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1
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Archie WH, Baimas-George M, Haynes N, Kundu S, Peterson K, Wehrle CJ, Huckleberry D, Eskind L, Levi D, Soto JR, Denny R, Casingal V, Cochran A, Rein EH, Vrochides D. Upper limit of normothermic machine preservation of liver grafts from donation after circulatory death yet to be defined. World J Transplant 2025; 15:99170. [DOI: 10.5500/wjt.v15.i2.99170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 11/07/2024] [Accepted: 12/11/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND The normothermic machine perfusion pump (NMPP) could shape the future of transplantation. Providing ex-vivo optimization, NMPP attenuates ischemic insult while replenishing energy. An understanding of machine perfusion time (MPT) impact and potential clinical benefits is paramount and necessitates exploration.
AIM To investigate the relationship between MPT and post-transplant graft function.
METHODS Retrospective review of the first 50 donation after circulatory death (DCD) grafts preserved using NMPP in a tertiary institution was performed. Essential preservation time points, graft parameters, recipient information, and postoperative outcomes were prospectively recorded. Early allograft dysfunction (EAD), L-Graft7 score and 90-day outcomes were collected for all grafts. The first 20 recipients were allocated into the early group, considered the learning curve population for the center. The subsequent 30 were allocated into the late group. Recipients were also stratified into cohorts depending on MPT, i.e., short (< 8 hours), medium (8-16 hours) and long (> 16 hours).
RESULTS NMPP operational parameters were not predictive of EAD, L-GrAFT7 or 90-day outcomes. The early group had significantly less MPT and cold ischemia time than the late group (553 minutes vs 850 minutes, P < 0.001) and (127.5 minutes vs 154 minutes, P = 0.025), respectively. MPT had no impact in either group.
CONCLUSION Increased MPT of DCD liver grafts had no adverse recipient results for the times utilized in this population, indicating its upper limits, likely beyond 24 hours, are not demonstrated within this study. Future studies are necessary to determine whether longer MPT is beneficial or detrimental to graft function and, if the latter, what is the maximum safe duration. Further studies of the effect of normothermic machine perfusion pump duration on long-term outcomes are also needed.
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Affiliation(s)
- William H Archie
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Maria Baimas-George
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Nathanael Haynes
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Souma Kundu
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Katheryn Peterson
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Chase J Wehrle
- Department of Hepato-Pancreato-Biliary/Liver Transplant Surgery, Cleveland Clinic Transplant Research Center, Cleveland, OH 44195, United States
| | - Damien Huckleberry
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Lon Eskind
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - David Levi
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Jose R Soto
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Roger Denny
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Vincent Casingal
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Allyson Cochran
- Department of Surgery, Carolinas Center for Surgical Outcomes Science, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Erin H Rein
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
| | - Dionisios Vrochides
- Division of Adominal Transplant, Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, United States
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2
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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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3
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Puchany AJ, Hilmi I. Post-reperfusion syndrome in liver transplant recipients: What is new in prevention and management? World J Crit Care Med 2025; 14:101777. [DOI: 10.5492/wjccm.v14.i2.101777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/22/2024] [Accepted: 12/19/2024] [Indexed: 02/27/2025] Open
Abstract
Post-reperfusion syndrome (PRS) in liver transplant recipients remains one of the most dreaded complications in liver transplant surgery. PRS can impact the short-term and long-term patient and graft outcomes. The definition of PRS has evolved over the years, from changes in arterial blood pressures and heart and/or decreases in the systemic vascular resistance and cardiac output to including the fibrinolysis and grading the severity of PRS. However, all that did not reflect on the management of PRS or its impact on the outcomes. In recent years, new scientific techniques and new technology have been in the pipeline to better understand, manage and maybe prevent PRS. These new methods and techniques are still in the infancy, and they have to be proven not in prevention and management of PRS but their effects in the patient and graft outcomes. In this article, we will review the long history of PRS, its definition, etiology, management and most importantly the new advances in science and technology to prevent and properly manage PRS.
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Affiliation(s)
- Austin James Puchany
- Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
| | - Ibtesam Hilmi
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Department of Anesthesiology and Perioperative Medicine, Clinical and Translational Science Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, United States
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4
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Li X, Zhu H, Wei X, Yang Q, Xiong C, Shi Z. Nanocellulose/activated carbon composite aerogel beads with high adsorption capacity for toxins in blood. Int J Biol Macromol 2025; 300:140279. [PMID: 39863232 DOI: 10.1016/j.ijbiomac.2025.140279] [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: 11/20/2024] [Revised: 01/06/2025] [Accepted: 01/22/2025] [Indexed: 01/27/2025]
Abstract
Activated carbon is extensively utilized in blood purification applications. However, its performance has been significantly limited by their poor blood compatibility. In this work, 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO)-oxidized cellulose nanofibers (TOCN) and activated carbon (AC) were used to form composite beads by the drop curing method to improve hemocompatibility. The TOCN/AC composite beads had porous surface and exhibited extraordinary adsorption properties. The beads had a high adsorption capacity for creatinine with the optimal adsorption capacity of 83.33 mg g-1. And the equilibrium adsorption of bilirubin, uric acid and Cu2+ by TOCN/AC beads was as high as 159.80 mg g-1, 114.61 mg g-1 and 154.0 mg g-1, respectively, with a mass ratio of TOCN to AC of 1:4. It is also observed that the adsorption behavior of TOCN/AC beads on creatinine was consistent with the second-order kinetics and Langmuir isothermal model. The hemolysis rate of TOCN/AC was 1.21 %, indicating that TOCN/AC beads had good blood compatibility. The clearance of creatinine toxin in blood by TOCN/AC beads was as high as 87 % within 90 min. Overall, our produced composite beads had great potential for application in the field of blood purification.
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Affiliation(s)
- Xiangxian Li
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China; School of Materials Science and Engineering, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China
| | - Hengfeng Zhu
- School of Materials Science and Engineering, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China
| | - Xuanru Wei
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China
| | - Quanling Yang
- School of Materials Science and Engineering, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China
| | - Chuanxi Xiong
- School of Materials Science and Engineering, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China
| | - Zhuqun Shi
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China; School of Materials Science and Engineering, Wuhan University of Technology, Luoshi Road 122, Wuhan 430070, China.
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5
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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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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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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 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, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, CIBERehd, Córdoba, Spain
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Gonzalo Crespo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Federico Piñero
- School of Medicine, Hospital Universitario Austral, Austral University, Buenos Aires, Argentina
| | - Eleonora De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, Université Paris-Saclay, FHU Hepatinov, Villejuif, France
| | - Jordi Colmenero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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8
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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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9
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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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10
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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°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 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 to conventional storage on ice. Using a porcine model of donation after circulatory death (DCD), we compared static storage of livers at 10°C to ice. Livers (N=5 per group) underwent ten hours of storage followed by four hours of normothermic machine perfusion (NMP) for real-time allograft assessment. Allografts were compared using established NMP viability criteria, tissue immunostaining, and tissue metabolomics. 10°C stored livers demonstrated lower portal venous vascular resistance and greater hepatic artery vasoresponsiveness. Lactate clearance during NMP was similar between groups. 10°C stored livers 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 DCD livers with extended cold ischemic time at 10°C demonstrates superior allograft function with evidence of improved biliary viability and mitochondrial function compared to 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, TN, USA
| | - Yutaka Shishido
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mark Petrovic
- Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Alexandria Murphy
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - TiOluwanimi Adesanya
- Vanderbilt University, Nashville, TN, USA; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Timothy R Harris
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Michael Cortelli
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - William D Tucker
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sean A François
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Brandon Petree
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Victoria Simon
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Carl A Johnson
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - John Poland
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Christian Crannell
- Department of Surgery, Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jiancong Liang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Andrea Marshall
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Antentor Hinton
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Ciara M Shaver
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Caitlin T Demarest
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rei Ukita
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ashish S Shah
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Michael Rizzari
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Martin Montenovo
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M Ameen Rauf
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Melanie McReynolds
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Matthew Bacchetta
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
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11
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Gadour E. Lesson learnt from 60 years of liver transplantation: Advancements, challenges, and future directions. World J Transplant 2025; 15:93253. [PMID: 40104199 PMCID: PMC11612893 DOI: 10.5500/wjt.v15.i1.93253] [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: 02/22/2024] [Revised: 09/06/2024] [Accepted: 09/14/2024] [Indexed: 11/26/2024] Open
Abstract
Over the past six decades, liver transplantation (LT) has evolved from an experimental procedure into a standardized and life-saving intervention, reshaping the landscape of organ transplantation. Driven by pioneering breakthroughs, technological advancements, and a deepened understanding of immunology, LT has seen remarkable progress. Some of the most notable breakthroughs in the field include advances in immunosuppression, a revised model for end-stage liver disease, and artificial intelligence (AI)-integrated imaging modalities serving diagnostic and therapeutic roles in LT, paired with ever-evolving technological advances. Additionally, the refinement of transplantation procedures, resulting in the introduction of alternative transplantation methods, such as living donor LT, split LT, and the use of marginal grafts, has addressed the challenge of organ shortage. Moreover, precision medicine, guiding personalized immunosuppressive strategies, has significantly improved patient and graft survival rates while addressing emergent issues, such as short-term complications and early allograft dysfunction, leading to a more refined strategy and enhanced post-operative recovery. Looking ahead, ongoing research explores regenerative medicine, diagnostic tools, and AI to optimize organ allocation and post-transplantation car. In summary, the past six decades have marked a transformative journey in LT with a commitment to advancing science, medicine, and patient-centered care, offering hope and extending life to individuals worldwide.
