veillette
- Department of Surgery, Westchester Medical Center, Valhalla, NY 10595, United States
| | - Seigo Nishida
- Department of Surgery, Westchester Medical Center, Valhalla, NY 10595, United States
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Jan MY, Patidar KR, Ghabril MS, Kubal CA. Optimization and Protection of Kidney Health in Liver Transplant Recipients: Intra- and Postoperative Approaches. Transplantation 2025; 109:938-944. [PMID: 39439013 PMCID: PMC12091220 DOI: 10.1097/tp.0000000000005252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 08/24/2024] [Accepted: 09/15/2024] [Indexed: 10/25/2024]
Abstract
Postoperative acute kidney injury after liver transplant (LT) has long-term implications for kidney health. LT recipients are at risk of acute kidney injury due to a number of factors related to the donor liver, intraoperative factors including surgical technique, as well as recipient factors, such as pre-LT kidney function and postoperative complications. This review discusses these factors in detail and their impact on posttransplant kidney function. Long-term risk factors such as calcineurin inhibitors have also been discussed. Additionally, the impact of liver allocation policies on pre- and post-LT kidney health is discussed.
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Affiliation(s)
- Muhammad Y. Jan
- Division of Transplant Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Kavish R. Patidar
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Marwan S. Ghabril
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Chandrashekhar A. Kubal
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
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Zhou AL, Akbar AF, Ruck JM, Weeks SR, Wesson R, Ottmann SE, Philosophe B, Cameron AM, Meier RP, King EA. Use of Ex Situ Machine Perfusion for Liver Transplantation: The National Experience. Transplantation 2025; 109:967-975. [PMID: 39724135 PMCID: PMC12097960 DOI: 10.1097/tp.0000000000005290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
BACKGROUND Machine perfusion (MP) for liver transplantation has become more widespread in the United States, but national studies on this growing practice are lacking. We investigated national use and outcomes of MP for liver transplantation. METHODS Adult (≥18 y) liver recipients transplanted between January 1, 2016 and September 30, 2023 in the United Network for Organ Sharing database were included. We used Cox regression to compare 1-y posttransplant recipient survival and all-cause graft failure by use of MP and performed subgroup analyses among circulatory death (DCD) and brain death (DBD) donors. RESULTS Of 52 626 deceased donors with liver recovery, 1799 (3.5%) utilized MP. The proportion of all liver transplants using MP increased from 0.3% in 2016 to 15.5% in 2023. MP for DCD transplants increased from 0.8% in 2016 to 50.0% in 2023. Donors of MP grafts were older (47 [34-57] versus 42 [29-55] y, P < 0.001), had higher body mass indexes (28.3 [24.4-33.3] versus 27.3 [23.7-31.8] kg/m 2 , P < 0.001), and were more likely to be DCD (47.1% versus 9.3%, P < 0.001). Among DBD transplants, MP and non-MP DBD transplants had similar all-cause graft failure out to 1 y (adjusted hazards ratios, 1.12 [95% confidence interval, 0.87-1.43], P = 0.38). Among DCD transplants, MP recipients had improved survival out to 1 y (adjusted hazards ratios, 0.50 [95% confidence interval, 0.35-0.70], P < 0.001). CONCLUSIONS MP use in liver transplantation is rapidly expanding and is associated with favorable outcomes compared with cold storage. MP is associated with increased posttransplant survival for DCD transplants, highlighting the potential for MP to expand utilization of DCD grafts.
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Affiliation(s)
- Alice L. Zhou
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | - Armaan F. Akbar
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | - Jessica M. Ruck
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | - Sharon R. Weeks
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | - Russell Wesson
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | - Shane E. Ottmann
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | - Benjamin Philosophe
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | - Andrew M. Cameron
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
| | | | - Elizabeth A. King
- Division of Transplant Surgery, Department of Surgery,
Johns Hopkins Hospital
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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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7
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Viana P, Castillo-Flores S, Mora MMR, Cabral TDD, Martins PN, Kueht M, Faria I. Normothermic Machine Perfusion vs. Static Cold Storage in Liver Transplantation: A Systematic Review and Meta-Analysis. Artif Organs 2025; 49:945-954. [PMID: 39887468 DOI: 10.1111/aor.14960] [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] [Revised: 12/30/2024] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) represents an alternative to prolong liver preservation and reduce organ discard rates. We performed an updated systematic review and meta-analysis to compare NMP with static cold storage (SCS) in liver transplantation. METHODS MEDLINE, Embase, and Cochrane were searched for randomized controlled trials (RCTs) or observational studies. Risk ratios (RR) and mean differences were calculated. p < 0.05 was considered significant. A random-effects model was applied for all outcomes. PROSPERO ID CRD42023486184. RESULTS We included 1295 patients from 5 RCTs and 6 observational studies from 2016 to 2023. 592 (45.7%) underwent NMP. A subgroup RCT analysis favored NMP for non-anastomotic strictures (RR 0.4; 95% CI 0.2, 0.9), postreperfusion syndrome (RR 0.4; 95% CI 0.27, 0.56), and early allograft dysfunction (RR 0.6; 95% CI 0.4, 0.9). NMP favored higher organ utilization rates (RR 1.1; 95% CI 1.02, 1.18). No significant differences between NMP and SCS were observed in graft survival or patient survival at 12 months, primary non-function, serious adverse events, overall biliary complications, AST, or bilirubin levels peak within the first 7 days, ICU or hospital length of stay. CONCLUSION Our findings suggest that NMP is associated with lower non-anastomotic biliary stricture rates, postreperfusion syndrome, early allograft dysfunction, and higher organ utilization in the RCT subgroup analysis, without increasing adverse events.
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Affiliation(s)
- Patricia Viana
- University of Extreme South of Santa Catarina, Criciuma, Brazil
| | | | - Maria M R Mora
- Univeristat Internacional de Catalunya, Barcelona, Spain
| | | | - Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, University of Massachusetts, Worcester, Massachusetts, USA
| | - Michael Kueht
- Division of Transplant Surgery, Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
| | - Isabella Faria
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
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8
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Yamamoto T, Koizumi N, Markmann JF. The Impact of Over Three Years Commercial Use of Ex Vivo Normothermic Machine Perfusion for Liver Transplantation in the USA: A UNOS/OPTN Database Analysis. Artif Organs 2025; 49:1030-1045. [PMID: 39967383 DOI: 10.1111/aor.14975] [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: 06/17/2024] [Revised: 01/30/2025] [Accepted: 02/06/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND Data to date using normothermic machine perfusion (NMP) devices to resuscitate and assess marginal livers such as donation after circulatory death (DCD) livers has shown impressive prevention of ischemic reperfusion injury and ischemic cholangiopathy (IC). We examined the impact of these NMP devices over 3 years after their release for commercial use on deceased donor liver transplantation (LT). METHODS We conducted a retrospective analysis of UNOS-SRTR data of livers recovered from DCD donors or older (≥ 60 years old) donation after brain death (DBD) donors for LT as well as the outcome of LT from DBD or DCD donors performed from 1/1/2016 to 6/30/2024 to compare differences with ischemic cold storage (ICS) versus NMP. RESULTS Among 10 778 donors of DCD livers, 1987 donors used NMP, and 8791 donors used ICS. In NMP group, the proportion of discarded livers was significantly less (7.25% vs. 30.52%), donors were older, donor BMI higher and more expanded criteria donor than those in ICS group (all, p < 0.001). For older donors, 416 cases used NMP and in 10 708 cases the liver was recovered via ICS. The discard rate of livers in NMP group was significantly less (4.33% vs. 12.18%, p < 0.001) and donors were older and donor BMI higher than that in ICS group. In DCD LT, the incidence of primary nonfunction (PNF), acute rejection within 1 year after LT as well as graft failure due to IC and hepatic artery thrombosis (HAT) in NMP group were significantly less than those in ICS group. CONCLUSION In conclusion, commercial use of NMP has expanded the donor pool by accelerated usage of marginal livers such as DCD and older donors by permitting longer preservation and functional assessment of the liver. In addition, the usage of NMP for DCD LTs was associate with a reduced incidence of rejection, PNF, graft failure due to IC and HAT.
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Affiliation(s)
- Takayuki Yamamoto
- Division of Transplant Surgery, Department of Surgery, Albany Medical Center/Albany Medical College, Albany, New York, USA
| | - Naoru Koizumi
- Schar School of Policy and Government, George Mason University, Arlington, Virginia, USA
| | - James F Markmann
- Department of Transplant Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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9
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Tan XY, Kuang WJ, Deng FW, Huang ZP, Ouyang Q, Huang XT, Ho WI, Liang MJ, Huo F, Chen HW. Six-hour local 4 °C dual hypothermic oxygenated machine perfusion improves the preservation of porcine liver after cardiac death using an ex vivo reperfusion model. Hepatobiliary Pancreat Dis Int 2025; 24:294-302. [PMID: 40055037 DOI: 10.1016/j.hbpd.2025.02.003] [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: 01/16/2024] [Accepted: 02/14/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND The use of grafts from donation after circulatory death (DCD) overcomes the inadequate donor organ supply. Our team developed a transportable dual hypothermic oxygenated machine perfusion (DHOPE) device, which initiates DHOPE at a recipient center to reduce static cold storage (SCS) time and the risk of graft failure in DCD liver transplantation. METHODS Six porcine livers per group with 30 min of warm ischemia exposure were preserved via SCS or DHOPE for 6 h and then reperfused for 12 h with whole blood to mimic transplantation. Hepatocellular and biliary function and injury were assessed in perfusate and bile samples. Molecular biomarkers and histology were compared between groups. RESULTS Reperfusion portal vein pressure, in a flow-constant manner, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyltransferase (γ-GGT) release were significantly lower in the DHOPE group than in the SCS group at all time points. Higher bile production paralleled the lower levels of ALP and γ-GGT in the DHOPE group. The DHOPE group secreted more total bilirubin (TBIL) in bile, resulting in decreased TBIL in the perfusate, and livers preserved with DHOPE exhibited better cholangiocellular function. Furthermore, improvements in hypoxia, the inflammatory response, cell-free microRNAs and energy metabolism were observed in the DHOPE group. There were fewer apoptotic cells and TGF-β1-positive cells in the liver parenchyma and extrahepatic bile duct in the DHOPE group than in the SCS group. CONCLUSIONS This study demonstrates the efficacy of local 4 °C DHOPE to protect porcine liver grafts from 30-min warm ischemia damage.
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Affiliation(s)
- Xiao-Yu Tan
- Department of Hepatobiliary Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China
| | - Wei-Jian Kuang
- Guangdong Shunde Industry Design Institute (Guangdong Shunde Innovative Design Institute), Foshan 528315, China
| | - Fei-Wen Deng
- Department of Hepatopancreatic Surgery, Foshan First People's Hospital, Foshan 528010, China
| | - Zhi-Ping Huang
- Department of Hepatobiliary Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China
| | - Qing Ouyang
- Department of Hepatobiliary Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China
| | - Xiao-Tao Huang
- Guangdong Shunde Industry Design Institute (Guangdong Shunde Innovative Design Institute), Foshan 528315, China
| | - Wai I Ho
- Department of Hepatopancreatic Surgery, Foshan First People's Hospital, Foshan 528010, China
| | - Ming-Ju Liang
- Guangdong Shunde Industry Design Institute (Guangdong Shunde Innovative Design Institute), Foshan 528315, China
| | - Feng Huo
- Department of Hepatobiliary Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China.
| | - Huan-Wei Chen
- Department of Hepatopancreatic Surgery, Foshan First People's Hospital, Foshan 528010, China
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10
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Lo DJ, Magliocca JF, Ross-Driscoll K. Waitlist outcomes after acuity circle-based distribution in pediatric liver transplantation. Am J Transplant 2025:S1600-6135(25)00273-4. [PMID: 40389160 DOI: 10.1016/j.ajt.2025.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/20/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025]
Abstract
Pediatric liver transplant (LT) waitlist mortality remains unacceptably high. In 2020, the Organ Procurement and Transplantation Network (OPTN) implemented acuity circle (AC)-based liver distribution and national pediatric prioritization for pediatric donor livers. Using OPTN data, waitlist outcomes for pediatric LT candidates listed between February 4, 2016 and February 3, 2024, were studied by age group and era relative to AC implementation. There were 5,605 waitlist registrations and 3,778 liver transplants. At 1 year, cumulative incidence of transplant was 77.8% pre-AC vs 79.9% post-AC; cumulative incidence of mortality was 5.4% pre-AC vs 5.9% post-AC. Median allocation Model for End-Stage Liver Disease/Pediatric Model for End-Stage Liver Disease score at LT significantly decreased across all age groups post-AC (p<0.001). Candidates age 12-17 years experienced higher cumulative incidence of transplant (65.6% pre-AC vs 79.5% post-AC at 1 year), decreased median time to transplant (66 days pre-AC vs 37 days post-AC, p<0.001), and increased proportion of pediatric donor livers (37.9% pre-AC vs 66.2% post-AC, p<0.001). AC group was associated with increased likelihood of transplant for those age 12-17 years and increased likelihood of waitlist mortality for those age 1-5 years. LT candidates age 12-17 years derived the most benefit from AC-based liver distribution.
