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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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2
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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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4
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Zhylko A, Morawski M, Rykowski P, Krasnodębski M, Wyporski A, Borkowski J, Zhylko D, Kobryń K, Stankiewicz R, Stypułkowski J, Hołówko W, Patkowski W, Wróblewski T, Szczepankiewicz B, Górnicka B, Mielczarek-Puta M, Struga M, Krawczyk M, Grąt M. Real-Time Biomarkers of Liver Graft Quality in Hypothermic Oxygenated Machine Perfusion. J Clin Med 2025; 14:471. [PMID: 39860477 PMCID: PMC11766178 DOI: 10.3390/jcm14020471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/21/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Background: Hypothermic oxygenated machine perfusion has emerged as a strategy to alleviate ischemic-reperfusion injury in liver grafts. Nevertheless, there is limited data on the effectiveness of hypothermic liver perfusion in evaluating organ quality. This study aimed to introduce a readily accessible real-time predictive biomarker measured in machine perfusate for post-transplant liver graft function. Methods: The study evaluated perfusate analytes over a 90-day postoperative period in 26 patients randomly assigned to receive a liver graft following dual hypothermic machine perfusion in a prospective randomized controlled trial. Machine perfusion was consistently conducted end-ischemically for at least 120 min, with real-time perfusate assessment at 30-min intervals. Graft functionality was assessed using established metrics, including Early Allograft Dysfunction (EAD). Results: Perfusate lactate concentration after 120 min of machine perfusion demonstrated significant predictive value for EAD (AUC ROC: 0.841, p = 0.009). Additionally, it correlated with post-transplant peak transaminase levels and extended hospital stays. Subgroup analysis revealed significantly higher lactate accumulation in livers with post-transplant EAD. Conclusions: Liver graft quality can be effectively assessed during hypothermic machine perfusion using simple perfusate lactate measurements. The reliability and accessibility of this evaluation support its potential integration into diverse transplant centers.
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Affiliation(s)
- Andriy Zhylko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Marcin Morawski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Paweł Rykowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Anya Wyporski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Jan Borkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Dmytro Zhylko
- Computer Engineering Division, New York University Abu Dhabi, Abu Dhabi P.O. Box 129188, United Arab Emirates
| | - Konrad Kobryń
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Rafał Stankiewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Jan Stypułkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Wacław Hołówko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Tadeusz Wróblewski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | | | - Barbara Górnicka
- Department of Pathology, Medical University of Warsaw, 02-004 Warsaw, Poland
| | | | - Marta Struga
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (M.M.); (M.K.); (M.G.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
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5
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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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Caballero-Marcos A, Rodríguez-Bachiller L, Baroja-Mazo A, Morales Á, Fernández-Cáceres P, Fernández-Martínez M, DíazFontenla F, Velasco E, Fernández-Yunquera A, Díaz-Zorita B, Cortese S, Pérez-Peña JM, Colón-Rodríguez A, Romero-Cristóbal M, Asencio JM, Bañares R, López-Baena JÁ, Salcedo-Plaza M. Dynamics of Ischemia/Reperfusion Injury Markers During Normothermic Liver Machine Perfusion. Transplant Direct 2024; 10:e1728. [PMID: 39553741 PMCID: PMC11567704 DOI: 10.1097/txd.0000000000001728] [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: 08/23/2024] [Accepted: 09/12/2024] [Indexed: 11/19/2024] Open
Abstract
Background A comprehensive mechanistic assessment of normothermic machine perfusion (NMP) is an essential step toward identifying biomarkers to assess liver viability. Although some studies have evaluated the effect of NMP on inflammation markers, there are other key pathological mechanisms involved in ischemia/reperfusion injury (IRI) that have not yet been evaluated. Methods Eight human donor livers preserved by NMP were included to analyze IRI during preservation. Concentrations of several biomarkers involved in different biological processes of IRI were measured in the perfusate. Results Perfusate levels of intercellular adhesion molecule 1, P-selectin, vascular cell adhesion molecule 1, metalloproteinase with thrombospondin motif type 1, member 13, phospholipase A2 group VII, and syndecan-1 progressively increased during NMP. Noteworthy, perfusate lactate levels showed a strong correlation with C-X-C motif chemokine ligand 10 (P = 0.001), intercellular adhesion molecule 1 (P = 0.01), and urokinase plasminogen activator (P = 0.001). Conclusions Perfusate lactate correlates with the main underlying biological mechanisms occurring in the NMP environment. Moreover, several IRI biomarkers accumulate during NMP, which may limit the extent of the benefits of this technology.