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Affiliation(s)
- Eyad Gadour
- Department of Gastroenterology and Hepatology, King Abdulaziz National Guard Hospital, Ahsa 36428, Saudi Arabia
- Internal Medicine, Zamzam University College, Khartoum 11113, Sudan
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12
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Ford SL, Rogers NM. Research Highlights. Transplantation 2025:00007890-990000000-01030. [PMID: 40082254 DOI: 10.1097/tp.0000000000005376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Affiliation(s)
- Sharon L Ford
- Department of Nephrology, Austin Health, Heidelberg, VIC, Australia
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia
- Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Australia
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13
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Yu JW, Xiang LB, Dong XJ, Yang CX, Wang L, Liu XY, Song YH, Bai XJ, Xiao JW, Ren L, Xu QH, Yang GH, Lv Y, Lu Q. Shortening the recipient warm ischemia time could be a strategy for expanding the liver donor pool. World J Gastroenterol 2025; 31:103188. [DOI: 10.3748/wjg.v31.i9.103188] [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: 11/11/2024] [Revised: 01/03/2025] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND Shortening the recipient warm ischemia time (rWIT) has been proven to be effective for improving the short- and long-term outcomes after liver transplantation (LT) and offsets the negative impact of an extended cold ischemia time. However, few studies have been conducted to explore the prognostic effects of shortening the rWIT in transplantations using a liver graft from an extended-criteria donor (ECD).
AIM To investigate whether shortening the rWIT could improve the outcomes of ECD LT.
METHODS Rat ECD autologous orthotopic LT were performed with variable rWITs (0, 10, 20, and 30 minutes). Near-infrared fluorescence imaging (FI) was used for the real-time assessment of liver graft ischemia-reperfusion injury after the anhepatic phase. Survival was assessed, and liver function and histological analyses were performed on the third day after transplantation.
RESULTS The FI curve growth rate and postoperative three-day survival rate significantly increased, and the liver function and Suzuki score of the liver grafts significantly improved when the rWIT was ≤ 10 minutes (P < 0.05).
CONCLUSION The post-transplant outcomes were significantly better with a shorter rWIT (10 minutes or less) than with a longer rWIT, which could be a strategy for expanding the liver donor pool.
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Affiliation(s)
- Jia-Wei Yu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Lin-Biao Xiang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xiao-Juan Dong
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Chen-Xi Yang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Lei Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xiao-Yu Liu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi-Hong Song
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xian-Jie Bai
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Jing-Wen Xiao
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Lu Ren
- Department of International Medical Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Qin-Hong Xu
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Gang-Hua Yang
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Qiang Lu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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14
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Wei X, Zhu H, Hong D, Li X, Shi Z, Yang Q. Nanocellulose/Graphene Oxide Composite Beads as a Novel Hemoperfusion Adsorbent for Efficient Removal of Bilirubin Plasma. Biomacromolecules 2025. [PMID: 40036674 DOI: 10.1021/acs.biomac.4c01838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Conventional hemoperfusion adsorbents suffer from inefficiency and poor biocompatibility. Cellulose, a natural polysaccharide with biocompatible, biodegradable, and nontoxic properties, was combined with graphene oxide (GO) to fabricate composite beads (TGO) for blood purification. GO synthesized via a modified Hummers method was complexed with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibrils (TOCNs). Increasing GO content (2-20 wt %) enhanced TGO's specific surface area (256.4-289.0 m2 g-1) while retaining an ∼10 nm pore size. TGO demonstrated exceptional adsorption capacities: bilirubin (418.4 mg g-1), creatinine (23.5 mg g-1), uric acid (146.6 mg g-1), and Cu2+ (171.9 mg g-1). The beads exhibited excellent hemocompatibility (hemolysis rate <5%) and prolonged recalcification time (585 ± 5.2 s). Notably, TGO restored blood bilirubin levels to normal within 30 min, highlighting its potential for blood purification.
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Affiliation(s)
- Xuanru Wei
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China
| | - Hengfeng Zhu
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China
- School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, China
| | - Dichan Hong
- School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, China
| | - Xiangxian Li
- School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, China
| | - Zhuqun Shi
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China
- School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, China
| | - Quanling Yang
- School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, China
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15
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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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16
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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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17
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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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18
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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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19
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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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20
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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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21
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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. [PMID: 39967383 DOI: 10.1111/aor.14975] [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: 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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22
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Safi K, Pawlicka AJ, Pradhan B, Sobieraj J, Zhylko A, Struga M, Grąt M, Chrzanowska A. Perspectives and Tools in Liver Graft Assessment: A Transformative Era in Liver Transplantation. Biomedicines 2025; 13:494. [PMID: 40002907 PMCID: PMC11852418 DOI: 10.3390/biomedicines13020494] [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: 12/16/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Liver transplantation is a critical and evolving field in modern medicine, offering life-saving treatment for patients with end-stage liver disease and other hepatic conditions. Despite its transformative potential, transplantation faces persistent challenges, including a global organ shortage, increasing liver disease prevalence, and significant waitlist mortality rates. Current donor evaluation practices often discard potentially viable livers, underscoring the need for refined graft assessment tools. This review explores advancements in graft evaluation and utilization aimed at expanding the donor pool and optimizing outcomes. Emerging technologies, such as imaging techniques, dynamic functional tests, and biomarkers, are increasingly critical for donor assessment, especially for marginal grafts. Machine learning and artificial intelligence, exemplified by tools like LiverColor, promise to revolutionize donor-recipient matching and liver viability predictions, while bioengineered liver grafts offer a future solution to the organ shortage. Advances in perfusion techniques are improving graft preservation and function, particularly for donation after circulatory death (DCD) grafts. While challenges remain-such as graft rejection, ischemia-reperfusion injury, and recurrence of liver disease-technological and procedural advancements are driving significant improvements in graft allocation, preservation, and post-transplant outcomes. This review highlights the transformative potential of integrating modern technologies and multidisciplinary approaches to expand the donor pool and improve equity and survival rates in liver transplantation.
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Affiliation(s)
- Kawthar Safi
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
| | | | - Bhaskar Pradhan
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
| | - Jan Sobieraj
- 1st Chair and Department of Cardiology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Andriy Zhylko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Marta Struga
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Alicja Chrzanowska
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
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23
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Xu J, Chen S, Liu D, Zhang Q, Luo T, Zhu J, Zhou L, Lin Y, Pan H, Chen Y, Zhao Q, Wang T, Andrea S, Nashan B, Stefan TG, Cai C, Cui J, He X, Guo Z. Suppression of Hepatocyte Ferroptosis via USP19-Mediated Deubiquitination of SLC7A11 in Ischemia-Free Liver Transplantation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406200. [PMID: 39574305 PMCID: PMC11809379 DOI: 10.1002/advs.202406200] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 10/17/2024] [Indexed: 02/11/2025]
Abstract
Ischemia-free liver transplantation (IFLT) is developed as a novel clinical approach to avoid ischemia-reperfusion injury (IRI). This study aims to identify the most distinguished programmed cell death pathway in grafts undergoing IFLT versus conventional liver transplantation (CLT) and to explore the underlying mechanism. Ferroptosis is the most distinct programmed cell death form between IFLT and CLT grafts. Among various cell death inhibitors, the ferroptosis inhibitor (Ferrostain-1) is the most effective one to prevent hepatocytes from damage induced by oxygen deprivation/reoxygenation (OGD/R). Hepatocyte ferroptosis is significantly alleviated in IFLT versus CLT grafts in both human beings and pigs. Ubiquitination enzyme screening identifies augmented amounts of ubiquitin-specific protease 19 (USP19) in IFLT versus CLT grafts. The upregulation of USP19 in the grafts is correlated with reduced pathological Suzuki's score, lower post-transplant peak liver enzyme level, and less early allograft dysfunction in liver transplant recipients. USP19 overexpression mitigates post-transplant liver injury in mice. Mechanistically, USP19 inhibits the degradation of solute carrier family 7 member 11 (SLC7A11) by removing its K63-linked ubiquitin chains. Notably, USP19 overexpression reduces ferroptosis and IRI in a SLC7A11-dependent manner in mice. Collectively, USP19-mediated suppression of hepatocyte ferroptosis via deubiquitinating SLC7A11 is a key mechanism by which IFLT abrogates graft IRI.