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Affiliation(s)
- Denise J Lo
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
| | - Joseph F Magliocca
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katherine Ross-Driscoll
- Department of Surgery, Indiana University, Indianapolis, IN, USA; Center for Health Services Research, Regenstrief Institute, Indianapolis, IN, USA; Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA
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11
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Currie IS, Hunt FM. Donation after circulatory death; cholangiopathy in the machine age. Curr Opin Organ Transplant 2025:00075200-990000000-00177. [PMID: 40314108 DOI: 10.1097/mot.0000000000001222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
PURPOSE OF REVIEW Published work evaluating machine perfusion of DCD (donation after circulatory death) liver grafts in situ and ex situ is rapidly evolving, with several landmark studies published in the last 6 months. The central question in DCD liver transplant remains; which strategies most effectively reduce cholangiopathy? This condition, which results in repeated hospital admissions, interventions, re-transplantation and death, is a major deterrent to DCD utilization. This review considers current evidence in the mitigation of transplant cholangiopathy by machine perfusion in DCD liver grafts. RECENT FINDINGS Studies which directly address DCD cholangiopathy as a primary outcome are few in number, despite their critical importance. In systematic reviews, Normothermic Regional Perfusion and Hypothermic Machine Perfusion consistently and significantly reduce transplant cholangiopathy rates. By contrast, the efficacy of Normothermic Machine Perfusion performed at donor or recipient centres is less well described and cautious interpretation is required. The most recent development, namely hypothermic followed by normothermic perfusion, has only now appeared in the literature but appears to offer advantages compared to either technology alone. SUMMARY To reduce DCD cholangiopathy, current data best support the use of donor centre NRP or recipient centre HMP. However, utilization is also improved when warm perfusion is involved.
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Affiliation(s)
- Ian S Currie
- Edinburgh Transplant Centre
- Institute for Regeneration and Repair, University of Edinburgh
- NHS Blood and Transplant, UK
| | - Fiona M Hunt
- Edinburgh Transplant Centre
- Institute for Regeneration and Repair, University of Edinburgh
- NHS Blood and Transplant, UK
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12
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Peery AF, Murphy CC, Anderson C, Jensen ET, Deutsch-Link S, Egberg MD, Lund JL, Subramaniam D, Dellon ES, Sperber AD, Palsson OS, Pate V, Baron TH, Moon AM, Shaheen NJ, Sandler RS. Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2024. Gastroenterology 2025; 168:1000-1024. [PMID: 39920892 PMCID: PMC12018144 DOI: 10.1053/j.gastro.2024.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 12/23/2024] [Accepted: 12/28/2024] [Indexed: 02/10/2025]
Abstract
BACKGROUND & AIMS A contemporary report describing the burden and expenditures of gastrointestinal (GI) diseases can be helpful for policy makers, administrators, and researchers. Using the most recent data, we estimated the burden and costs associated with GI diseases in the United States. METHODS We generated estimates using data from the Rome Foundation Global Epidemiology Study 2017-2018 (symptoms), National Ambulatory Medical Care Survey 2019 and National Hospital Ambulatory Medical Care Survey 2019 (ambulatory visits), Nationwide Emergency Department Sample 2021 (emergency department visits), National Inpatient Sample 2021 (admissions), Kids' Inpatient Database 2019 (admissions), National Program of Cancer Registries 2001-2021 (cancer incidence), National Center for Health Statistics 2001-2021 (cancer mortality), Centers for Disease Control Wide-ranging Online Data for Epidemiologic Research 2021 (non-cancer mortality), MarketScan Commercial Claims and Encounters data 2002-2021 (endoscopy), MarketScan Medicare Supplemental data 2002-2021 (endoscopy), United Network for Organ Sharing Registry 2023 (transplant), Medical Expenditure Panel Survey 2021 (expenditures), and National Institutes of Health (NIH) 2012-2025 (research). RESULTS In 2021, GI health care expenditures totaled $111.8 billion. A GI diagnosis or symptom led to 14.5 million emergency department visits and 2.9 million hospital admissions. There were 315,065 new GI cancers diagnosed. GI diseases caused 281,413 deaths. In 2022, an estimated 23.5 million GI endoscopies were performed. In 2023, the NIH supported $3.6 billion for GI research, which represents 7.4% of the NIH budget. CONCLUSION GI diseases are responsible for a considerable and growing burden of health care use and costs. Funding innovative GI science and supporting the practice of GI medicine are critical to meeting the burden of GI illness.
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Affiliation(s)
- Anne F Peery
- University of North Carolina School of Medicine, Chapel Hill, North Carolina.
| | - Caitlin C Murphy
- University of Texas Health Science Center at Houston, Houston, Texas
| | - Chelsea Anderson
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | | | - Sasha Deutsch-Link
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Matthew D Egberg
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Jennifer L Lund
- Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Disha Subramaniam
- Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Evan S Dellon
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Ami D Sperber
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Olafur S Palsson
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Virginia Pate
- Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Todd H Baron
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Andrew M Moon
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Nicholas J Shaheen
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Robert S Sandler
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
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13
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Jaber F, Abuelazm M, Soliman Y, Madi M, Abusuilik H, Mazen Amin A, Saeed A, Gowaily I, Abdelazeem B, Rana A, Qureshi K, Lee TH, Cholankeril G. Machine perfusion strategies in liver transplantation: A systematic review, pairwise, and network meta-analysis of randomized controlled trials. Liver Transpl 2025; 31:596-615. [PMID: 39868927 DOI: 10.1097/lvt.0000000000000567] [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: 01/26/2024] [Accepted: 12/04/2024] [Indexed: 01/28/2025]
Abstract
Machine perfusion (MP), including hypothermic oxygenated machine perfusion (HOPE), dual HOPE, normothermic machine perfusion (NMP), NMP ischemia-free liver transplantation (NMP-ILT), and controlled oxygenated rewarming (COR), is increasingly being investigated to improve liver graft quality from extended criteria donors and donors after circulatory death and expand the donor pool. This network meta-analysis investigates the comparative efficacy and safety of various liver MP strategies versus traditional static cold storage (SCS). We searched PubMed, Scopus, Web of Science, and Cochrane Controlled Register of Trials for randomized controlled trials comparing liver transplantation outcomes between SCS and MP techniques. The primary outcome was the incidence of early allograft dysfunction. Secondary endpoints included 1-year graft survival, the incidence of graft failure/loss, post-reperfusion syndrome, biliary complications, the need for renal replacement therapy, graft-related patient mortality, and the length of intensive care unit and hospital stay. R-software was used to conduct a network meta-analysis using a frequentist framework (PROSPERO ID: CRD42024549254). We included 12 randomized controlled trials involving 1628 patients undergoing liver transplantation (801 in the liver MP groups and 832 in the SCS group). Compared to SCS, HOPE/dHOPE, but not other MP strategies, was associated with a significantly lower risk of early allograft dysfunction (RR: 0.53, 95% CI [0.37, 0.74], p =0.0002), improved 1-year graft survival rate (RR: 1.07, 95% CI [1.01, 1.14], p =0.02), decreased graft failure/loss (RR: 0.38, 95% CI [0.16, 0.90], p =0.03), and reduced the risk of biliary complications (RR: 0.52, 95% CI [0.43, 0.75], p < 0.0001). Compared to SCS, NMP (RR: 0.49, 95% CI [0.24, 0.96]) and NMP-ILT (RR: 0.15, 95% CI [0.04, 0.57]), both significantly reduced the risk of postperfusion syndrome. There is no difference between SCS and MP groups in the risk of renal replacement therapy, graft-related patient mortality, and intensive care unit and hospital stay length. Our meta-analysis showed that HOPE/dual-HOPE is a promising alternative to SCS for donor liver preservation. These new techniques can help expand the donor pool with similar or even better post-liver transplantation outcomes.
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Affiliation(s)
- Fouad Jaber
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Mohamed Abuelazm
- Department of Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Youssef Soliman
- Department of Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud Madi
- Division of Gastroenterology and Hepatology, Department of Medicine, University School of Medicine, Saint Louis, Missouri, USA
| | - Husam Abusuilik
- Department of Medicine, The Hashemite University, Zarqa, Jordan
| | | | - Abdallah Saeed
- Department of Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ibrahim Gowaily
- Department of Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Basel Abdelazeem
- Department of Cardiology, West Virginia University, Morgantown, West Virginia, USA
| | - Abbas Rana
- Hepatology Program, Department of General Surgery, Division of Abdominal Transplantation, Michael E DeBakey Baylor College of Medicine, Houston, Texas, USA
| | - Kamran Qureshi
- Division of Gastroenterology and Hepatology, Department of Medicine, University School of Medicine, Saint Louis, Missouri, USA
| | - Tzu-Hao Lee
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Hepatology Program, Department of General Surgery, Division of Abdominal Transplantation, Michael E DeBakey Baylor College of Medicine, Houston, Texas, USA
| | - George Cholankeril
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Hepatology Program, Department of General Surgery, Division of Abdominal Transplantation, Michael E DeBakey Baylor College of Medicine, Houston, Texas, USA
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14
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Goldberg D, Sandhu S. Expanding the Liver Donor Pool: Promise and Peril. Clin Liver Dis 2025; 29:235-252. [PMID: 40287269 DOI: 10.1016/j.cld.2024.12.004] [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] [Indexed: 04/29/2025]
Abstract
Liver transplantation remains a life-saving therapy for a growing list of indications. Although 10,660 adult liver transplants were performed in the United States in 2023, a 50% increase over the preceding decade, the demand continues to far exceed the supply. Efforts to expand the liver donor pool by using donors that were previously considered unsuitable have remained an important strategy to help overcome shortages. We discuss the progress that has been made over the past decade, as well as potential future barriers that will need to be overcome to help successfully expand the liver donor pool.
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Affiliation(s)
- David Goldberg
- Division of Digestive Health and Liver Diseases, Department of Medicine, Miller School of Medicine at the University of Miami, Miami, FL, USA.
| | - Sunny Sandhu
- Division of Digestive Health and Liver Diseases, Department of Medicine, Miller School of Medicine at the University of Miami, Miami, FL, USA
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15
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Nakamura T, Longchamp A, Markmann JF. Innovations to Expand the Liver Donor Pool: Machine Perfusion and Xenotransplantation. Clin Liver Dis 2025; 29:337-346. [PMID: 40287275 DOI: 10.1016/j.cld.2024.12.010] [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: 04/29/2025]
Abstract
The number of patients awaiting liver transplant exceeds the number of liver grafts available. However, emerging technologies offer hope. Machine perfusion enhances the preservation, graft quality, and utilization of marginal livers, thereby reducing unnecessary graft discards. Xenotransplantation provides an alternative organ source, augmenting the donor supply or serving as a bridge for critically ill patients. These innovations are described in this review, as the recent clinical applications of these technologies promise to alleviate organ scarcity, improve transplant outcomes, and save lives.
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Affiliation(s)
- Tsukasa Nakamura
- Division of Transplant Surgery, Department of Surgery, University of Arkansas for Medical Sciences, AR, USA
| | - Alban Longchamp
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - James F Markmann
- Penn Transplant Institute, The University of Pennsylvania, 1 Convention Avenue, Philadelphia, PA 19104, USA.
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16
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Lee C, Mathur AK, Mao S, Heimbach JK, Taner CB, Aqel B, Croome KP. Prolonged time from cross-clamp until normothermic machine perfusion start is associated with an increased risk of early allograft dysfunction following DCD liver transplant. Liver Transpl 2025; 31:616-622. [PMID: 39652008 DOI: 10.1097/lvt.0000000000000548] [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: 08/13/2024] [Accepted: 11/30/2025] [Indexed: 02/02/2025]
Abstract
There is a paucity of data on the impact of cold ischemia time before the initiation of normothermic machine perfusion (NMP), particularly in more susceptible organs such as livers from donation after circulatory death (DCD) donors. The present analysis aimed to investigate the impact of prolonged time from cross-clamp until NMP start on early allograft dysfunction and other peri-liver transplant (LT) outcomes. All DCD LT performed and placed on NMP at Mayo Clinic Arizona, Florida, and Rochester from January 2022 to March 2024 were included. The decision was made a priori to divide the population into 2 groups based on terciles: typical cross-clamp to on-pump time (lower 2 terciles) versus prolonged cross-clamp to on-pump time (upper tercile; >2 h 45.6 min). Three hundred eighty-four DCD LT undergoing NMP met the inclusion criteria. The rate of early allograft dysfunction was significantly higher in the prolonged cross-clamp to on-pump group (51.2%) compared to the typical cross-clamp to on-pump group (37.6%) ( p = 0.01). The prolonged cross-clamp to on-pump group also had higher rates of acute kidney injury and the number of packed red blood cells transfused during LT. No significant difference in ischemic cholangiopathy (2.4% vs. 3.1%; p = 0.68) or graft survival at 12 months was seen between the prolonged cross-clamp to on-pump and typical cross-clamp to on-pump group, respectively. Following cross-clamp, DCD liver grafts should be placed on the NMP pump as quickly as is safely and logistically possible. In cases where delays are unavoidable, such as waiting for biopsy results or liver reallocation with another center, acceptable results can still be achieved, and therefore, livers with prolonged times should still be used.