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Affiliation(s)
- Jinghong Xu
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Department of AnesthesiologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Shirui Chen
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Organ MedicineGuangzhouGuangdong510080China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation)GuangzhouGuangdong510080China
| | - Di Liu
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Organ MedicineGuangzhouGuangdong510080China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation)GuangzhouGuangdong510080China
| | - Qi Zhang
- Department of Thyroid and Breast SurgeryThe Second Affiliated Hospital of Anhui Medical UniversityHefeiAnhui230601China
| | - Tao Luo
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Organ MedicineGuangzhouGuangdong510080China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation)GuangzhouGuangdong510080China
| | - Jiaxing Zhu
- Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Liang Zhou
- School of Life SciencesSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Yuan Lin
- Department of PathologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Hongyu Pan
- Department of PathologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Yichao Chen
- Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Qiang Zhao
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Organ MedicineGuangzhouGuangdong510080China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation)GuangzhouGuangdong510080China
| | - Tielong Wang
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Organ MedicineGuangzhouGuangdong510080China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation)GuangzhouGuangdong510080China
| | - Schlegel Andrea
- Transplantation CenterDigestive Disease and Surgery Institute and Department of ImmunologyLerner Research Institute, Cleveland ClinicClevelandOhio44113USA
| | - Björn Nashan
- Organ Transplant CenterThe First Affiliated Hospital of the University of Science and Technology of ChinaHefeiAnhui230001China
| | - Tullius G. Stefan
- Division of Transplant SurgeryBrigham and Women's HospitalHarvard Medical SchoolBostonMA02115USA
| | - Changjie Cai
- Department of Critical CareThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Jun Cui
- School of Life SciencesSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Xiaoshun He
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Organ MedicineGuangzhouGuangdong510080China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation)GuangzhouGuangdong510080China
| | - Zhiyong Guo
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Organ MedicineGuangzhouGuangdong510080China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation)GuangzhouGuangdong510080China
- NHC Key Laboratory of Assisted CirculationSun Yat‐sen UniversityGuangzhouGuangdong510080China
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24
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Bahadori K, Lee CY, Ferdinand JR, Cabantous M, Butler AJ, Rouhani FJ, Watson CJ, Clatworthy MR. Inflammatory Gene Expression in Livers Undergoing Ex Situ Normothermic Perfusion Is Attenuated by Leukocyte Removal From the Perfusate. Transplantation 2025; 109:332-345. [PMID: 39350310 PMCID: PMC11745667 DOI: 10.1097/tp.0000000000005214] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 06/26/2024] [Accepted: 08/06/2024] [Indexed: 01/23/2025]
Abstract
BACKGROUND Ex situ normothermic perfusion (ESNP) is a method to evaluate and potentially recondition organs before transplantation. However, increased expression of inflammatory molecules, including by tissue-resident immune cells, may occur during the perfusion process, potentially negating the beneficial effects of perfusion. METHODS We used RNA sequencing to assess gene expression in 31 livers undergoing ESNP, including 23 donated after circulatory death (DCD) and 8 donated after brain death. In 7 DCD livers, a leucocyte filter was added to the circuit during perfusion. Biopsies were available for transcriptomic assessment in all cases at the start of perfusion and at varying time points postperfusion. RESULTS During ESNP in DCD livers, we observed an increase in proinflammatory, profibrinolytic, and prorepair pathway genes. SERPINE1 , encoding plasminogen activator inhibitor-1, was among the genes most significantly upregulated during perfusion in DCD livers, potentially promoting fibrin clot persistence in vasculature. We also found increased expression of monocyte and neutrophil recruiting chemokine and proinflammatory cytokine transcripts during ESNP, but several prorepair molecules, including thymic stromal lymphopoietin, were also upregulated. In both DCD and donation after brain death livers, interferon-gamma response genes were enriched, whereas oxidative phosphorylation genes decreased in organs with high perfusate alanine transaminase, a biomarker associated with adverse clinical outcomes. The inclusion of a leukocyte filter in the perfusion circuit mitigated the induction of inflammation/immune pathway genes during perfusion and was associated with enrichment in oxidative phosphorylation genes. CONCLUSIONS Leukocyte removal during ESNP abrogates transcriptional changes that are associated with unfavorable clinical outcomes, potentially benefiting human livers undergoing ESNP.
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Affiliation(s)
- Kasra Bahadori
- Molecular Immunity Unit, Department of Medicine, Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
| | - Colin Y.C. Lee
- Molecular Immunity Unit, Department of Medicine, Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
| | - John R. Ferdinand
- Molecular Immunity Unit, Department of Medicine, Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
- National Institute of Health Research Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, United Kingdom
| | - Mia Cabantous
- Molecular Immunity Unit, Department of Medicine, Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
- National Institute of Health Research Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, United Kingdom
| | - Andrew J. Butler
- National Institute of Health Research Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, United Kingdom
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Foad J. Rouhani
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | - Christopher J.E. Watson
- National Institute of Health Research Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, United Kingdom
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Menna R. Clatworthy
- Molecular Immunity Unit, Department of Medicine, Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
- National Institute of Health Research Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, United Kingdom
- Cellular Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
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25
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Jeddou H, Tzedakis S, Chaouch MA, Sulpice L, Samson M, Boudjema K. Viability Assessment During Normothermic Machine Liver Perfusion: A Literature Review. Liver Int 2025; 45:e16244. [PMID: 39821671 PMCID: PMC11740183 DOI: 10.1111/liv.16244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 12/25/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
BACKGROUND AND OBJECTIVE The discrepancy between donor organ availability and demand leads to a significant waiting-list dropout rate and mortality. Although quantitative tools such as the Donor Risk Index (DRI) help assess organ suitability, many potentially viable organs are still discarded due to the lack of universally accepted markers to predict post-transplant outcomes. Normothermic machine perfusion (NMP) offers a platform to assess viability before transplantation. Thus, livers considered unsuitable for transplantation based on the DRI can be evaluated and potentially transplanted. During NMP, various viability criteria have been proposed. These criteria are neither homogeneous nor consensual. In this review, we aimed to describe the viability criteria during NMP and evaluate their ability to predict hepatic graft function following transplantation. We conducted a PubMed search using the terms 'liver transplantation', 'normothermic machine perfusion' and 'assessment', including only English publications up to February 2024. Viability assessment during NMP includes multiple hepatocellular and cholangiocellular criteria. Lactate clearance and bile production are commonly used indicators, but their ability to predict post-transplant outcomes varies significantly. The predictive value of cholangiocellular criteria such as bile pH, bicarbonate and glucose levels remains under investigation. Novel markers, such as microRNAs and proteomic profiles, offer the potential to enhance graft evaluation accuracy and provide insights into the molecular mechanisms underlying liver viability. Combining perfusion parameters with biomarkers may improve the prediction of long-term graft survival. Future research should focus on standardising viability assessment protocols and exploring real-time biomarker evaluations, which could enhance transplantation outcomes and expand the donor pool.
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Affiliation(s)
- Heithem Jeddou
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Stylianos Tzedakis
- Department of Hepato‐Biliary, Digestive and Endocrine SurgeryCochin Hospital, APHPParisFrance
- Université Paris CitéParisFrance
| | - Mohamed Ali Chaouch
- Department of Visceral and Digestive SurgeryMonastir University HospitalMonastirTunisia
| | - Laurent Sulpice
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- INSERM OSS U1242, University Hospital, Rennes 1 UniversityRennesFrance
| | - Michel Samson
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
| | - Karim Boudjema
- Department of Hepatobiliary and Digestive SurgeryUniversity Hospital, Rennes 1 UniversityRennesFrance
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)‐UMR_S 1085, Université de RennesRennesFrance
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Krendl FJ, Primavesi F, Oberhuber R, Neureiter D, Ocker M, Bekric D, Kiesslich T, Mayr C. The importance of preclinical models for cholangiocarcinoma drug discovery. Expert Opin Drug Discov 2025; 20:205-216. [PMID: 39840603 DOI: 10.1080/17460441.2025.2457637] [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: 10/29/2024] [Revised: 01/09/2025] [Accepted: 01/20/2025] [Indexed: 01/23/2025]
Abstract
INTRODUCTION Biliary tract cancer (BTC) comprises a clinically diverse and genetically heterogeneous group of tumors along the intra- and extrahepatic biliary system (intrahepatic and extrahepatic cholangiocarcinoma) and gallbladder cancer with the common feature of a poor prognosis, despite increasing molecular knowledge of associated genetic aberrations and possible targeted therapies. Therefore, the search for even more precise and individualized therapies is ongoing and preclinical tumor models are central to the development of such new approaches. AREAS COVERED The models described in the current review include simple and advanced in vitro and in vivo models, including cell lines, 2D monolayer, spheroid and organoid cultures, 3D bioprinting, patient-derived xenografts, and more recently, machine-perfusion platform-based models of resected liver specimens. All these models have individual advantages, disadvantages and limitations that need to be considered depending on the desired application. EXPERT OPINION In addition to potential cost limitations, availability of BTC cell types, time required for model establishment and growth success rate, the individual models differently reflect relevant characteristics such as tumor heterogeneity, spatial tumor-stroma microenvironment interactions, metabolic and nutritional gradients and immunological interactions. Therefore, a consequent combination of different models may be required to improve clinical study outcomes by strengthening the preclinical data basis.
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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
| | - Florian Primavesi
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, 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
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
| | - Matthias Ocker
- Medical Department, Division of Hematology, Oncology, and Cancer Immunology, Campus Charité Mitte, Charité University Medicine Berlin, Berlin, Germany
- EO Translational Insights Consulting GmbH, Berlin, Germany
- Tacalyx GmbH, Berlin, Germany
| | - Dino Bekric
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
| | - Tobias Kiesslich
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
| | - Christian Mayr
- Center of Physiology, Pathophysiology and Biophysics, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), Salzburg, Austria
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Jakhete N, Majeed NA, Maluf D, Shetty K. The Role of Liver Transplantation in Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:73-85. [PMID: 39608959 DOI: 10.1016/j.cld.2024.08.009] [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: 11/30/2024]
Abstract
Liver transplantation (LT) is the standard-of-care for early hepatocellular carcinoma (HCC). Current selection criteria depend primarily on measures of tumor burden and alpha-fetoprotein levels. Evolving strategies include the application of prognostic scores and the development of specialized molecular markers to predict recurrence. New technologies such as machine perfusion of donor organs are expected to dramatically improve the availability and access to LT in HCC.
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Affiliation(s)
- Neha Jakhete
- Division of Gastroenterology and Hepatology, Program in Transplantation, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, MD 21201, USA
| | - Nehna Abdul Majeed
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, MD 21201, USA
| | - Daniel Maluf
- Department of Surgery, University of Maryland School of Medicine, Program in Transplantation, 22 S. Greene Street, Baltimore, MD 21201, USA
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, Program in Transplantation, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, MD 21201, USA.
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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. [PMID: 39887468 DOI: 10.1111/aor.14960] [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: 11/11/2024] [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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29
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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 2025:2829515. [PMID: 39878966 PMCID: PMC11780509 DOI: 10.1001/jamasurg.2024.6520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [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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Kim JJ, Kurial SNT, Choksi PK, Nunez M, Lunow-Luke T, Bartel J, Driscoll J, Her CL, Dhillon S, Yue W, Murti A, Mao T, Ramos JN, Tiyaboonchai A, Grompe M, Mattis AN, Syed SM, Wang BM, Maher JJ, Roll GR, Willenbring H. AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion. Nat Biotechnol 2025:10.1038/s41587-024-02523-6. [PMID: 39881029 DOI: 10.1038/s41587-024-02523-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 12/02/2024] [Indexed: 01/31/2025]
Abstract
Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV capsid performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently and specifically than AAV5, AAV8 and AAV6, which are most commonly used clinically, and AAV-NP59, which is better at transducing human hepatocytes engrafted in immune-deficient mice. AAV-LK03 preferentially transduced periportal hepatocytes in normal liver, whereas AAV5 targeted pericentral hepatocytes in steatotic liver. AAV5 and AAV8 transduced liver sinusoidal endothelial cells as efficiently as hepatocytes. AAV capsid and steatosis influenced vector episome formation, which determines gene therapy durability, with AAV5 delaying concatemerization. Our findings inform capsid choice in clinical AAV liver gene therapy, including consideration of disease-relevant hepatocyte zonation and effects of steatosis, and facilitate the development of AAV capsids that transduce hepatocytes or other therapeutically relevant cell types in the human liver with maximum efficiency and specificity.
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Affiliation(s)
- Jae-Jun Kim
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Simone N T Kurial
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
| | - Pervinder K Choksi
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA, USA
| | - Miguel Nunez
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Tyler Lunow-Luke
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Jan Bartel
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Julia Driscoll
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Chris L Her
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Simaron Dhillon
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Stone Research Foundation, San Francisco, CA, USA
| | - William Yue
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Abhishek Murti
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Tin Mao
- Ambys Medicines, South San Francisco, CA, USA
- Genentech, South San Francisco, CA, USA
| | - Julian N Ramos
- Ambys Medicines, South San Francisco, CA, USA
- Adverum Biotechnologies, Redwood City, CA, USA
| | - Amita Tiyaboonchai
- Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
| | - Markus Grompe
- Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | - Aras N Mattis
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Shareef M Syed
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Bruce M Wang
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jacquelyn J Maher
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Garrett R Roll
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Holger Willenbring
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
- Liver Center, University of California, San Francisco, San Francisco, CA, USA.
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31
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Zhao Y, Lyu X, Sun Z, Zhang X, Cen J, Yang T, Xu X, Xing W, Zhao S, Wang B, Luo G. Continuous Blood Gas Control Based on Active Disturbance Rejection Control During Ex Vivo Porcine Liver Perfusion. Artif Organs 2025. [PMID: 39868805 DOI: 10.1111/aor.14955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/20/2024] [Accepted: 01/10/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND Membrane oxygenators facilitate extracorporeal gas exchange, necessitating the monitoring of blood gas. Recent advances in normothermic machine perfusion (NMP) for ex vivo liver offer solutions to the shortage of donor liver. However, maintaining physiological blood gas levels during prolonged NMP is complex and costly. METHODS We introduce a noninvasive and economical approach for regulating the blood gas during NMP of ex vivo porcine livers. By monitoring gas fractions at the outlet of oxygenator, real-time adjustments of blood gas can be made without the online blood gas analyzer. The method involves constructing multivariate linear regression (MLR) models, aligning target setpoints of gas, and employing active disturbance rejection control (ADRC) to achieve closed-loop regulation. RESULTS Ex vivo porcine liver perfusion experiments demonstrated the effectiveness of the method, maintaining blood gas within physiological levels over 24 h (oxygen partial pressure: 150.36 ± 3.33 mmHg, carbon dioxide partial pressure: 41.34 ± 0.91 mmHg). CONCLUSION ADRC-based continuous regulation of gas fraction at the outlet of oxygenator is a feasible and effective approach for managing blood gas during ex vivo porcine liver perfusion.