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Affiliation(s)
- Charles Lee
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida, USA
| | - Amit K Mathur
- Department of Surgery, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Shennen Mao
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida, USA
| | - Julie K Heimbach
- Department of Surgery, Mayo Clinic Rochester, Rochester, Minnesota, USA
| | - C Burcin Taner
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida, USA
| | - Bashar Aqel
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic Arizona, Phoenix, Arizona, USA
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17
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Krendl FJ, Cardini B, Fodor M, Singh J, Ponholzer F, Messner F, Weissenbacher A, Resch T, Maglione M, Margreiter C, Eschertzhuber S, Irsara C, Griesmacher A, Schennach H, Breitkopf R, Schlosser L, Zoller H, Tilg H, Oberhuber R, Schneeberger S. Normothermic Liver Machine Perfusion at a Large European Center: Real-world Outcomes following 238 Applications. Ann Surg 2025; 281:872-883. [PMID: 39829417 PMCID: PMC11974633 DOI: 10.1097/sla.0000000000006634] [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: 01/22/2025]
Abstract
OBJECTIVE To report outcomes from routine clinical practice of liver transplantation (LT) following normothermic liver machine perfusion (NLMP) and compare to LT after static cold storage (SCS). BACKGROUND NLMP is emerging as a clinical routine in LT and has recently received renewed attention; however, outcomes outside of clinical trials are lacking. METHODS All adult LT between February 2018 and January 2023 were included. A comprehensive viability assessment was applied during NLMP. Outcomes were compared between NLMP and SCS recipients, as well as benchmark and non-benchmark cases. RESULTS Of the 332 LT included, 174 underwent NLMP and 158 were transplanted after SCS. Sixty-seven organs were accepted and transplanted only under the premise of NLMP. One-year graft survival for SCS and NLMP recipients was 83.8% versus 81.3% and 93.4% for benchmark cases in the overall cohort. Total preservation time had no influence on graft survival in the NLMP group but was associated with inferior 1-year graft survival in the SCS group. NLMP usage increased significantly over the duration of the study period, as did the median total preservation time. With increasing NLMP use and longer preservation times, nighttime surgery decreased significantly from 41.9% to 4.2%. CONCLUSIONS Prolonged preservation times ease logistics and enable daytime surgery. The possibility of NLMP offers to expand LT without negatively affecting outcomes.
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Affiliation(s)
- Felix J. Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Margot Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Jessica Singh
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Florian Ponholzer
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Franka Messner
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Resch
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Christian Irsara
- Central Institute of Clinical Chemistry and Laboratory Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Andrea Griesmacher
- Central Institute of Clinical Chemistry and Laboratory Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Harald Schennach
- Central Institute for Blood Transfusion and Immunology, University Hospital of Innsbruck, Tirol Kliniken GmbH, Innsbruck, Austria
| | - Robert Breitkopf
- Department of Anesthesia and Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Heinz Zoller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
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18
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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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19
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Sun X, De Brouwer E, Liu C, Krishnaswamy S, Batra R. Deep learning unlocks the true potential of organ donation after circulatory death with accurate prediction of time-to-death. Sci Rep 2025; 15:13565. [PMID: 40253393 PMCID: PMC12009369 DOI: 10.1038/s41598-025-95079-7] [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: 12/09/2024] [Accepted: 03/19/2025] [Indexed: 04/21/2025] Open
Abstract
Increasing the number of organ donations after circulatory death (DCD) has been identified as one of the most important ways of addressing the ongoing organ shortage. While recent technological advances in organ transplantation have increased their success rate, a substantial challenge in increasing the number of DCD donations resides in the uncertainty regarding the timing of cardiac death after terminal extubation, impacting the risk of prolonged ischemic organ injury, and negatively affecting post-transplant outcomes. In this study, we trained and externally validated an ODE-RNN model, which combines recurrent neural network with neural ordinary equations and excels in processing irregularly-sampled time series data. The model is designed to predict time-to-death following terminal extubation in the intensive care unit (ICU) using the history of clinical observations. Our model was trained on a cohort of 3,238 patients from Yale New Haven Hospital, and validated on an external cohort of 1,908 patients from six hospitals across Connecticut. The model achieved accuracies of [Formula: see text] and [Formula: see text] for predicting whether death would occur in the first 30 and 60 minutes, respectively, with a calibration error of [Formula: see text]. Heart rate, respiratory rate, mean arterial blood pressure (MAP), oxygen saturation (SpO2), and Glasgow Coma Scale (GCS) scores were identified as the most important predictors. Surpassing existing clinical scores, our model sets the stage for reduced organ acquisition costs and improved post-transplant outcomes.
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Affiliation(s)
- Xingzhi Sun
- Department of Computer Science, Yale University, New Haven, 06511, USA
| | | | - Chen Liu
- Department of Computer Science, Yale University, New Haven, 06511, USA
| | - Smita Krishnaswamy
- Department of Computer Science, Yale University, New Haven, 06511, USA.
- Department of Genetics, Yale University, New Haven, 06511, USA.
| | - Ramesh Batra
- Department of Surgery, Yale University, New Haven, 06511, USA.
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20
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Matevish LE, Guo J, Shubin AD, MacConmara M, Hwang CS, Raschzok N, Rich NE, Mufti AR, Singal AG, Vagefi PA, Patel MS. Transplantation of Patients with Hepatocellular Carcinoma Through Increased Utilization of Machine Perfusion Technology. Transplant Direct 2025; 11:e1777. [PMID: 40078822 PMCID: PMC11896107 DOI: 10.1097/txd.0000000000001777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 03/14/2025] Open
Abstract
Background With the intent to mitigate waitlist disparities, the median model for end-stage liver disease (MELD) at transplant minus 3 policy nevertheless decreased access to liver transplant for patients with hepatocellular carcinoma (HCC). However, the adoption of machine perfusion (MP) technologies has shown promise in improving deceased donor graft yield and utilization. To understand current use for patients with HCC, we examined liver transplant patterns with MP and the characteristics of patients with HCC receiving an MP liver. Methods Adult patients with HCC undergoing deceased donor liver transplant from September 29, 2021, to March 30, 2024, were identified using the United Network for Organ Sharing Standard Transplant Analysis and Research files. Patients were excluded if listed as status 1A or they underwent multiorgan or split liver transplant. Multivariate analysis compared patients with HCC receiving an MP liver with those receiving a static cold storage liver. Results Of 3774 liver recipients with HCC, 593 (15.7%) underwent transplant with an MP graft. Compared with patients donation after circulatory death graft receiving a graft with static cold storage preservation, those with MP had less advanced disease (ie, Child-Pugh class C cirrhosis 22.9% versus 29.9%, P < 0.01) and lower median match MELD (13 versus 17, P < 0.001). Tumor characteristics were similar between groups, including alpha-fetoprotein level, maximum tumor size, and locoregional treatments. Donor factors, and not tumor burden, were most predictive of receipt of an MP liver (donation after circulatory death graft: odds ratio [OR], 14.81; macrosteatosis >30%; OR, 3.85; donor age older than 60 y; OR, 2.34). A shorter waitlist time (6.5 versus 7.2 mo, P < 0.01), with similar 1-y patient survival (93.6% versus 93.2%, P = 0.82) and graft survival (92.0% versus 91.6%, P = 0.84), was also noted in patients undergoing MP transplant. Conclusions The strategic use of MP livers may improve graft utilization and access to liver transplants, helping offset the disadvantages of the MELD at transplant minus 3 policy for patients with HCC.
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Affiliation(s)
- Lauren E. Matevish
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Jason Guo
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Andrew D. Shubin
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Christine S. Hwang
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Nicole E. Rich
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Arjmand R. Mufti
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Parsia A. Vagefi
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Madhukar S. Patel
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
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21
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de Goeij FHC, Wehrle CJ, Abassi F, Satish S, Zhang M, Panconesi R, Hashimoto K, Miller CM, Polak WG, Clavien PA, de Jonge J, Schlegel A. Mastering the narrative: Precision reporting of risk and outcomes in liver transplantation. J Hepatol 2025; 82:729-743. [PMID: 39557163 DOI: 10.1016/j.jhep.2024.11.013] [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: 06/23/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 11/20/2024]
Abstract
Liver transplantation is associated with a high risk of postoperative complications due to the complexity of the surgical procedure, recipient disease severity and the wide range of graft quality, which remains somewhat unpredictable. However, survival rates after transplantation continue to improve and the focus has thus turned to other clinically relevant endpoints including post-transplant complications, patient quality of life and costs. Procedures like liver transplantation offer the entire spectrum of post-surgical events, even in donor-recipient constellations deemed of low risk within recently defined benchmark criteria. The Clavien-Dindo classification and the CCI (comprehensive complication index) were established to assess postoperative morbidity and are widely utilised across surgical specialties. These scores depend on the number and grade of complications, which reflect the interventions required, and are frequently used to assess specific donor-recipient risk profiles and new approaches, such as machine perfusion. However, these scores are associated with inter-observer variability when used in practice, mainly due to the lack of uniform definitions. The concept of benchmarking was recently introduced in surgery and transplantation as a mechanism of standardising expected donor/recipient risk with outcomes within the first year after surgery. However, the management of complications differs significantly worldwide, as does the rating scale assigned to various complications. This may lead to inhomogeneous interpretation of study results, leading to difficulty in assessing the clinical effects of novel preservation technologies and other therapeutics in liver transplantation. This article critically discusses frequent challenges associated with risk and outcome assessment following liver transplantation.
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Affiliation(s)
- Femke H C de Goeij
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Chase J Wehrle
- Transplantation Center, Cleveland Clinic, Cleveland, OH, USA
| | - Fariba Abassi
- Department of Abdominal Surgery and Transplantation, University of Zurich, Zurich, Switzerland; Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Sangeeta Satish
- Transplantation Center, Cleveland Clinic, Cleveland, OH, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mingyi Zhang
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Rebecca Panconesi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Koji Hashimoto
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Abdominal Surgery and Transplantation, University of Zurich, Zurich, Switzerland
| | | | - Wojciech G Polak
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Jeroen de Jonge
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Andrea Schlegel
- Transplantation Center, Cleveland Clinic, Cleveland, OH, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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22
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Mauro E, Rodríguez‐Perálvarez M, D'Alessio A, Crespo G, Piñero F, De Martin E, Colmenero J, Pinato DJ, Forner A. New Scenarios in Liver Transplantation for Hepatocellular Carcinoma. Liver Int 2025; 45:e16142. [PMID: 39494583 PMCID: PMC11891387 DOI: 10.1111/liv.16142] [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: 06/23/2024] [Revised: 10/03/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND AND AIMS Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS. METHODS AND RESULTS In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.
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Affiliation(s)
- Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPSUniversity of BarcelonaBarcelonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Manuel Rodríguez‐Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina SofíaUniversidad de Córdoba, IMIBIC, CIBERehdCórdobaSpain
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College LondonHammersmith HospitalLondonUK
- Division of Oncology, Department of Translational MedicineUniversity of Piemonte OrientaleNovaraItaly
| | - Gonzalo Crespo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPSUniversity of BarcelonaBarcelonaSpain
| | - Federico Piñero
- School of MedicineHospital Universitario Austral, Austral UniversityBuenos AiresArgentina
| | - Eleonora De Martin
- AP‐HP Hôpital Paul‐Brousse, Centre Hépato‐Biliaire, INSERM Unit 1193Université Paris‐Saclay, FHU HepatinovVillejuifFrance
| | - Jordi Colmenero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPSUniversity of BarcelonaBarcelonaSpain
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College LondonHammersmith HospitalLondonUK
- Division of Oncology, Department of Translational MedicineUniversity of Piemonte OrientaleNovaraItaly
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPSUniversity of BarcelonaBarcelonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
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23
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Chumdermpadetsuk RR, Lee DD. The impact of normothermic machine perfusion on coagulation function and transfusion practice: Miracle machine or anticipatory bias. Liver Transpl 2025; 31:423-424. [PMID: 39679924 DOI: 10.1097/lvt.0000000000000558] [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: 12/10/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
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24
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Nguyen MC, Li X, Linares N, Jadlowiec C, Moss A, Reddy KS, Mathur AK. Ex-situ machine perfusion in clinical liver transplantation: Current practices and future directions. Liver Transpl 2025; 31:531-544. [PMID: 38967460 DOI: 10.1097/lvt.0000000000000428] [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: 11/17/2023] [Accepted: 06/17/2024] [Indexed: 07/06/2024]
Abstract
Ex-situ machine perfusion of the liver has surmounted traditional limitations associated with static cold storage in the context of organ preservation. This innovative technology has changed the landscape of liver transplantation by mitigating ischemia perfusion injury, offering a platform for continuous assessment of organ quality, and providing an avenue for optimizing the use of traditionally marginal allografts. This review summarizes the contemporary clinical applications of machine perfusion devices and discusses potential future strategies for real-time viability assessment, therapeutic interventions, and modulation of organ function after recovery.