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Affiliation(s)
- Yilong Zhao
- Division of Life Science and Medicine, School of Biomedical Engineering (Suzhou), University of Science and Technology of China, Hefei, China
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Xin Lyu
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Zhen Sun
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiaoliang Zhang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Jin Cen
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tianhang Yang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Xiaoliang Xu
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Wenhui Xing
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Sihan Zhao
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Bidou Wang
- Division of Life Science and Medicine, School of Biomedical Engineering (Suzhou), University of Science and Technology of China, Hefei, China
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Gangyin Luo
- Division of Life Science and Medicine, School of Biomedical Engineering (Suzhou), University of Science and Technology of China, Hefei, China
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
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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] [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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Irsara C, Weissenbacher A, Krendl FJ, Anliker M, Hofmann J, Hautz T, Schneeberger S, Griesmacher A, Loacker L. Expression of sPD-L1 levels in an ex vivo liver perfusion model. Clin Exp Immunol 2025; 219:uxae094. [PMID: 39435859 PMCID: PMC11773811 DOI: 10.1093/cei/uxae094] [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: 03/14/2024] [Revised: 08/13/2024] [Accepted: 10/18/2024] [Indexed: 10/23/2024] Open
Abstract
The programmed cell death protein 1 (PD-1) acts as a central inhibitory immune checkpoint receptor. The soluble form of its primary ligand, sPD-L1, was found to be elevated in the serum of patients with cancer, infectious diseases, and chronic inflammation. So far, the hepatic origin of sPD-L1 has received relatively little attention and is therefore the subject of this study in the context of normothermic machine perfusion (NMP) of liver grafts. sPD-L1 concentrations as well as several well-established clinically relevant laboratory parameters were determined in the perfusate of 16 donor liver grafts undergoing NMP up to 30 hours. sPD-L1 levels continuously increased during NMP and significantly correlated with markers of hepatic synthesis (cholinesterase), acute-phase proteins (von Willebrand factor, procalcitonin, antithrombin, interleukin-6, fibrinogen), and liver decay markers (gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase). Perfusate leukocytes were in the lower reference range and decreased after 12 hours. Mean sPD-L1 levels in the perfusate correlated with donor levels of gamma-glutamyltransferase, alanine aminotransferase, creatinine, and blood urea nitrogen. Our study reveals a significant increase in the concentration of sPD-L1 following ischemia-reperfusion injury in a hepatic ex vivo model. sPD-L1 concentrations during NMP correlate with established acute-phase proteins and liver cell decay markers, suggesting that hepatic sPD-L1 synthesis or shedding increases during the acute phase and cell decay. Furthermore, sPD-L1 correlates with established liver function and synthesis parameters as well as with donor laboratory values and might therefore be a potential biomarker for the hepatic function of liver grafts.
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Affiliation(s)
- Christian Irsara
- Central Institute of Clinical and Chemical Laboratory Diagnostics, University Hospital of Innsbruck, Innsbruck, Austria
| | - Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, and organLife Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Julius Krendl
- Department of Visceral, Transplant and Thoracic Surgery, and organLife Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Anliker
- Central Institute of Clinical and Chemical Laboratory Diagnostics, University Hospital of Innsbruck, Innsbruck, Austria
| | - Julia Hofmann
- Department of Visceral, Transplant and Thoracic Surgery, and organLife Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Theresa Hautz
- Department of Visceral, Transplant and Thoracic Surgery, and organLife Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, and organLife Laboratory, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Andrea Griesmacher
- Central Institute of Clinical and Chemical Laboratory Diagnostics, University Hospital of Innsbruck, Innsbruck, Austria
| | - Lorin Loacker
- Central Institute of Clinical and Chemical Laboratory Diagnostics, University Hospital of Innsbruck, Innsbruck, Austria
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Puttappa A, Gaurav R, Kakhandki V, Swift L, Fear C, Webster R, Radwan A, Mohammed M, Butler A, Klinck J, Watson C. Normothermic regional and ex situ perfusion reduces postreperfusion syndrome in donation after circulatory death liver transplantation: A retrospective comparative study. Am J Transplant 2025:S1600-6135(25)00007-3. [PMID: 39826893 DOI: 10.1016/j.ajt.2025.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 12/13/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
In controlled donation after circulatory death (DCD) liver transplantation, ischemia-reperfusion injury is linked to postreperfusion syndrome (PRS), acute kidney injury (AKI), and early allograft dysfunction. Normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) are techniques that mitigate ischemic injury and associated complications. In this single-center retrospective study, we compared early transplant outcomes of DCD livers undergoing direct procurement (DP) and static cold storage (SCS) (DCD-DP-SCS), NRP procurement with SCS (DCD-NRP-SCS), or DP with NMP (DCD-DP-NMP). Two hundred thirty-eight DCD liver recipients were evaluated, comprising 59 DCD-DP-SCS, 101 DCD-NRP-SCS, and 78 DCD-DP-NMP. Overall, the PRS incidence was 19%. DCD-DP-SCS had a higher incidence of PRS (37%; P < .001), AKI stage ≥2 (47%; P = .033), and an increased model for early allograft function score (P < .001). In adjusted multivariate analysis, recipient age (odds ratio [OR] 1.10, 95% CI 1.05-1.17; P < 0.001), and normothermic perfusion (DCD-NRP-SCS: OR 0.16, 95% CI 0.06-0.39; P < .001; DCD-DP-NMP: OR 0.38, 95% CI 0.15-0.91; P = .032) were significant predictors of PRS, which itself was associated with worse 5-year transplant survival (graft survival non-censored-to-death; Hazard ratio (HR) 2.9, 95% CI 1.3-6.7; P = .012). Compared to SCS alone, the use of either NRP or NMP significantly reduced the incidence of PRS and AKI with better early graft function.
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Affiliation(s)
- Anand Puttappa
- Division of Anaesthesia and Perioperative care, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Rohit Gaurav
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; University of Cambridge Department of Surgery, Cambridge, UK; National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), UK.
| | - Vibhay Kakhandki
- Division of Anaesthesia and Perioperative care, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Lisa Swift
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Corrina Fear
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Rachel Webster
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Ahmed Radwan
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Musab Mohammed
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Andrew Butler
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; University of Cambridge Department of Surgery, Cambridge, UK; National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), UK
| | - John Klinck
- Division of Anaesthesia and Perioperative care, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Christopher Watson
- Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; University of Cambridge Department of Surgery, Cambridge, UK; National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), UK
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Shi D. Application of extended criteria donor liver grafts in liver transplantation. Hepatobiliary Pancreat Dis Int 2025:S1499-3872(25)00025-6. [PMID: 39855994 DOI: 10.1016/j.hbpd.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/29/2024] [Indexed: 01/27/2025]
Affiliation(s)
- Dan Shi
- Department of Child Health Care, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
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Zhang Z, Dong C, Zhao S, Si Z, Zheng W, Wang K, Sun C, Song Z, Gao W. Myosin Light Chain 9 Mediates Graft Fibrosis After Pediatric Liver Transplantation Through TLR4/MYD88/NF-κB Signaling. Cell Mol Gastroenterol Hepatol 2025; 19:101453. [PMID: 39778656 PMCID: PMC11946870 DOI: 10.1016/j.jcmgh.2024.101453] [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: 04/11/2024] [Revised: 12/21/2024] [Accepted: 12/22/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND & AIMS The incidence of graft fibrosis is elevated after pediatric liver transplantation (pLT) and is influenced by cold ischemic time (CIT). Myosin light chain 9 (MYL9), a member of the myosin family, could act on hepatic stellate cells (HSCs) and induce a transition to active phase. We hypothesized that cold ischemic injury could stimulate MYL9 expression and lead to graft fibrosis. METHODS We tested the hypothesis by analyzing multi-omics data from human protocol liver biopsy samples 2 years after LT, performing rat LT with different CIT and conducting in vitro studies in HSC cell lines with MYL9 knockdown and overexpression. RESULTS Clinically, CIT is an independent risk factor for graft fibrosis after pLT. Omics analysis identified MYL9 as a prominent contributor in graft fibrosis. MYL9 is strongly correlated with liver fibrosis grade and the progression of fibrosis. The study of rat LT model demonstrated MYL9 expression increases with the prolongation of CIT, and its role is specific to transplant setting. Mechanistically, in vitro experiments with HSCs exposed to hypoxia/reoxygenation revealed a substantial decrease in HSCs activation after MYL9 knockdown. Conversely, overexpression of MYL9 significantly enhanced the activation of HSCs. Subsequent transcriptome sequencing of HSCs with MYL9 knockdown unveiled that MYL9 primarily functions through the TLR4/MYD88/NF-κB signaling pathway. Liver graft fibrosis was ameliorated when toll like receptor 4 signaling was inhibited in rats. CONCLUSIONS Our findings demonstrate that prolonged CIT up-regulates the expression of MYL9 in liver graft after LT. MYL9 activates HSCs and promotes fibrosis through a TLR4/MYD88/NF-κB signaling dependent manner.
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Affiliation(s)
- Zhixin Zhang
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chong Dong
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Shengqiao Zhao
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhuyuan Si
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Weiping Zheng
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Kai Wang
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chao Sun
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China.
| | - Zhuolun Song
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China.
| | - Wei Gao
- Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China.
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Watson CJE. Bile Chemistry During Ex Situ Normothermic Liver Perfusion Does Not Always Predict Cholangiopathy. Transplantation 2025; 109:e76-e77. [PMID: 39656138 PMCID: PMC11627308 DOI: 10.1097/tp.0000000000005244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 07/29/2024] [Indexed: 12/13/2024]
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Maeda A, Starkey G, Spano S, Chaba A, Eastwood G, Yoshino O, Perini MV, Fink M, Bellomo R, Jones R. Perfusate hemoglobin during normothermic liver machine perfusion as biomarker of early allograft dysfunction: A pilot study. Artif Organs 2025; 49:108-118. [PMID: 39291684 DOI: 10.1111/aor.14862] [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: 06/14/2024] [Revised: 08/01/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) aims to reduce ischemia-reperfusion injury in donor livers and its clinical manifestation, early allograft dysfunction (EAD) by maintaining perfusion and oxygenation. However, there is limited data on which NMP perfusate biomarkers might be associated with such EAD and the role of perfusate hemoglobin has not been assessed. METHODS We performed a pilot retrospective analysis of adult donor livers undergoing NMP between 2020 and 2022 at our center. NMP was commenced at the recipient hospital after initial static cold storage. All NMP circuits were primed in the same manner according to the manufacturer's instructions. Livers were stratified by initial perfusate hemoglobin below (≤5.2 mmol/L) or above (>5.2 mmol/L) the median. The association between hemoglobin levels and EAD or recipient peak transaminase levels was assessed. RESULTS Among 23 livers, eight were considered unsuitable for transplantation, leaving 15 livers for assessment. Higher initial hemoglobin was associated with a lower risk of EAD (0% vs. 55.6%, p = 0.04). Perfusate hemoglobin decreased after NMP initiation (p = 0.003) and negatively correlated with recipient peak transaminase levels (ALT: ρ = -0.72, p = 0.002; AST: ρ = -0.79, p < 0.001). Consistently, higher hemoglobin livers also demonstrated lower perfusate liver enzymes. CONCLUSIONS Perfusate hemoglobin levels decreased during NMP, and lower perfusate hemoglobin levels were associated with a higher incidence of EAD and higher levels of liver injury markers. Maintaining higher hemoglobin levels during NMP may help reduce ischemia-reperfusion injury and prevent or attenuate EAD. Larger prospective studies are needed to validate the findings of this pilot study.
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Affiliation(s)
- Akinori Maeda
- Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia
- Department of Emergency and Critical Care Medicine, The University of Tokyo, Tokyo, Japan
| | - Graham Starkey
- Victorian Liver Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, Austin Hospital, The University of Melbourne, Melbourne, Victoria, Australia
- Australian Centre for Transplantation Excellence and Research, Austin Hosptial, Melbourne, Victoria, Australia
| | - Sofia Spano
- Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia
| | - Anis Chaba
- Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia
| | - Glenn Eastwood
- Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia
| | - Osamu Yoshino
- Victorian Liver Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, Austin Hospital, The University of Melbourne, Melbourne, Victoria, Australia
- Australian Centre for Transplantation Excellence and Research, Austin Hosptial, Melbourne, Victoria, Australia
| | - Marcos Vinicius Perini
- Victorian Liver Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, Austin Hospital, The University of Melbourne, Melbourne, Victoria, Australia
- Australian Centre for Transplantation Excellence and Research, Austin Hosptial, Melbourne, Victoria, Australia
| | - Michael Fink
- Victorian Liver Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, Austin Hospital, The University of Melbourne, Melbourne, Victoria, Australia
- Australian Centre for Transplantation Excellence and Research, Austin Hosptial, Melbourne, Victoria, Australia
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia
- Australian Centre for Transplantation Excellence and Research, Austin Hosptial, Melbourne, Victoria, Australia
- Data Analytics Research and Evaluation Centre, Austin Hospital, Melbourne, Victoria, Australia
| | - Robert Jones
- Victorian Liver Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, Austin Hospital, The University of Melbourne, Melbourne, Victoria, Australia
- Australian Centre for Transplantation Excellence and Research, Austin Hosptial, Melbourne, Victoria, Australia
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Mesnard B, Ogbemudia E, Bruneau S, Le Bas-Bernardet S, Minault D, Hervouet J, Kervella D, Masset C, Cantarovich D, Rigaud J, Badet L, Friend P, Ploeg R, Blancho G, Hunter J, Prudhomme T, Branchereau J. Pancreas Preservation: Hypothermic Oxygenated Perfusion to Improve Graft Reperfusion. Transplantation 2025; 109:e1-e10. [PMID: 39656523 DOI: 10.1097/tp.0000000000005111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
BACKGROUND The clinical standard for pancreas preservation for transplantation is static cold storage (SCS). Oxygenation during preservation has been shown to be advantageous in clinical studies. This study evaluates the efficiency of different oxygenation modalities during hypothermic pancreas preservation. METHODS Thirty-two porcine pancreases were procured in a controlled donation after circulatory death model and were divided to be preserved in 8 groups: (1) SCS, (2) hypothermic machine perfusion (HMP), (3) hypothermic oxygenated machine perfusion (HOPE) with 21% oxygen, (4) HOPE and 100%, (5) SCS and oxygen carrier, M101, (6) HMP and M101, (7) HOPE 21% and M101, and (8) HOPE 100% and M101. All the groups underwent 24 h of hypothermic preservation, followed by 2 h of normothermic reperfusion. Oxygen partial pressures were assessed using parenchymal probes. Perfusion parameters, perfusate samples, and tissue biopsies were analyzed. RESULTS This study showed that HMP was linked to higher tissue oxygen partial pressures, lower succinate levels, and better reperfusion parameters. Furthermore, the addition of M101 to either SCS or HMP was associated with lower succinate and creatinine phosphokinase accumulation, suggesting a protective effect against ischemia. CONCLUSIONS Our research has demonstrated the efficacy of machine perfusion in hypothermic conditions in providing oxygen to the pancreas during preservation and conditioning the pancreatic microvasculature for reperfusion during transplantation. Furthermore, the addition of M101 suggests a protective effect on the graft from ischemia.
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Affiliation(s)
- Benoit Mesnard
- Department of Urology and Transplantation Surgery, Nantes University Hospital, Nantes, France
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | | | - Sarah Bruneau
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - David Minault
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Jeremy Hervouet
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Delphine Kervella
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Christophe Masset
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Diego Cantarovich
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Jérôme Rigaud
- Department of Urology and Transplantation Surgery, Nantes University Hospital, Nantes, France
| | - Lionel Badet
- Department of Urology Surgery and Transplantation, Edouard Herriot Hospital, Lyon, France
| | - Peter Friend
- Nuffield Department of Surgical Science, Oxford, United Kingdom
| | - Rutger Ploeg
- Nuffield Department of Surgical Science, Oxford, United Kingdom
| | - Gilles Blancho
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - James Hunter
- Nuffield Department of Surgical Science, Oxford, United Kingdom
| | - Thomas Prudhomme
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Julien Branchereau
- Department of Urology and Transplantation Surgery, Nantes University Hospital, Nantes, France
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
- Nuffield Department of Surgical Science, Oxford, United Kingdom
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Czigany Z, Shirini K, Putri AJ, Longchamp AE, Bhusal S, Kamberi S, Meier RPH. Bridging Therapies-Ex Vivo Liver Xenoperfusion and the Role of Machine Perfusion: An Update. Xenotransplantation 2025; 32:e70011. [PMID: 39825617 DOI: 10.1111/xen.70011] [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: 01/20/2025]
Abstract
Advancements in xenotransplantation intersecting with modern machine perfusion technology offer promising solutions to patients with liver failure providing a valuable bridge to transplantation and extending graft viability beyond current limitations. Patients facing acute or acute chronic liver failure, post-hepatectomy liver failure, or fulminant hepatic failure often require urgent liver transplants which are severely limited by organ shortage, emphasizing the importance of effective bridging approaches. Machine perfusion is now increasingly used to test and use genetically engineered porcine livers in translational studies, addressing the limitations and costs of non-human primate models. Current reports about artificial and bioartificial liver support combined with xenografts showcase the potential in ex vivo xenogeneic perfusion. Breakthroughs, such as the perfusion of genetically modified porcine liver with FDA-approved machine perfusion systems connected to human blood circulation, underscore the interest and potential feasibility of a "liver dialysis" bridge to allotransplantation or recovery. This review provides an overview of the past and current research in the field of ex vivo pig liver xenoperfusion.