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Affiliation(s)
- Michelle C Nguyen
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Pheonix, Arizona, USA
| | - Xingjie Li
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Pheonix, Arizona, USA
| | | | - Caroline Jadlowiec
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Pheonix, Arizona, USA
| | - Adyr Moss
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Pheonix, Arizona, USA
| | - Kunam S Reddy
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Pheonix, Arizona, USA
| | - Amit K Mathur
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Pheonix, Arizona, USA
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25
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Lai Q, Angelico R, Guglielmo N, Pagano D, Martins PN, Ghinolfi D. Ex-situ normothermic machine perfusion prevents ischemic cholangiopathy after liver transplantation: A meta-regression analysis. Transplant Rev (Orlando) 2025; 39:100915. [PMID: 40158289 DOI: 10.1016/j.trre.2025.100915] [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: 01/06/2025] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND & AIMS Liver transplantation (LT) is the gold standard for end-stage liver disease, but ischemic cholangiopathy (IC) remains a significant complication. Ex-situ normothermic machine perfusion (ESNMP) has emerged as a potential strategy to mitigate ischemic injury. However, the effect of ESNMP on reducing post-LT IC remains controversial. This study aimed to perform an updated meta-analysis to evaluate the impact of ESNMP on IC incidence. METHODS A systematic review and meta-analysis were conducted following PRISMA guidelines. The literature search included studies from 2015 to 2025 comparing LT outcomes using ESNMP vs. static cold storage (SCS). The primary outcome was the incidence of IC. Risk of bias was assessed using the ROBINS-E tool. Statistical analysis, including random-effects meta-analysis, sensitivity analysis, and meta-regression, was performed to evaluate heterogeneity, potential confounders, and the impact of follow-up duration. RESULTS Seventeen studies, including 76,045 patients (4843 ESNMP; 71,202 SCS), were analyzed. No statistically significant difference in IC incidence was found between ESNMP and SCS (1.3 % vs. 0.6 %; RR = 0.68, 95 %CI = 0.41-1.13; P = 0.14). Sensitivity analysis excluding one outlier study revealed a reduction in IC risk with ESNMP (RR = 0.62, 95 %CI = 0.38-1.01; P = 0.054). Two sub-analyses of studies with ≥12 months of follow-up (RR = 0.51, 95 %CI = 0.26-0.99; P = 0.049) and DCDs (RR = 0.33, 95 %CI = 0.16-0.67; P = 0.002) showed risk reduction. The meta-regression revealed that the back-to-base perfusion approach was associated with the occurrence of IC, with an OR of 1.03 (95 %CI = 1.00-1.07, P = 0.035). CONCLUSIONS a correlation between ESNMP use and IC reduced risk appears to exist, especially with longer follow-up periods and DCDs, though more high-quality studies are needed to confirm this finding.
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Affiliation(s)
- Quirino Lai
- General surgery and Organ Transplantation Unit, Department of General and Specialty Surgery, Sapienza University of Rome, AOU Policlinico Umberto I, Rome, Italy.
| | - Roberta Angelico
- Department of Surgical Sciences, HPB and Transplant Unit, University of Rome Tor Vergata, Rome, Italy
| | - Nicola Guglielmo
- Department of General Surgery and Transplantation Unit, San Camillo Forlanini Hospital, Rome, 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
| | - Paulo N Martins
- Department of Surgery, Transplant Institute, Oklahoma University, Oklahoma City, USA
| | - Davide Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
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26
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Pagano D, Toniutto P, Burra P, Gruttadauria S, Vella R, Martini S, Morelli MC, Svegliati-Baroni G, Marrone G, Ponziani FR, Caraceni P, Angeli P, Calvaruso V, Giannelli V. Perioperative administration of albumin in adult patients undergoing liver transplantation: A systematic review. Dig Liver Dis 2025; 57:819-826. [PMID: 39645428 DOI: 10.1016/j.dld.2024.11.006] [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: 06/12/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 12/09/2024]
Abstract
Hypoalbuminemia is a risk factor for mortality in patients with end-stage liver disease (ESLD) and in those undergoing orthotopic liver transplantation (OLT), since it represents a biomarker of post-operative delayed functional recovery of the graft. Despite albumin infusion during and after OLT is frequently adopted in recipients with hypoalbuminemia, it remains unclear whether this procedure could improve post OLT clinical outcomes. Observational studies indicated that treatment with albumin after OLT might be beneficial in reducing ascites and acute kidney injury (AKI) development. However, considering potential complications and the cost of albumin therapy, the decision to use albumin after OLT should be based on careful consideration of patient's individual needs and risks. In addition, the threshold plasma value of albumin below which it could be clinically useful to infuse albumin has not been clearly defined. This systematic review, prepared in accordance with the PRISMA 2020 guidelines, aimed to assess the efficacy of albumin infusion in patients undergoing OLT, in the prevention or treatment of ascites, AKI, and ischemia reperfusion syndrome, as well as its potential impact on patient survival. Furthermore, this review aimed to illustrate the pathophysiological bases justifying the use of albumin infusion in a subset of patients receiving OLT.
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Affiliation(s)
- Duilio Pagano
- Department for the Treatment and the Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto Mediterraneoper i Trapianti e Terapie ad alta specializzazione), UPMCI (University of Pittsburgh Medical Center Italy), Palermo, Italy
| | - Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Azienda Ospedaliero Universitaria, University of Udine 33100, Udine, Italy.
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova 35122, Padova, Italy
| | - Salvatore Gruttadauria
- Department for the Treatment and the Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto Mediterraneoper i Trapianti e Terapie ad alta specializzazione), UPMCI (University of Pittsburgh Medical Center Italy) Palermo, Italy; University of Catania, Catania, Italy
| | - Roberta Vella
- Department for the Treatment and the Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto Mediterraneoper i Trapianti e Terapie ad alta specializzazione), UPMCI (University of Pittsburgh Medical Center Italy) Palermo, Italy; Department of Precision Medicine in the Medical, Surgical and Critical Care Area University of Palermo, Palermo, Italy
| | - Silvia Martini
- Gastrohepatology Unit, AOU Città della Salute e della Scienza di Torino, Torino, Italy
| | - Maria Cristina Morelli
- RCCS Azienda Ospedaliero-Universitaria di Bologna, Internal Medicine Unit for the treatment of Severe Organ Failure, Bologna, Italy
| | | | - Giuseppe Marrone
- Liver Transplant Medicine Unit, Fondazione Policlinico Universitario Gemelli, Catholic University of the Sacred Heart, Rome, Italy
| | - Francesca Romana Ponziani
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy; Unit of Semeiotics, IRCCS AOU Bologna, Bologna, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Vincenza Calvaruso
- Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo 90127 Palermo, Italy
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27
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Wehrle CJ, Hong H, Gross A, Liu Q, Ali K, Cazzaniga B, Miyazaki Y, Tuul M, Modaresi Esfeh J, Khalil M, Pita A, Fernandes E, Kim J, Diago-Uso T, Aucejo F, Kwon DCH, Fujiki M, Quintini C, Schlegel A, Pinna A, Miller C, Hashimoto K. The impact of normothermic machine perfusion and acuity circles on waitlist time, mortality, and cost in liver transplantation: A multicenter experience. Liver Transpl 2025; 31:438-449. [PMID: 38833290 DOI: 10.1097/lvt.0000000000000412] [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: 03/16/2024] [Accepted: 05/13/2024] [Indexed: 06/06/2024]
Abstract
Ex situ normothermic machine perfusion (NMP) helps increase the use of extended criteria donor livers. However, the impact of an NMP program on waitlist times and mortality has not been evaluated. Adult patients listed for liver transplant (LT) at 2 academic centers from January 1, 2015, to September 1, 2023, were included (n=2773) to allow all patients ≥6 months follow-up from listing. Routine NMP was implemented on October 14, 2022. Waitlist outcomes were compared from pre-NMP pre-acuity circles (n=1460), pre-NMP with acuity circles (n=842), and with NMP (n=381). Median waitlist time was 79 days (IQR: 20-232 d) at baseline, 49 days (7-182) with acuity circles, and 14 days (5-56) with NMP ( p <0.001). The rate of transplant-per-100-person-years improved from 61-per-100-person-years to 99-per-100-person-years with acuity circles and 194-per-100-person-years with NMP ( p <0.001). Crude mortality without transplant decreased from 18.3% (n=268/1460) to 13.3% (n=112/843), to 6.3% (n=24/381) ( p <0.001) with NMP. The incidence of mortality without LT was 15-per-100-person-years before acuity circles, 19-per-100 with acuity circles, and 9-per-100-person-years after NMP ( p <0.001). Median Model for End-Stage Liver Disease at LT was lowest with NMP, but Model for End-Stage Liver Disease at listing was highest in this era ( p <0.0001). The median donor risk index of transplanted livers at baseline was 1.54 (1.27-1.82), 1.66 (1.42-2.16) with acuity circles, and 2.06 (1.63-2.46) with NMP ( p <0.001). Six-month post-LT survival was not different between eras ( p =0.322). The total cost of health care while waitlisted was lowest in the NMP era ($53,683 vs. $32,687 vs. $23,688, p <0.001); cost-per-day did not differ between eras ( p =0.152). The implementation of a routine NMP program was associated with reduced waitlist time and mortality without compromising short-term survival after liver transplant despite increased use of riskier grafts. Routine NMP use enables better waitlist management with reduced health care costs.
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Affiliation(s)
- Chase J Wehrle
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Hanna Hong
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Abby Gross
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Qiang Liu
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Khaled Ali
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Beatrice Cazzaniga
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Yuki Miyazaki
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Munkhbold Tuul
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Jamak Modaresi Esfeh
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Mazhar Khalil
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Alejandro Pita
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Eduardo Fernandes
- Cleveland Clinic Florida, Abdominal Transplant Center, Weston, Florida, USA
| | - Jaekeun Kim
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Teresa Diago-Uso
- Cleveland Clinic Abu Dhabi, Digestive Disease Institute, Abu Dhabi, United Arab Emirates
| | - Federico Aucejo
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - David C H Kwon
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Masato Fujiki
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Cristiano Quintini
- Cleveland Clinic Abu Dhabi, Digestive Disease Institute, Abu Dhabi, United Arab Emirates
| | - Andrea Schlegel
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Antonio Pinna
- Cleveland Clinic Abu Dhabi, Digestive Disease Institute, Abu Dhabi, United Arab Emirates
| | - Charles Miller
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
| | - Koji Hashimoto
- Department of General Surgery, Cleveland Clinic, Digestive Disease & Surgery Institute, Cleveland, Ohio, USA
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Su LL, Secor DT, McGary AK, Nguyen MC, Jadlowiec CC, Williams LA, Kinard TN, Adamski J, Stoker AD, Frasco PE. Preservation of coagulation function by normothermic machine perfusion in liver transplant as evidenced by thromboelastography parameters. Liver Transpl 2025; 31:464-475. [PMID: 39641139 DOI: 10.1097/lvt.0000000000000507] [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: 06/28/2024] [Accepted: 09/12/2024] [Indexed: 12/07/2024]
Abstract
The use of normothermic machine perfusion (NMP) over static cold storage in liver transplantation has been shown to reduce posttransplant risks of early allograft dysfunction, primary nonfunction, and ischemic cholangiopathy, and its increasing use has played a role in the expanded utilization of marginal livers. While studies have demonstrated improved clinical outcomes using NMP over static cold storage preservation, real-time intraoperative data reflecting the quality and viability of NMP livers is limited. This retrospective, single-center study compared NMP versus static cold storage livers in first-time recipients of liver transplants through the evaluation of synthetic coagulation function as measured by thromboelastography and conventional coagulation testing. Secondarily, transfusion utilization between the 2 cohorts was reviewed. One hundred eighty-six recipients of liver transplants receiving allografts from donors after circulatory death were included in the study, of which 99 (53%) allografts were preserved in static cold storage, and 87 (47%) allografts were placed on the TransMedics Organ Care System. Study findings showed NMP livers supported with the TransMedics Organ Care System were associated with increased synthetic coagulation function and less excess fibrinolysis in the postreperfusion period compared to static cold storage livers, and that these findings were better reflected in real-time with thromboelastography monitoring versus conventional coagulation testing. Following reperfusion, there was a significant decrease in the transfusion of blood products in the NMP group compared with that in the static cold storage group. Overall, we determined that the use of intraoperative thromboelastography can provide real-time data to assess one aspect of reperfusion liver quality and viability.