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Affiliation(s)
- Zoltan Czigany
- Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Kasra Shirini
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Aghnia J Putri
- Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Alban E Longchamp
- Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Subarna Bhusal
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Shani Kamberi
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Raphael P H Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Gao Q, Cai JZ, Dong H. A Review of the Risk Factors and Approaches to Prevention of Post-Reperfusion Syndrome During Liver Transplantation. Organogenesis 2024; 20:2386730. [PMID: 39097866 PMCID: PMC11299628 DOI: 10.1080/15476278.2024.2386730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 06/22/2024] [Accepted: 07/26/2024] [Indexed: 08/05/2024] Open
Abstract
Post-reperfusion syndrome (PRS) is a severe and highly lethal syndrome that occurs after declamping the portal vein forceps during liver transplantation. It is marked by severe hemodynamic disturbances manifested by decreased mean arterial pressure, increased heart rate and elevated pulmonary artery pressure. The complex pathogenesis of PRS remains understudied. It is generally believed to be related to the large amount of acidic, cold blood that enters the circulation after release of the portal clamp. This blood is rich in oxygen-free radicals and metabolic toxins, which not only aggravate the ischemia-reperfusion injury of the liver but also further attack the systemic organs indiscriminately. Considering the range of possible adverse prognoses including acute kidney injury, delirium and graft nonfunction, it is imperative that clinicians increase their awareness and prevention of PRS. The aim of this article is to review the current risk factors, pathophysiological mechanisms and prevention strategies for PRS.
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Affiliation(s)
- Qian Gao
- Department of Anesthesiology, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jin-Zhen Cai
- Organ Transplant Center, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - He Dong
- Department of Anesthesiology, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Yemaneberhan KH, Kang M, Jang JH, Kim JH, Kim KS, Park HB, Choi D. Beyond the icebox: modern strategies in organ preservation for transplantation. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:377-403. [PMID: 39743232 PMCID: PMC11732768 DOI: 10.4285/ctr.24.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 01/04/2025]
Abstract
Organ transplantation, a critical treatment for end-stage organ failure, has witnessed significant advancements due to the integration of improved surgical techniques, immunosuppressive therapies, and donor-recipient matching. This review explores the progress of organ preservation, focusing on the shift from static cold storage (SCS) to advanced machine perfusion techniques such as hypothermic (HMP) and normothermic machine perfusion (NMP). Although SCS has been the standard approach, its limitations in preserving marginal organs and preventing ischemia-reperfusion injury (IRI) have led to the adoption of HMP and NMP. HMP, which is now the gold standard for high-risk donor kidneys, reduces metabolic activity and improves posttransplant outcomes. NMP allows real-time organ viability assessment and reconditioning, especially for liver transplants. Controlled oxygenated rewarming further minimizes IRI by addressing mitochondrial dysfunction. The review also highlights the potential of cryopreservation for long-term organ storage, despite challenges with ice formation. These advances are crucial for expanding the donor pool, improving transplant success rates, and addressing organ shortages. Continued innovation is necessary to meet the growing demands of transplantation and save more lives.
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Affiliation(s)
- Kidus Haile Yemaneberhan
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
| | - Minseok Kang
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Jun Hwan Jang
- Department of Energy Engineering, Hanyang University, Seoul, Korea
| | - Jin Hee Kim
- Department of Energy Engineering, Hanyang University, Seoul, Korea
| | - Kyeong Sik Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Ho Bum Park
- Department of Energy Engineering, Hanyang University, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul, Korea
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Lascaris B, Bodewes SB, Thorne AM, van den Heuvel MC, de Haas RJ, Nijsten MWN, de Meijer VE, Porte RJ. Perfusion Pressures and Weight Loss During Normothermic Machine Perfusion of Human Donor Livers. Artif Organs 2024. [PMID: 39737605 DOI: 10.1111/aor.14939] [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: 06/03/2024] [Revised: 12/11/2024] [Accepted: 12/17/2024] [Indexed: 01/01/2025]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) is increasingly used to preserve and assess donor livers prior to transplantation. Due to its success, it is expected that more centers will start using this technology. However, NMP may also cause adverse effects. METHODS In this retrospective, observational study, we investigated the effect of NMP pressures on donor liver weight, post-transplant outcomes, and hepatic perfusion characteristics. A total of 36 livers were transplanted after NMP. NMP perfusion pressure settings were lowered from a median (IQR) of 47 mmHg (42-54) to 34 mmHg (30-39) for the hepatic artery (HA), and from 8 mmHg (7-10) to 7 mmHg (6-8) for the portal vein (PV) to diminish potential edema formation inside the liver. RESULTS This change appeared to lead to a reduction of liver weight after NMP (-22 g to -143 g, p = 0.02), without affecting the PV flow velocity (35.5 to 48.0 cm/s, p = 0.54), or hepatocellular injury markers during NMP (AST 1511-1148 U/L, p = 0.44; ALT 318-849 U/L, p = 0.35), and post-transplantation outcomes. Changes in liver weight correlated significantly with the applied PV pressure during NMP (r = 0.52, p < 0.01) and the HA flow (r = 0.38, p < 0.05). CONCLUSION NMP can lead to a reduction in liver weight, which might be masked by edema when high perfusion pressures are used. We encourage applying the lowest perfusion pressures possible to reach adequate flows and oxygen supply during liver NMP.
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Affiliation(s)
- Bianca Lascaris
- 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
| | - Adam M Thorne
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marius C van den Heuvel
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robbert J de Haas
- Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Maarten W N Nijsten
- Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - 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
- Erasmus MC Transplant Institute, Department of Surgery, Division of HPB and Transplant Surgery, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Zhou AL, Akbar AF, Ruck JM, Weeks SR, Wesson R, Ottmann SE, Philosophe B, Cameron AM, Meier RPH, King EA. Use of Ex Situ Machine Perfusion for Liver Transplantation: The National Experience. Transplantation 2024:00007890-990000000-00967. [PMID: 39724135 DOI: 10.1097/tp.0000000000005290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [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/m2, 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, Baltimore, Maryland
| | - Armaan F Akbar
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Jessica M Ruck
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Sharon R Weeks
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Russell Wesson
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Shane E Ottmann
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Benjamin Philosophe
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Andrew M Cameron
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Raphael P H Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Elizabeth A King
- Division of Transplant Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
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Shishido Y, Tracy KM, Petrovic M, Adesanya T, Fortier AK, Raietparvar K, Glomp GA, Simonds E, Harris TR, Simon V, Tucker WD, Petree B, Cortelli M, Cardwell NL, Crannell C, Liang J, Murphy AC, Fields BL, McReynolds M, Demarest CT, Ukita R, Rizzari M, Montenovo M, Magliocca JF, Karp SJ, Rauf MA, Shah AS, Bacchetta M. Novel Dynamic Organ Storage System Enhances Liver Graft Function in a Porcine Donation After Circulatory Death Model. ASAIO J 2024:00002480-990000000-00611. [PMID: 39693205 DOI: 10.1097/mat.0000000000002365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Donation after circulatory death (DCD) livers face increased risks of critical complications when preserved with static cold storage (SCS). Although machine perfusion (MP) may mitigate these risks, its cost and logistical complexity limit widespread application. We developed the Dynamic Organ Storage System (DOSS), which delivers oxygenated perfusate at 10°C with minimal electrical power requirement and allows real-time effluent sampling in a portable cooler. In a porcine DCD model, livers were preserved using DOSS or SCS for 10 hours and evaluated with 4 hours of normothermic MP, with n = 5 per group. After 4 hours of normothermic MP, the DOSS group demonstrated significantly lower perfusate lactate (p = 0.023), increased perfusate fibrinogen (p = 0.005), higher oxygen consumption (p = 0.018), greater bile production (p = 0.013), higher bile bicarbonate levels (p = 0.035) and bile/perfusate sodium ratio (p = 0.002), and lower hepatic arterial resistance after phenylephrine administration (p = 0.018). Histological analysis showed lower apoptotic markers in DOSS-preserved livers, with fewer cleaved caspase-3 (p = 0.039) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL; p = 0.009) positive cells. These findings suggest that DOSS can enhance DCD allograft function during transport, offering potential clinical benefits and contributing to the expansion of the donor pool.