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Affiliation(s)
- Leon L Su
- Department of Laboratory Medicine and Pathology, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Daniel T Secor
- Mayo Clinic Alix School of Medicine, Phoenix, Arizona, USA
| | - Alyssa K McGary
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Michelle C Nguyen
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Caroline C Jadlowiec
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Lance A Williams
- Department of Laboratory Medicine and Pathology, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Theresa N Kinard
- Department of Laboratory Medicine and Pathology, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Jill Adamski
- Department of Laboratory Medicine and Pathology, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Alex D Stoker
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - Peter E Frasco
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic in Arizona, Phoenix, Arizona, USA
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Tracy KM, Shishido Y, Petrovic M, Murphy A, Adesanya T, Fortier AK, Harris TR, Cortelli M, Tucker WD, François SA, Petree B, Raietparvar K, Simon V, Johnson CA, Simonds E, Poland J, Glomp GA, Crannell C, Liang J, Marshall A, Hinton A, Shaver CM, Demarest CT, Ukita R, Shah AS, Rizzari M, Montenovo M, Rauf MA, McReynolds M, Bacchetta M. 10 degree C static storage of porcine donation after circulatory death livers improves biliary viability and mitigates ischemia-reperfusion injury. Am J Transplant 2025:S1600-6135(25)00147-9. [PMID: 40120647 DOI: 10.1016/j.ajt.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 03/04/2025] [Accepted: 03/13/2025] [Indexed: 03/25/2025]
Abstract
Optimized static cold storage has the potential to improve the preservation of organs most vulnerable to ischemia-reperfusion injury. Data from lung transplantation suggest that storage at 10 °C improves mitochondrial preservation and subsequent allograft function compared with conventional storage on ice. Using a porcine model of donation after circulatory death, we compared static storage of livers at 10 °C to ice. Livers (N = 5 per group) underwent 10 hours of storage followed by 4 hours of normothermic machine perfusion (NMP) for real-time allograft assessment. Allografts were compared using established NMP viability criteria, tissue immunostaining, and tissue metabolomics. Livers stored at 10 °C demonstrated lower portal venous vascular resistance and greater hepatic artery vasoresponsiveness. Lactate clearance during NMP was similar between the groups. Livers stored at 10 °C showed favorable biochemical parameters of biliary viability, including greater bile volume, pH, and bicarbonate. Metabolomics analysis revealed increased aerobic respiration, improved electron transport chain function, and less DNA damage after reperfusion of livers stored at 10 °C. Static storage of donation after circulatory death livers with extended cold ischemic time at 10 °C demonstrates superior allograft function with evidence of improved biliary viability and mitochondrial function compared with ice. These data suggest that storage at 10 °C should be considered for translation to clinical practice.
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Affiliation(s)
- Kaitlyn M Tracy
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yutaka Shishido
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mark Petrovic
- Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
| | - Alexandria Murphy
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA
| | - TiOluwanimi Adesanya
- Vanderbilt University, Nashville, Tennessee, USA; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Timothy R Harris
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Michael Cortelli
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - William D Tucker
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sean A François
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Brandon Petree
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Victoria Simon
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Carl A Johnson
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - John Poland
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Christian Crannell
- Department of Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jiancong Liang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Andrea Marshall
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Antentor Hinton
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Ciara M Shaver
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Caitlin T Demarest
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Rei Ukita
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ashish S Shah
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Michael Rizzari
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Martin Montenovo
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Muhammad Ameen Rauf
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Melanie McReynolds
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Matthew Bacchetta
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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Chen K, Yang M, Li G, Wang W. Liver transplantation for NASH-related hepatocellular carcinoma versus non-NASH etiologies of hepatocellular carcinoma: A systematic review and meta-analysis. PLoS One 2025; 20:e0317730. [PMID: 40106456 PMCID: PMC11922278 DOI: 10.1371/journal.pone.0317730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 01/05/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) has been emerging a predominant reason for liver transplantation (LT). The complexity of comorbidities in this population increases the possibility of poor transplant outcomes. The purpose of this study was to evaluate the differences in survival after transplantation among patients with NASH HCC and those with non-NASH HCC. METHOD We conducted systematic searches of the PubMed, Embase, Web of Science, and Cochrane Library databases. To analyze the data, both fixed and random-effects models were employed to aggregate hazard ratios (HRs) along with 95% confidence intervals (CIs) for recurrence-free survival (RFS) and overall survival (OS) outcomes. This study is registered with PROSPERO as CRD42024578441. RESULTS A total of seven studies were included in this study. This study revealed that there was no significant difference in OS between liver transplant recipients with NASH HCC and those with non-NASH HCC. The RFS of NASH HCC patients were significantly longer. The HRs were 0.70 (95% CI: 0.51-0.97, P = 0.03) for RFS and 0.88 (95% CI: 0.72-1.07, P = 0.21) for OS, respectively. CONCLUSION This study indicates that patients with NASH HCC who undergo LT have comparable OS as those with non-NASH HCC, while NASH HCC was associated with increased RFS. However, further research in randomized trials is necessary to verify these results and address potential selection biases.
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Affiliation(s)
- Kunlin Chen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guangjun Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Wentao Wang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
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Stoerzer S, Kruszona S, Wand P, Linge H, Zlatev H, Hoeffler K, Singh J, Roters N, Muth V, Tavil S, Saipbaev A, Cvitkovic K, Kues WA, Zardo P, Ius F, Mengwasser J, Splith K, Schmidt-Ott KM, Goecke T, Schwinzer R, Niemann H, Ruhparwar A, Schmelzle M, Ramm R, Felgendreff P. Advances in Xenotransplantation: Evaluation of αGal-KO Porcine Livers and Lungs Using Normothermic Machine Perfusion in a Collaborative Perfusion Hub. Transpl Int 2025; 38:13781. [PMID: 40124174 PMCID: PMC11925705 DOI: 10.3389/ti.2025.13781] [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: 09/11/2024] [Accepted: 02/17/2025] [Indexed: 03/25/2025]
Abstract
Recently, initial clinical experience has been gained with the xenotransplantation of pig organs such as heart and kidney into terminally ill human patients in an effort to overcoming organ shortage. Here, we investigated the use of normothermic machine perfusion (NMP) to advance xenotransplantation research and develop bridging therapies for acute organ failure such as the use of pig livers as a liver dialysis system. We simultaneously analyzed livers and lungs from genetically modified pigs, carrying a knock-out of the GGTA1 gene, which is essential for xenoreactive αGal-KO-epitopes, by applying clinically established normothermic perfusion systems, solutions and human blood. Experiments involved perfusing organs with cell-free solutions as well as human erythrocyte concentrates for up to six hours, analyzing organ quality using invasive and non-invasive methods, and the isolation and analysis of immune cells from the perfusate. The results obtained show stable flow characteristics with physiological perfusion and oxygenation levels of the organs, and a largely intact organ architecture, confirmed by histological sections before and after perfusion. Overall, this study demonstrates the feasibility of normothermic machine perfusion of xenogeneic organs by an interdisciplinary team, thus paving the way for clinical applications of porcine xenografts involving NMP.
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Affiliation(s)
- S. Stoerzer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - S. Kruszona
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - P. Wand
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - H. Linge
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - H. Zlatev
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - K. Hoeffler
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
| | - J. Singh
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - N. Roters
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
| | - V. Muth
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - S. Tavil
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - A. Saipbaev
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
| | - K. Cvitkovic
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
| | - W. A. Kues
- Biotechnology/Stem Cell Physiology, Institute of Farm Animal Genetics (FLI), Federal Research Institute for Animal Health, Neustadt, Germany
| | - P. Zardo
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
- Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - F. Ius
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
| | - J. Mengwasser
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - K. Splith
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - K. M. Schmidt-Ott
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - T. Goecke
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
- Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - R. Schwinzer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - H. Niemann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - A. Ruhparwar
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
- Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - M. Schmelzle
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - R. Ramm
- Department for Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany
- Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - P. Felgendreff
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
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Muth V, Strobl F, Michelotto J, Gilles L, Kirwan JA, Eisenberger A, Marchand J, Roschke NN, Moosburner S, Pratschke J, Sauer IM, Raschzok N, Gassner JMGV. Quality Assessment by Bile Composition in Normothermic Machine Perfusion of Rat Livers. Tissue Eng Part A 2025; 31:244-254. [PMID: 38832856 DOI: 10.1089/ten.tea.2024.0048] [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: 06/06/2024] Open
Abstract
Background: The persistent challenge of organ scarcity in liver transplantation leads to an escalating dependence on organs obtained from extended criteria donors (ECD). Normothermic machine perfusion (NMP) is used for improved preservation. Due to the mimicked in vivo conditions during normothermic machine perfusion, the liver is metabolically active, which allows quality assessment during perfusion. Bile seems to be of rising interest in clinical studies, as it is easily collectible for analysis. As there are currently no data on biliary bile acids during NMP, the primary objective of this study was to use our experimental rodent NMP model to assess changes in bile composition through organ damage during perfusion to inform clinical evaluation of donor organs during NMP. Methods: Thirty livers from male Sprague-Dawley rats in five groups underwent 6 h of NMP using either erythrocyte-supplemented DMEM or Steen solution, with or without 30 min of warm ischemia time (WIT). We conducted regular measurements of AST, ALT, LDH, and urea levels in the perfusate at 3-hour intervals. Bile samples were analyzed for biliary pH, LDH, and gamma glutamyltransferase, as well as biliary bile acids via mass spectrometry and UHPLC. Results: Compared with regular livers, liver injury parameters were significantly higher in our donation after circulatory death (DCD) model. Bile production was significantly reduced in livers exposed to WIT, and the bile showed a significantly more alkaline pH. This correlated with the concentration of total bile acids, which was significantly higher in livers experiencing WIT. However, regular livers produced a higher total amount of biliary bile acids during perfusion. Taurocholic acid and its metabolites were most prominent. Secondary bile acids were significantly reduced during perfusion due to the missing enterohepatic circulation. Conclusions: WIT-induced liver injury affects bile composition within our small-animal NMP model. We hypothesize this phenomenon to be attributed to the energy-driven nature of bile secretion, potentially explaining why DCD livers produce less, yet more concentrated, bile. Our results may inform clinical studies, in which biliary bile acids might have a potential as a quantifiable viability marker in human NMP liver transplantation studies.
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Affiliation(s)
- Vanessa Muth
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Felix Strobl
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Julian Michelotto
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Linda Gilles
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jennifer A Kirwan
- Metabolomics Platform, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Max Delbrück Center, Berlin, Germany
| | - Alina Eisenberger
- Metabolomics Platform, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Max Delbrück Center, Berlin, Germany
| | - Jeremy Marchand
- Metabolomics Platform, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Max Delbrück Center, Berlin, Germany
| | - Nathalie N Roschke
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Simon Moosburner
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Igor M Sauer
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nathanael Raschzok
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Berlin, Germany
| | - Joseph M G V Gassner
- Department of Surgery CCM|CVK, Experimental Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Berlin, Germany
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Baimas-George M, Russo M, Soto JR, Eskind L, Levi D, Vrochides D. Liver Transplantation for Colorectal Cancer Metastasis: An Evolving Option With Hope in Selected Patients. Gastroenterology 2025; 168:444-449. [PMID: 39592094 DOI: 10.1053/j.gastro.2024.11.002] [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: 03/26/2024] [Revised: 11/03/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024]
Affiliation(s)
- Maria Baimas-George
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Atrium Health, Wake Forest University School of Medicine, Charlotte, North Carolina
| | - Mark Russo
- Division of Hepatology, Carolinas Medical Center, Atrium Health, Wake Forest University School of Medicine, Charlotte, North Carolina
| | - Jose Raul Soto
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Atrium Health, Wake Forest University School of Medicine, Charlotte, North Carolina
| | - Lon Eskind
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Atrium Health, Wake Forest University School of Medicine, Charlotte, North Carolina
| | - David Levi
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Atrium Health, Wake Forest University School of Medicine, Charlotte, North Carolina
| | - Dionisios Vrochides
- Division of Abdominal Transplantation, Department of Surgery, Carolinas Medical Center, Atrium Health, Wake Forest University School of Medicine, Charlotte, North Carolina
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Nguyen MC, Zhang C, Chang YH, Li X, Ohara SY, Kumm KR, Cosentino CP, Aqel BA, Lizaola-Mayo BC, Frasco PE, Nunez-Nateras R, Hewitt WR, Harbell JW, Katariya NN, Singer AL, Moss AA, Reddy KS, Jadlowiec C, Mathur AK. Improved Outcomes and Resource Use With Normothermic Machine Perfusion in Liver Transplantation. JAMA Surg 2025; 160:322-330. [PMID: 39878966 PMCID: PMC11780509 DOI: 10.1001/jamasurg.2024.6520] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 11/02/2024] [Indexed: 01/31/2025]
Abstract
Importance Normothermic machine perfusion (NMP) has been shown to reduce peritransplant complications. Despite increasing NMP use in liver transplant (LT), there is a scarcity of real-world clinical experience data. Objective To compare LT outcomes between donation after brain death (DBD) and donation after circulatory death (DCD) allografts preserved with NMP or static cold storage (SCS). Design, Setting, and Participants This single-center, retrospective observational cohort study included all consecutive adult LTs performed between January 2019 and December 2023 at the Mayo Clinic in Arizona. Data analysis was performed between February 2024 and June 2024. Outcomes of DBD-SCS, DBD-NMP, DCD-SCS, and DCD-NMP transplants were compared. Exposure DBD and DCD livers preserved on NMP or SCS. Main Outcomes and Measures The primary outcomes were early allograft dysfunction (EAD), intraoperative transfusion, and post-LT hospital resource use, including length of stay (LOS) and readmissions. Secondary outcomes included acute kidney injury (AKI) and 1-year graft and patient survival. Results A total of 1086 LTs were included in the following 4 groups: DBD-SCS (n = 480), DBD-NMP (n = 63), DCD-SCS (n = 264), and DCD-NMP (n = 279). Among LT recipients, median (IQR) age was 60.0 years (52.0-66.0); 399 LT recipients (36.7%) were female. DCD-NMP had the lowest EAD rate (17.5%), followed by DCD-SCS (50.0%), DBD-NMP (36.8%), and DBD-SCS (27.3%) (P < .001). DCD-NMP had the lowest intraoperative transfusion requirement compared to all other groups. Hospital and intensive care unit (ICU) LOS were shortest in DCD-NMP (median [IQR] hospital LOS, 5.0 days [4.0-7.0]; P = .01; median [IQR] ICU LOS, 1.5 days [1.2-3.1]; P = .01). One-year cumulative readmission probability was 86% lower for DCD-NMP vs DCD-SCS (95% CI, 0.09-0.22; P < .001) and 53% lower for DBD-NMP vs DBD-SCS (95% CI, 0.26-0.87; P < .001). AKI events were lower in DCD-NMP (31.1%) vs DCD-SCS (47.4%) (P = .001). Compared to SCS, the NMP group had a 78% overall reduction in graft failure (hazard ratio [HR], 0.22; 95% CI, 0.10-0.49; P < .001). For those receiving DCD allografts, the risk reduction was even more pronounced, with an 87% decrease in graft failure (HR, 0.13; 95% CI, 0.05-0.33; P < .001). NMP was significantly protective from patient mortality vs SCS (HR, 0.31; 95% CI, 0.12-0.80; P = .02). Conclusions and Relevance In this observational high-volume cohort study, NMP significantly improved LT clinical outcomes and reduced hospital resource use, especially in DCD allografts. NMP may enhance access to LT by addressing the challenges historically linked with DCD liver use.
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Affiliation(s)
- Michelle C. Nguyen
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Chi Zhang
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Yu-Hui Chang
- Department of Quantitative Health Sciences, Mayo Clinic Arizona, Phoenix
| | - Xingjie Li
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Stephanie Y. Ohara
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Kayla R. Kumm
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | | | - Bashar A. Aqel
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Mayo Clinic Arizona, Phoenix
| | - Blanca C. Lizaola-Mayo
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Mayo Clinic Arizona, Phoenix
| | | | | | - Winston R. Hewitt
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Jack W. Harbell
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Nitin N. Katariya
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Andrew L. Singer
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Adyr A. Moss
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Kunam S. Reddy
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Caroline Jadlowiec
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
| | - Amit K. Mathur
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix
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Wehrle CJ, de Goeij FHC, Zhang M, Abbassi F, Satish S, Jiao C, Sun K, Pinna AD, Hashimoto K, Miller C, Polak WG, Clavien PA, De Jonge J, Schlegel A. Core outcome sets and benchmarking complications: Defining best practices for standardized outcome reporting in liver transplantation. Liver Transpl 2025; 31:395-409. [PMID: 39311852 DOI: 10.1097/lvt.0000000000000494] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 09/05/2024] [Indexed: 12/06/2024]
Abstract
The comparison of outcomes in liver transplantation (LT) is hampered by using clinically nonrelevant surrogate endpoints and considerable variability in reported relevant posttransplant outcomes. Such variability stems from nonstandard outcome measures across studies, variable definitions of the same complication, and different timing of reporting. The Clavien-Dindo classification was established to improve the rigor of outcome reporting but is nonspecific to an intervention, and there are unsolved dilemmas specifically related to LT. Core outcome sets (COSs) have been used in other specialties to standardize outcomes research, but have not been defined for LT. Thus, we use the 5 major benchmarking studies published to date to define a 10-measure COS for LT using previously validated metrics. We further provide standard definitions for each of the 10 measures that may be used in international research on the topic. These definitions also include standard time points for recording to facilitate between-study comparisons and future meta-analysis. These 10 outcomes are paired with 3 validated, procedure-independent metrics, including the Clavien-Dindo Classification and the Comprehensive Complications Index. The Clavien scale and Comprehensive Complications Index are specifically reviewed to enhance their utility in LT, and their use, along with the COS, is explored. We encourage future studies to employ this COS along with the Clavien-Dindo grading system and Comprehensive Complications Index to improve the reproducibility and generalizability of research concerning LT.
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Affiliation(s)
- Chase J Wehrle
- Transplant Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Femke H C de Goeij
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Mingyi Zhang
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Fariba Abbassi
- Department of Surgery & Transplantation, University of Zurich, Zurich, Switzerland
| | | | - Chunbao Jiao
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Keyue Sun
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Antonio D Pinna
- Transplant Center, Cleveland Clinic Florida, Weston, Florida, USA
| | - Koji Hashimoto
- Transplant Center, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Charles Miller
- Transplant Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Wojciech G Polak
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Pierre-Alain Clavien
- Transplant Center, Wyss Translational Center, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Jeroen De Jonge
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Andrea Schlegel
- Transplant Center, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Wall A, Snoddy M, Du J, Bayer J, Danobeitia S, Lee SH, Martinez E, Gupta A, Ran G, Parker WF, Asrani SK, Testa G. The current landscape of in situ and ex situ machine perfusion utilization for liver grafts from cardiac donation after circulatory death donors in the US. Am J Transplant 2025; 25:574-582. [PMID: 39293517 DOI: 10.1016/j.ajt.2024.09.012] [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: 05/20/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/20/2024]
Abstract
Donation after circulatory death (DCD) is driving the increase in deceased organ donors in the United States. Normothermic regional perfusion (NRP) and ex situ machine perfusion (es-MP) have been instrumental in improving liver transplant outcomes and graft utilization. This study examines the current landscape of liver utilization from cardiac DCD donors in the United States. Using the United Network for Organ Sharing Standard Transplant Analysis and Research file, all adult (≥18 years old) DCD donors in the United States from which the heart was used for transplantation from October 1, 2020, to September 30, 2023, were compared by procurement technique (NRP versus super rapid recovery [SRR]) and storage strategy (es-MP versus static cold storage). One hundred eighty-eight livers were transplanted from 309 thoracoabdominal NRP donors (61% utilization) versus 305 (56%) liver transplants from 544 SRR donors. es-MP was used in 20% (n = 38) of NRP cases versus 32% (98) of SRR cases. Of the liver grafts, 281 (59%) were exposed to NRP, es-MP, or both. While there is widespread utilization of machine perfusion, more research is needed to determine optimal graft management strategies, particularly concerning the use of multiple technologies in complementary ways. More complete data collection is necessary at a national level to address these important research questions.
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Affiliation(s)
- Anji Wall
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA.
| | - Matthew Snoddy
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Jinyu Du
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Johanna Bayer
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Sebastian Danobeitia
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Seung Hee Lee
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Eric Martinez
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Amar Gupta
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Gege Ran
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - William F Parker
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Sumeet K Asrani
- Department of Medicine, Baylor University Medical Center in Dallas, Dallas, Texas, USA
| | - Giuliano Testa
- Division of Abdominal Transplantation, Department of Surgery, Baylor University Medical Center in Dallas, Dallas, Texas, USA
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Stoker AD, Gorlin AW, Rosenfeld DM, Nguyen MC, Mathur AK, Buckner-Petty SA, Lizaola-Mayo BC, Frasco PE. Donation After Circulatory Death Liver Transplantation: Impact of Normothermic Machine Perfusion on Key Variables. Anesth Analg 2025; 140:687-696. [PMID: 39808582 PMCID: PMC11805485 DOI: 10.1213/ane.0000000000007093] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND During orthotopic liver transplantation, allograft reperfusion is a dynamic point in the operation and often requires vasoactive medications and blood transfusions. Normothermic machine perfusion (NMP) of liver allografts has emerged to increase the number of transplantable organs and may have utility during donation after circulatory death (DCD) liver transplantation in reducing transfusion burden and vasoactive medication requirements. METHODS This is a single-center retrospective study involving 226 DCD liver transplant recipients who received an allograft transported with NMP (DCD-NMP group) or with static cold storage (DCD-SCS group). Veno-venous bypass was not used in any patients. Infusion doses of norepinephrine, epinephrine, and vasopressin as well as bolus doses of vasoactive medications during reperfusion were recorded. Blood component therapy was recorded according to phase of liver transplantation and during the first 24 hours postprocedure. RESULTS A total of 103 recipients in the DCD-NMP group and 123 patients in the DCD-SCS group were included. Post-reperfusion syndrome (PRS) incidence was reduced in the DCD-NMP group compared to the DCD-SCS group (10.7% [95% confidence interval, CI, 5.5%-18.3%] vs 42.3% [95% CI, 33.4%-51.5%]; P < .001). During the reperfusion period, patients in the DCD-SCS group required increased bolus doses of epinephrine and vasopressin compared to the DCD-NMP group (24.6 vs 7.5 µg; P < .001) and (5.4 vs 2.4 units; P < .001), respectively. The DCD-SCS group received a higher infusion dose of epinephrine during anhepatic phase, at reperfusion, and up to 90 minutes after reperfusion. In the postreperfusion period, there were significant increases in the transfusion of red blood cells (RBCs; 5.3 vs 3.7 units; P = .006), fresh frozen plasma (FFP; 3.4 vs 1.9 units; P < .001), cryoprecipitate (2.7 vs 1.8 pooled units; P = .015) and platelets (0.9 vs 0.4 units; P = .008) in the DCD-SCS group compared to the DCD-NMP group. During the first 24 hours postprocedure, transfusion of RBCs, FFP, and cryoprecipitate in the DCD-SCS group was increased compared to the DCD-NMP group ([2.6 vs 1.7 units; P = .028], [1.6 vs 0.8 units; P < .001], [1.5 vs 0.9 pooled units; P = .031]) respectively. Administration of tranexamic acid was more frequent in the DCD-SCS group during the post-reperfusion period compared to the DCD-NMP group (13% [95% CI, 5.7%-17.4%] vs 3.9% [95% CI, 1.1%-9.6% 95%]; P = .018). CONCLUSIONS In DCD liver transplantation, use of NMP was associated with reduced incidence of PRS and decreased vasopressor and inotrope requirements at the time of allograft reperfusion compared to using SCS. Additionally, NMP was associated with reduced transfusion of all blood product components as well as antifibrinolytic agent administration in the post-reperfusion period. Reduced transfusion burden in the DCD-NMP group also occurred during the first 24 hours posttransplant.