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Affiliation(s)
- Yutaka Shishido
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kaitlyn M Tracy
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mark Petrovic
- Vanderbilt University Medical School , Nashville, Tennessee
| | | | | | | | | | | | - Timothy R Harris
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Victoria Simon
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - William D Tucker
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Brandon Petree
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Michael Cortelli
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Nancy L Cardwell
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Christian Crannell
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jiancong Liang
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Alexandria C Murphy
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Blanche L Fields
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Melanie McReynolds
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Caitlin T Demarest
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rei Ukita
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Michael Rizzari
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Martin Montenovo
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Joseph F Magliocca
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Seth J Karp
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - M Ameen Rauf
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ashish S Shah
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew Bacchetta
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
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46
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Samuel D, De Martin E, Berg T, Berenguer M, Burra P, Fondevila C, Heimbach JK, Pageaux GP, Sanchez-Fueyo A, Toso C. EASL Clinical Practice Guidelines on liver transplantation. J Hepatol 2024; 81:1040-1086. [PMID: 39487043 DOI: 10.1016/j.jhep.2024.07.032] [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: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 11/04/2024]
Abstract
Liver transplantation (LT) is an established life-saving procedure. The field of LT has changed in the past 10 years from several perspectives, with the expansion of indications, transplantation of patients with acute-on-chronic liver failure, evolution of transplant oncology, the use of donations after cardiac death, new surgical techniques, and prioritisation of recipients on the waiting list. In addition, the advent of organ perfusion machines, the recognition of new forms of rejection, and the attention paid to the transition from paediatric to adult patients, have all improved the management of LT recipients. The purpose of the EASL guidelines presented here is not to cover all aspects of LT but to focus on developments since the previous EASL guidelines published in 2016.
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Wisel SA, Steggerda JA, Kim IK. Use of Machine Perfusion in the United States Increases Organ Utilization and Improves DCD Graft Survival in Liver Transplantation. Transplant Direct 2024; 10:e1726. [PMID: 39534757 PMCID: PMC11554346 DOI: 10.1097/txd.0000000000001726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 11/16/2024] Open
Abstract
Background Adoption of machine perfusion (MP) technology has rapidly expanded in liver transplantation without real-world data on utilization and outcomes, which are critical to understand the appropriate application of MP technology. Methods The Organ Procurement and Transplant Network/Standard Transplant Analysis and Research database was used to identify all deceased donor livers procured with intent for transplant between October 27, 2015 (date of first recorded MP) and June 30, 2023 (n = 67 795). Liver allografts were cohorted by donation after brain death (DBD; n = 59 957) or circulatory death (DCD; n = 7873) and analyzed by static cold storage (SCS) or MP preservation method. Donor demographics, organ utilization, and graft survival were evaluated. Results By 2023, 12.5% of all livers and 37.2% of DCD livers underwent MP preservation (82.6% normothermic, 6.7% hypothermic, and 10.8% other/unknown). Compared with SCS, MP liver donors were older (DBD: 48 versus 40 y [P < 0.001]; DCD: 43 versus 38 y [P < 0.001]) with higher body mass index (DBD: 28.8 versus 26.9 kg/m2 [P < 0.001]; DCD: 27.7 versus 26.9 kg/m2 [P = 0.004]). Donor livers had similar levels of macrosteatosis (median 5%). Graft utilization was higher for MP than SCS after DBD (96.4% versus 93.0%, P < 0.001) and DCD (91.4% versus 70.3%, P < 0.001) donation. Graft survival was similar between MP and SCS livers from DBD donors (P = 0.516), whereas MP-preserved grafts had superior survival from DCD donors at 1 and 3 y posttransplant (P = 0.013 and 0.037). Patient survival was similar across all groups at 3 y (P = 0.322). Conclusions The use of MP in liver transplantation increased rates of liver utilization and improved graft survival after DCD. Further monitoring of MP outcomes is required to understand long-term benefits.
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Affiliation(s)
- Steven A. Wisel
- Comprehensive Transplant Center, Jim and Eleanor Randall Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Justin A. Steggerda
- Comprehensive Transplant Center, Jim and Eleanor Randall Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Irene K. Kim
- Comprehensive Transplant Center, Jim and Eleanor Randall Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
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Simonetto DA, Winder GS, Connor AA, Terrault NA. Liver transplantation for alcohol-associated liver disease. Hepatology 2024; 80:1441-1461. [PMID: 38889100 DOI: 10.1097/hep.0000000000000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/31/2024] [Indexed: 06/20/2024]
Abstract
Alcohol-associated liver disease (ALD) is a major cause of morbidity and mortality worldwide, and a leading indication for liver transplantation (LT) in many countries, including the United States. However, LT for ALD is a complex and evolving field with ethical, social, and medical challenges. Thus, it requires a multidisciplinary approach and individualized decision-making. Short-term and long-term patient and graft survival of patients undergoing LT for ALD are comparable to other indications, but there is a continued need to develop better tools to identify patients who may benefit from LT, improve the pretransplant and posttransplant management of ALD, and evaluate the impact of LT for ALD on the organ donation and transplantation systems. In this review, we summarize the current evidence on LT for ALD, from alcohol-associated hepatitis to decompensated alcohol-associated cirrhosis. We discuss the indications, criteria, outcomes, and controversies of LT for these conditions and highlight the knowledge gaps and research priorities in this field.
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Affiliation(s)
- Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Ashton A Connor
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Norah A Terrault
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, University of Southern California, Los Angeles, California, USA
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Wilson EA, Weinberg DL, Patel GP. Intraoperative Anesthetic Strategies to Mitigate Early Allograft Dysfunction After Orthotopic Liver Transplantation: A Narrative Review. Anesth Analg 2024; 139:1267-1282. [PMID: 38442076 DOI: 10.1213/ane.0000000000006902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
Orthotopic liver transplantation (OLT) is the most effective treatment for patients with end-stage liver disease (ESLD). Hepatic insufficiency within a week of OLT, termed early allograft dysfunction (EAD), occurs in 20% to 25% of deceased donor OLT recipients and is associated with morbidity and mortality. Primary nonfunction (PNF), the most severe form of EAD, leads to death or retransplantation within 7 days. The etiology of EAD is multifactorial, including donor, recipient, and surgery-related factors, and largely driven by ischemia-reperfusion injury (IRI). IRI is an immunologic phenomenon characterized by dysregulation of cellular oxygen homeostasis and innate immune defenses in the allograft after temporary cessation (ischemia) and later restoration (reperfusion) of oxygen-rich blood flow. The rising global demand for OLT may lead to the use of marginal allografts, which are more susceptible to IRI, and thus lead to an increased incidence of EAD. It is thus imperative the anesthesiologist is knowledgeable about EAD, namely its pathophysiology and intraoperative strategies to mitigate its impact. Intraoperative strategies can be classified by 3 phases, specifically donor allograft procurement, storage, and recipient reperfusion. During procurement, the anesthesiologist can use pharmacologic preconditioning with volatile anesthetics, consider preharvest hyperoxemia, and attenuate the use of norepinephrine as able. The anesthesiologist can advocate for normothermic regional perfusion (NRP) and machine perfusion during allograft storage at their institution. During recipient reperfusion, the anesthesiologist can optimize oxygen exposure, consider adjunct anesthetics with antioxidant-like properties, and administer supplemental magnesium. Unfortunately, there is either mixed, little, or no data to support the routine use of many free radical scavengers. Given the sparse, limited, or at times conflicting evidence supporting some of these strategies, there are ample opportunities for more research to find intraoperative anesthetic strategies to mitigate the impact of EAD and improve postoperative outcomes in OLT recipients.
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Affiliation(s)
- Elizabeth A Wilson
- From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia
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50
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van Leeuwen LL, Irizar H, Kim-Schluger L, Florman S, Akhtar MZ. The potential of machine learning to predict early allograft dysfunction after normothermic machine perfusion in liver transplantation. J Hepatol 2024; 81:e298-e300. [PMID: 39094744 DOI: 10.1016/j.jhep.2024.07.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 07/27/2024] [Indexed: 08/04/2024]
Affiliation(s)
- L Leonie van Leeuwen
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
| | - Haritz Irizar
- Center for Biostatistics, Department of Population Health Science & Policy, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Leona Kim-Schluger
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Sander Florman
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - M Zeeshan Akhtar
- Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
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