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Affiliation(s)
- Alexander D. Stoker
- From the Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Phoenix, Arizona
| | - Andrew W. Gorlin
- From the Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Phoenix, Arizona
| | - David M. Rosenfeld
- From the Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Phoenix, Arizona
| | | | - Amit K. Mathur
- Division of Transplant Surgery, Mayo Clinic, Phoenix, Arizona
| | | | | | - Peter E. Frasco
- From the Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Phoenix, Arizona
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Montano-Loza AJ, Corpechot C, Burra P, Schramm C, Selzner N, Ronca V, Oo YH. Recurrence of autoimmune liver diseases after liver transplantation: Review and expert opinion statement. Liver Transpl 2025; 31:369-383. [PMID: 38857316 DOI: 10.1097/lvt.0000000000000419] [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: 01/08/2024] [Accepted: 05/24/2024] [Indexed: 06/12/2024]
Abstract
Autoimmune liver diseases (AILDs) constitute the fourth most common indication for liver transplantation (LT) across the world. In general, the outcomes after LT are acceptable; however, disease recurrence after LT is common for all AILD, which can negatively affect graft and overall survival. Several questions persist, including the risk factors associated with recurrent disease, optimal antirejection medications, strategies to reduce the risk of recurrence, and how to best incorporate these strategies into clinical practice. For that reason, we assembled an international group of experts to review evidence to address these outstanding questions regarding LT for AILD. Survival rates after LT are ~90% and 70% at 1 and 5 years, and recurrent disease occurs in 10%-50% of patients with AILD. In patients with disease recurrence, graft survival decreased by 18% and 28% and overall survival by 8% and 12% at 5 and 10 years after LT, respectively. Recurrent autoimmune hepatitis is associated with high aminotransferases and immunoglobulin G (IgG) before LT, lymphoplasmacytic infiltrates in the explants, and may be associated with the absence of steroids after LT. However, the efficiency and safety of triple immunosuppressive maintenance therapy is still debatable. Younger age at diagnosis with primary biliary cholangitis or LT is associated with primary biliary cholangitis recurrence. Preventive use of ursodeoxycholic acid reduces the risk of recurrence and has a benefit in graft and patient survival. Episodes of systemic inflammation, including T-cell-mediated rejection, active ulcerative colitis, and episodes of cholangitis, are associated with recurrent PSC. Recurrent disease for AILD is associated with worse graft and patient survival. Patients with autoimmune hepatitis could be considered for long-term low-dose predniso(lo)ne, whereas patients with primary biliary cholangitis should be placed on preventive ursodeoxycholic acid after LT. There are no specific treatments for PSC recurrence; however, adequate control of inflammatory bowel disease and optimal immunosuppression to avoid T-cell-mediated rejection should be encouraged.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network for Hepatological Diseases (ERN RARE-LIVER), Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris; Inserm UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, European Reference Network for Hepatological Diseases (ERN RARE-LIVER), University of Padova, Padova, Italy
| | - Christoph Schramm
- Martin Zeitz Center for Rare Diseases, and 1st Department of Medicine, European Reference Network for Hepatological Diseases (ERN RARE-LIVER), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nazia Selzner
- Ajmera Transplant Center, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
| | - Vincenzo Ronca
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Ye H Oo
- Center for Liver and Gastro Research & National Institute of Health Research Birmingham Biomedical Research Centre, University of Birmingham; Centre for Rare Disease and ERN Rare Liver Centre, Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
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Li X, Chang YH, Ohara SY, Reddy KS, Jadlowiec CC, Mathur AK, Nguyen MC. Normothermic Machine Perfusion Improves Outcomes for Donation After Cardiac Death Allografts With Extended Donor Warm Ischemia Time. Clin Transplant 2025; 39:e70133. [PMID: 40089898 DOI: 10.1111/ctr.70133] [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: 07/25/2024] [Revised: 12/19/2024] [Accepted: 03/02/2025] [Indexed: 03/17/2025]
Abstract
INTRODUCTION Donation after circulatory death (DCD) allografts are underutilized in liver transplantation (LT) due to increased risk of complications. These risks stem from ischemic injury sustained during the total donor warm ischemia time (tDWIT), historically limited to 30 min. Normothermic machine perfusion (NMP) can mitigate these risks and facilitate LT of DCD grafts with extended tDWIT. We aimed to compare outcomes of DCD allografts with extended tDWIT preserved on NMP versus static cold storage (SCS). METHODS This single-center study included adult DCD LT with tDWIT ≥ 30 from 2019 to 2023. Outcomes of NMP and SCS were compared including EAD, IC, graft survival, and patient survival. RESULTS Among 68 DCD LT with tDWIT ≥ 30, 64.7% (n = 44) were preserved with NMP and 35.3% (n = 24) with SCS. No differences in donor or recipient demographics were observed. The median tDWIT was 33 min for NMP and 30.5 min for SCS (p < 0.01). Despite longer tDWIT, the NMP group had lower rates of EAD (4.5% vs. 66.7%, p < 0.01) and IC (2.3% vs. 29.2%, p < 0.01). One-year graft survival was higher in NMP (p < 0.01), and 1-year patient survival was comparable between groups (p = 0.18). CONCLUSION NMP challenges traditional tDWIT constraints and can increase the pool of viable DCD allografts for transplantation.
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Affiliation(s)
- Xingjie Li
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Yu-Hui Chang
- Department of Quantitative Health Sciences, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Stephanie Y Ohara
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Kunam S Reddy
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Caroline C Jadlowiec
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Amit K Mathur
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Michelle C Nguyen
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA
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Bababekov YJ, Ha AH, Nydam TL, Goncalves C, Choudhury R, Shinsako J, Baimas-George M, Reynolds DM, Yoshida C, Racke CA, Grewal H, Pomposelli S, Rodriguez IE, Hoffman JR, Schold JD, Kaplan B, Pomfret EA, Pomposelli JJ. Thoracoabdominal Normothermic Regional Perfusion: Real-world Experience and Outcomes of DCD Liver Transplantation. Transplant Direct 2025; 11:e1767. [PMID: 40034160 PMCID: PMC11875611 DOI: 10.1097/txd.0000000000001767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/27/2024] [Accepted: 12/31/2024] [Indexed: 03/05/2025] Open
Abstract
Background Donation after circulatory death liver transplantation (DCD LT) is underused given historical outcomes fraught with ischemic cholangiopathy (IC). We aimed to assess 6-mo IC in LT from DCD via normothermic regional perfusion (NRP) compared with DCD via static cold storage (SCS). Methods A retrospective review of adult Maastricht-III DCD liver donors and recipients at the University of Colorado Hospital from January 1, 2017, to August 27, 2024, was performed. The 6-mo IC rate was compared between NRP and SCS. Secondary outcomes included biochemical assessments of accepted versus declined NRP liver allografts and allograft and patient survival for NRP and SCS groups. Results One hundred sixty-two DCD LTs (SCS = 79; NRP = 97) were performed and 150 recipients (SCS = 74; NRP = 86) reached 6-mo follow-up. Six-month IC was lower for NRP compared with SCS (1.2% versus 9.5%, P = 0.03). The Donor Risk Index (2.44 [2.02-2.82] versus 2.17 [1.97-2.30], P = 0.002) and UK DCD Risk Score (4.2 ± 2.9 versus 3.2 ± 2.3, P = 0.008) were higher for NRP versus SCS. The Liver Graft assessment Following Transplantation score was less for NRP compared with SCS (-3.3 versus -3.1, P < 0.05). There were several differences in median biochemical parameters during NRP between accepted and declined livers, including higher terminal biliary bicarbonate (22.7 [20.9-29.1] versus 10.8 [7.6-13.1] mEq/L, P = 0.004). There were no significant differences in 12-mo allograft or patient survival for NRP versus SCS. Conclusions NRP is a disruptive innovation that improves the utilization of DCD livers. Despite higher-risk donor-recipient pairing for NRP compared with SCS, we demonstrate a decrease in IC for NRP. These data facilitate benchmarking of thoracoabdominal NRP DCD LT and support further protocol development.
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Affiliation(s)
- Yanik J. Bababekov
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Anna H. Ha
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Trevor L. Nydam
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Carlos Goncalves
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Rashikh Choudhury
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - JoLynn Shinsako
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Maria Baimas-George
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - David M. Reynolds
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Cassidy Yoshida
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Caroline A. Racke
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Han Grewal
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Sophia Pomposelli
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Ivan E. Rodriguez
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Jordan R.H. Hoffman
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Jesse D. Schold
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Bruce Kaplan
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - Elizabeth A. Pomfret
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
| | - James J. Pomposelli
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
- Colorado Center for Transplantation Care, Research and Education (CCTCARE), Aurora, CO
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Paterson AL, Gaurav R, Swift L, Webster R, Fear C, Butler AJ, Watson CJE. Evolution of morphological changes in donor livers undergoing normothermic machine perfusion. Histopathology 2025; 86:516-524. [PMID: 39564610 DOI: 10.1111/his.15371] [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: 06/07/2024] [Revised: 09/02/2024] [Accepted: 11/03/2024] [Indexed: 11/21/2024]
Abstract
AIMS There is a shortage of livers for transplantation in the United Kingdom; despite this, more than a fifth of those retrieved are not transplanted. Normothermic machine perfusion (NMP) allows a functional assessment of marginal organs using biochemical parameters. This study describes the histological changes in livers undergoing NMP. METHODS AND RESULTS A total of 170 biopsies taken pre-NMP, after 4 h of NMP, end-NMP and at implantation from 50 livers undergoing NMP as part of standard local transplant practice were retrospectively reviewed. Thirty-eight per cent had large droplet macrovesicular steatosis pre-NMP, which was associated with reduced organ utilisation, P = 0.096, subsequent extracellular fat and a neutrophilic reaction; 32% had small droplet macrovesicular steatosis pre-NMP suggestive of acute cellular stress, the severity of which was unchanged in 64% during the perfusion period. Those showing at least moderate hepatocellular necrosis at end-NMP were less likely to be transplanted (55 versus 24%, P = 0.0505). Variation in the extent of hepatocyte necrosis was seen between biopsies, with 43% of transplanted cases showing less hepatocyte necrosis at implantation compared to end-NMP and 21% more severe necrosis. Patchy portal inflammation was present in 96% of pre-NMP biopsies, although identifiable duct injury was rare and portal thrombi were not identified. Sinusoidal dilation pre-NMP was more frequent in donation after circulatory death donors, typically persisted during NMP although had improved by implantation in most and had resolved in cases with an early post-transplant biopsy. CONCLUSIONS Histological changes in NMP livers predominantly comprise donor-derived steatosis, stress-associated small droplet steatosis, retrieval- and procedure-associated sinusoidal dilation and ischaemic injury.
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Affiliation(s)
- A L Paterson
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - R Gaurav
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - L Swift
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - R Webster
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - C Fear
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - A J Butler
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- The University of Cambridge Department of Surgery, Cambridge, UK
| | - C J E Watson
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- The University of Cambridge Department of Surgery, Cambridge, UK
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42
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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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43
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van Leeuwen OB, Lantinga VA, Lascaris B, Thorne AM, Bodewes SB, Nijsten MW, de Meijer VE, Porte RJ. 'Back-to-base' combined hypothermic and normothermic machine perfusion of human donor livers. Nat Protoc 2025:10.1038/s41596-024-01130-8. [PMID: 40011689 DOI: 10.1038/s41596-024-01130-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/05/2024] [Indexed: 02/28/2025]
Abstract
The shortage of suitable donor organs has resulted in the use of suboptimal, high-risk, extended-criteria donor (ECD) livers, which are at an increased risk of failure after transplantation. Compared with traditional static cold storage, dynamic preservation by ex situ machine perfusion reduces the risks associated with the transplantation of ECD organs. Ex situ machine perfusion strategies differ in timing (that is, speed of procurement and transport), perfusion duration and perfusion temperature. For 'back-to-base' protocols, the donor liver is statically cold stored during transportation to the recipient hospital (the 'base') and then perfused, instead of transporting the liver using a portable perfusion system. While dual hypothermic (8-12 °C) oxygenated machine perfusion (DHOPE) allows safe prolongation of preservation duration and reduces ischemia-reperfusion injury-related complications, including post-transplant cholangiopathy, normothermic machine perfusion (NMP) at 35-37 °C facilitates ex situ viability testing of both liver parenchyma and bile ducts. Here, we describe a clinical protocol for 'back-to-base' combined DHOPE and NMP, linked by a period of controlled oxygenated rewarming (COR), which we call the DHOPE-COR-NMP protocol. This protocol enables restoration of mitochondrial function after static ischemic preservation and minimizes both ischemia-reperfusion and temperature-shift-induced injury during the start of NMP. The NMP phase allows viability assessment before final donor liver acceptance for transplantation. Sequential DHOPE and COR-NMP may reduce the risks associated with transplantation of ECD livers and facilitate enhanced utilization, thereby helping to alleviate the organ shortage.
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Affiliation(s)
- Otto B van Leeuwen
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Veerle A Lantinga
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bianca Lascaris
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Adam M Thorne
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Silke B Bodewes
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Maarten W Nijsten
- Department of Anesthesiology and 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 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.
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Wiemann BA, Beetz O, Weigle CA, Tessmer P, Störzer S, Kleine-Döpke D, Vondran FWR, Richter N, Schmelzle M, Oldhafer F. Early Allograft Dysfunction after liver transplantation- definition, incidence and relevance in a single-centre analysis. Langenbecks Arch Surg 2025; 410:76. [PMID: 39969574 PMCID: PMC11839853 DOI: 10.1007/s00423-025-03633-8] [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: 11/02/2024] [Accepted: 02/01/2025] [Indexed: 02/20/2025]
Abstract
PURPOSE Early Allograft Dysfunction (EAD) is a serious complication following liver transplantation. With more marginal donors and critical recipients, identifying EAD risk factors and their impact on long-term outcomes is crucial. METHODS We reviewed all liver transplants performed between 2007 and 2017 at our institution, excluding pediatric recipients, combined thoracic transplants, and retransplants in the same hospital stay. EAD was defined as either: (i) AST/ALT > 2000 IU/l in first 7 postoperative days (POD), (ii) Bilirubin ≥ 10 mg/dl on POD 7, (iii) INR ≥ 1.6 on POD 7. RESULTS Of the 621 cases analyzed, the EAD rate was 53.6%. Multivariate analysis identified only donor-dependent variables as independent risk factors for the onset of EAD: donor age (p = 0.012), donor serum sodium (p = 0.021), cold ischemic time (p = 0.007) and graft weight (p < 0.001). EAD significantly impaired graft survival (69.2% vs. 86.2% after 1 year; p = 0.005) but did not impact long-term patient survival (76.3% vs. 87.6% after 1 year; p = 0.162). Of the EAD components, elevated INR proved to be the only reliable predictor of patient mortality. Additionally, an AST/ALT concentration of > 4000 IU/l significantly improved the predictive value of the EAD definition for patient survival (p = 0.002). CONCLUSIONS EAD risk factors are primarily donor-based and significantly impair graft but not patient survival. The high EAD rates and increased use of marginal grafts suggest the need to adjust conventional EAD definitions to optimize graft allocation in the future.
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Affiliation(s)
- Bengt A Wiemann
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
| | - Oliver Beetz
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
- Department of General, Visceral, Pediatric and Transplant Surgery, RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074, Aachen, Germany
| | - Clara A Weigle
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
- Department of General, Visceral, Pediatric and Transplant Surgery, RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074, Aachen, Germany
| | - Philipp Tessmer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
- Department of General, Visceral, Pediatric and Transplant Surgery, RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074, Aachen, Germany
| | - Simon Störzer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
| | - Dennis Kleine-Döpke
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
| | - Florian W R Vondran
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
- Department of General, Visceral, Pediatric and Transplant Surgery, RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074, Aachen, Germany
| | - Nicolas Richter
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
| | - Moritz Schmelzle
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany
| | - Felix Oldhafer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany.
- Department of General, Visceral, Pediatric and Transplant Surgery, RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074, Aachen, Germany.
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45
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Pezzati D, Torri F, Franzini M, Balzano E, Catalano G, Tincani G, Bronzoni J, Martinelli C, Trizzino A, Petagna L, Carrai P, Petruccelli S, Masini M, Rotondo MI, Babboni S, Del Turco S, Morganti R, De Tata V, Biancofiore G, Peris A, Lazzeri C, Basta G, Paolicchi A, Ghinolfi D. Association of perfusate cytokine concentrations during liver graft ex situ normothermic perfusion to donor type and postoperative outcomes. Liver Transpl 2025:01445473-990000000-00562. [PMID: 39927817 DOI: 10.1097/lvt.0000000000000583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 01/20/2025] [Indexed: 02/11/2025]
Abstract
The use of the so-called extended criteria donors increases the number of grafts available for transplantation. Many studies reported their good outcomes but their use is debated due to increased risk of complications. Ex situ liver perfusion has reduced graft discard rate and helped to test their function before implantation. Cytokines are known to be involved in ischemia-reperfusion injury, but their potential to predict liver function during normothermic machine perfusion (NMP) has not been fully investigated. The aim of this study was to compare cytokines levels during NMP in 3 different types of donors (donation after brain death, donation after circulatory death [DCD]-II, DCD-III) and correlate these data to postoperative clinical and biochemical outcomes. All donations after brain deaths older than 70 years and DCDs transplanted after NMP were included. IL-6, IL-10, and TNF-α were measured during NMP and correlated with clinical outcomes. Thirty liver grafts were transplanted after NMP: 16 donations after brain deaths, 7 DCD-II, and 7 DCD-III. There were 6 cases of early allograft dysfunction (20.0%), 10 of post-reperfusion syndrome (33.3%), and 11 cases of acute kidney injury (36.7%), with no major differences among groups. A positive correlation was found between perfusate IL-6 levels and the bilirubin peak within 7 days after liver transplantation, while IL-10 was associated with the intensive care unit stay and TNF-α to the international normalized ratio peak within 7 days. IL-6 was negatively associated with postoperative ALT levels and IL-10 to bilirubin peak. A correlation between higher IL-6 levels at 2 hours and graft loss was found. This is the first study to compare cytokines profile during NMP in 3 different types of donors and correlate it to clinical outcomes. A correlation between IL-6 concentration and graft failure was found. The role and significance of inflammatory markers in machine perfusion perfusate and their potential to assess graft viability and the risk of post-liver transplantation complications have to be further addressed.
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Affiliation(s)
- Daniele Pezzati
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Francesco Torri
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Maria Franzini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, Pisa, Italy
| | - Emanuele Balzano
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Gabriele Catalano
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Giovanni Tincani
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Jessica Bronzoni
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Caterina Martinelli
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Arianna Trizzino
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Lorenzo Petagna
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Paola Carrai
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Stefania Petruccelli
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Matilde Masini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, Pisa, Italy
| | | | - Serena Babboni
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Serena Del Turco
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | | | - Vincenzo De Tata
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, Pisa, Italy
| | - Giandomenico Biancofiore
- Division of Transplant Anesthesia, Department of Anesthesia, University of Pisa Hospital, Pisa, Italy
| | - Adriano Peris
- Regional Transplant Authority of Tuscany (OTT), Florence, Italy
| | - Chiara Lazzeri
- Regional Transplant Authority of Tuscany (OTT), Florence, Italy
| | - Giuseppina Basta
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Aldo Paolicchi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, Pisa, Italy
| | - Davide Ghinolfi
- Division of Hepatic Surgery and Liver Transplantation, Department of Endocrine and Metabolic Surgery and Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
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46
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Zhang MX, Zhao Q, He XS. Research progress of ischemia-free liver transplantation. Hepatobiliary Pancreat Dis Int 2025; 24:18-22. [PMID: 39489635 DOI: 10.1016/j.hbpd.2024.10.002] [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: 07/01/2024] [Accepted: 10/17/2024] [Indexed: 11/05/2024]
Abstract
Ischemia-reperfusion injury (IRI) is an inherent issue in organ transplantation. Because of the allograft shortage, more and more extended criteria donor (ECD) organs are used, unfortunately these grafts are more susceptible to IRI. Although machine perfusion technology has brought hope to alleviate IRI, this technology is still unable to eradicate IRI-related organ damage. Ischemia-free liver transplantation (IFLT) can completely avoid IRI, thereby improve graft function and recipient outcome, and allow to expand organ pool. This review summarized the latest progresses in IFLT, and speculated the future development of this concept.
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Affiliation(s)
- Ming-Xi Zhang
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510000, China
| | - Qiang Zhao
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510000, China
| | - Xiao-Shun He
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou 510000, China.
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47
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Vidgren M, Delorme C, Oniscu GC. Challenges and opportunities in organ donation after circulatory death. J Intern Med 2025; 297:124-140. [PMID: 39829342 PMCID: PMC11771584 DOI: 10.1111/joim.20051] [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] [Indexed: 01/22/2025]
Abstract
In recent years, there has been resurgence in donation after circulatory death (DCD). Despite that, the number of organs transplanted from these donors remains low due to concerns about their function and a lack of an objective assessment at the time of donation. This overview examines the current DCD practices and the classification modifications to accommodate regional perspectives. Several risk factors underscore the reluctance to accept DCD organs, and we discuss the modern strategies to mitigate them. The advent of machine perfusion technology has revolutionized the field of DCD transplantation, leading to improved outcomes and better organ usage. With many strategies at our disposal, there is an urgent need for comparative trials to determine the optimal use of perfusion technologies for each donated organ type. Additional progress in defining therapeutic strategies to repair the damage sustained during the dying process should further improve DCD organ utilization and outcomes. However, there remains wide variability in access to DCD donation and transplantation, and organizational efforts should be doubled up with consensus on key ethical issues that still surround DCD donation in the era of machine perfusion.
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Affiliation(s)
- Mathias Vidgren
- Division of Transplantation SurgeryCLINTEC, Karolinska InstitutetStockholmSweden
- Department of Transplantation SurgeryKarolinska Universitetssjukhuset HuddingeHuddingeSweden
| | - Capucine Delorme
- Division of Transplantation SurgeryCLINTEC, Karolinska InstitutetStockholmSweden
- Department of Transplantation SurgeryKarolinska Universitetssjukhuset HuddingeHuddingeSweden
| | - Gabriel C. Oniscu
- Division of Transplantation SurgeryCLINTEC, Karolinska InstitutetStockholmSweden
- Department of Transplantation SurgeryKarolinska Universitetssjukhuset HuddingeHuddingeSweden
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48
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Morawski M, Zhylko A, Kubiszewski H, Rochoń J, Rykowski P, Staszewski M, Krasnodębski M, Figiel W, Krawczyk M, Grąt M. Normothermic Machine Perfusion in Orphan Liver Graft Viability Assessment. J Clin Med 2025; 14:777. [PMID: 39941448 PMCID: PMC11818235 DOI: 10.3390/jcm14030777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/31/2024] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Liver transplantation constitutes a well-established treatment for patients with end-stage liver disease and selected hepatic malignancies. The introduction of normothermic machine perfusion (NMP) offers a platform for both extracorporeal organ maintenance and viability assessment, especially for organs with suspicious malfunction. These organs, discarded by the majority of transplant centers (so-called 'orphan livers'), may help to safely expand the donor pool thanks to pre-transplant appraisal; Methods: We identified all grafts undergoing normothermic ma-chine perfusions performed in the Department of General, Transplant, and Liver Surgery between December 2022 and August 2023. Their perfusion characteristics and immediate postoperative periods, as well as complications that occurred in the 90-day postoperative periods, were analyzed; Results: There were eight orphan liver grafts that underwent NMP in our Department. Postoperative complications occurring in patients receiving grafts after NMP did not seem associated with the procedure. One patient required laparotomy within the 90-day postoperative period due to biliary fistula and underwent bile duct stenting due to both fistula and nonanastomotic stricture. In one patient we observed the occurrence of anastomotic biliary stricture more than 90 days after LTx; Conclusions: NMP allows for the viability assessment of grafts with suspicious prepreservation malfunction. Some of these organs may help to expand the donor pool.
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Affiliation(s)
- Marcin Morawski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.Z.); (H.K.); (J.R.); (P.R.); (M.S.); (M.K.); (W.F.); (M.K.); (M.G.)
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49
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Likhitsup A, Fontana RJ. Indications and Outcomes with Liver Retransplantation in 2025. Dig Dis Sci 2025; 70:29-38. [PMID: 39576429 DOI: 10.1007/s10620-024-08741-x] [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: 07/09/2024] [Accepted: 11/06/2024] [Indexed: 01/25/2025]
Abstract
Five to 10% of the annual liver transplants in the United States are performed in prior liver recipients with 70% occurring within 1 year of transplantation. Fortunately, the incidence of primary non-function (PNF) has significantly decreased from 8% in the 1980's to < 2%, but PNF and hepatic artery thromboses remain the leading reasons for early emergency retransplantation. Other indications for early retransplantation include severe biliary or vascular complications and refractory rejection. Fortunately, the need for late retransplantation (> 1 year) has also declined due to improved immunosuppression, earlier detection of recurrent disease, and use of oral antiviral agents for recurrent hepatitis C. Patient survival with retransplantation is consistently lower than with primary liver transplantation. Risk factors for poor outcomes with retransplantation include a higher MELD score, ICU status, renal failure, and use of marginal allografts. Therefore, most centers use younger, whole deceased brain-dead donor organs whenever possible. However, increased use of machine perfused livers has expanded the donor pool for these more complex and technically challenging cases. Retransplant recipients have a higher rate of early technical, infectious, and cardiovascular complications compared to primary LT recipients. Going forward, LT recipients with recurrent steatotic and alcoholic liver disease will likely pose ethical, medical, and surgical challenges to the transplant community.
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Affiliation(s)
- Alisa Likhitsup
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, Ann Arbor, MI, 48109-0362, USA
| | - Robert J Fontana
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, Ann Arbor, MI, 48109-0362, USA.
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Punjala SR, Logan AJ, Subramanian J, Von Stein L, Limkemann A, Al-Ebrahim M, Black S, Schenk AD, Washburn WK, Singh N. Outcomes of Liver Transplantation From Hepatitis C Virus-positive DCD Donors and Its Utilization Among Centers in the United States. Transplantation 2025; 109:186-195. [PMID: 39169451 PMCID: PMC11627318 DOI: 10.1097/tp.0000000000005174] [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: 12/19/2023] [Revised: 06/25/2024] [Accepted: 07/09/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND Donation after circulatory death (DCD) or hepatitis C virus (HCV + ) liver grafts are underused among transplant centers in the United States. The study aimed to evaluate organ utilization and outcomes of liver grafts from DCD donors with HCV infection. METHODS National registry and local center data of all deceased donor liver transplants performed between November 2016 and December 2021 were analyzed. All transplants were divided into 4 groups: HCV - DCD, HCV - donation after brain death [DBD], HCV + DCD, and HCV + DBD. The outcome of interest was 1-y graft survival. RESULTS Out of 146 liver transplant centers in the United States, liver transplants were not performed from DCD donors, HCV + donors, and a combination of DCD and HCV + donors by 28.7%, 27%, and 70%-72% of centers, respectively. In multivariate analysis, increasing center acceptance ratio was associated with increased utilization of liver grafts from DCD HCV - and DCD HCV antibody-positive nucleic acid test negative donors. Nationally, 1-y graft survival of HCV - DCD liver grafts was lower compared with other groups (89% versus 92% HCV + DCD versus 93% HCV + DBD versus 92% HCV - DBD, log rank P < 0.0001). There was no difference in 1-y graft survival among groups locally. CONCLUSIONS Liver grafts from HCV + DCD donors have 1-y patient and graft survival comparable with DBD liver grafts from donors with or without HCV infection. These results encourage the widespread use of liver grafts from DCD and HCV + donors and standardization of practice in DCD donation to expand the donor pool without compromising short-term outcomes.
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Affiliation(s)
- Sai Rithin Punjala
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - April J. Logan
- Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH
| | - Jayanthan Subramanian
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Lauren Von Stein
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Ashley Limkemann
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Musab Al-Ebrahim
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Sylvester Black
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Austin D. Schenk
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - William K. Washburn
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Navdeep Singh
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
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