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Affiliation(s)
- Aránzazu Caballero-Marcos
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Luis Rodríguez-Bachiller
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | - Álvaro Morales
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Paloma Fernández-Cáceres
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
| | - María Fernández-Martínez
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Fernando DíazFontenla
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Enrique Velasco
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Ainhoa Fernández-Yunquera
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Benjamin Díaz-Zorita
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Sergio Cortese
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - José María Pérez-Peña
- Department of Anesthesiology, Reanimation and Intensive Care, Hospital General Universitario Gregorio Marañon, Madrid, Spain
| | - Arturo Colón-Rodríguez
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Mario Romero-Cristóbal
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - José Manuel Asencio
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Rafael Bañares
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - José Ángel López-Baena
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Magdalena Salcedo-Plaza
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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7
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Canizares S, Montalvan A, Chumdermpadetsuk R, Modest A, Eckhoff D. Machine Perfusion Technology Drives a Major Growth Surge in Liver Transplantation. J Surg Res 2024; 302:454-462. [PMID: 39167899 DOI: 10.1016/j.jss.2024.07.077] [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: 12/04/2023] [Revised: 07/12/2024] [Accepted: 07/19/2024] [Indexed: 08/23/2024]
Abstract
INTRODUCTION Machine perfusion (MP) opens the possibility to overcome the existing disbalance between supply and demand in liver transplantation. However, it has not been widely adopted across the country. We explored trends of MP adoption in the United States and their effect on center volume (CV). METHODS We used the Standard Transplant Analysis and Research datafile from January 2010 to July 2023 to assess CV changes following MP implementation. We classified centers into MP nonusers, low MP users, and high MP (HMP) users. We used interrupted time series analysis to measure changing patterns of HMP CV before and after January 2016, marking the occurrence of the first MP case. High-volume institutions in 2015 were additionally compared to their equivalents in 2022 stratified by their MP status using Wilcoxon rank sum test. RESULTS In our controlled interrupted time series, HMP centers had a sustained yet moderate positive trend in volume (P < 0.001). Comparing only high-volume institutions, we found no difference in the number of transplants performed in 2015 to their equivalents in 2022. In the stratified analysis, only HMP centers had a significant increase in the total number of transplants in 2022 (P = 0.032). CONCLUSIONS MP has demonstrated to greatly improve outcomes for recipients of liver transplantation. Here, we demonstrate that centers that incorporate MP could potentially benefit from a growth in their practice as well. Further studies are needed to better characterize the features that drive transplant centers to grow across time.
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Affiliation(s)
- Stalin Canizares
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
| | - Adriana Montalvan
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Ritah Chumdermpadetsuk
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Anna Modest
- Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts
| | - Devin Eckhoff
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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8
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Canizares S, Montalvan A, Chumdermpadetsuk R, Modest A, Eckhoff D, Lee DD. Liver machine perfusion technology: Expanding the donor pool to improve access to liver transplantation. Am J Transplant 2024; 24:1664-1674. [PMID: 38508317 DOI: 10.1016/j.ajt.2024.03.013] [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: 10/14/2023] [Revised: 03/01/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
The imbalance between organ supply and demand continues to limit the broader benefits of organ transplantation. Machine perfusion (MP) may increase the supply of donor livers by expanding the use of extended-criteria donors. Using the United Network for Organ Sharing/Organ Procurement and Transplantation Network and the Standard Transplant Analysis and Research dataset, we reviewed the effect of MP implementation on the behavior of transplant centers. We identified 15 high-utilizing MP centers that were matched to suitable controls based on volume and geographical proximity. We conducted a differences-in-differences analysis using linear regression to estimate the impact of MP adoption on the transplant centers' donor utilization. We found a significant increase in cold ischemia time and organs with donor warm ischemia time over 30 minutes (P < .05). After removing one outlier center, the analysis showed that these centers through MP accepted overall more donation after circulatory death donors, donation after circulatory death donors over 50 years old, donors with macrovesicular steatosis greater than 30% on liver biopsy, and donor warm ischemia time over 30 minutes (P < .05). MP has allowed centers to expand their use of extended-criteria donors beyond traditional cutoffs and to increase patient access to liver transplantation.
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Affiliation(s)
- Stalin Canizares
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Adriana Montalvan
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Ritah Chumdermpadetsuk
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Anna Modest
- Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Devin Eckhoff
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - David D Lee
- Division of Transplant Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
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9
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. S2k-Leitlinie Lebertransplantation der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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10
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Wehrle CJ, Zhang M, Khalil M, Pita A, Modaresi Esfeh J, Diago-Uso T, Kim J, Aucejo F, Kwon DCH, Ali K, Cazzaniga B, Miyazaki Y, Liu Q, Fares S, Hong H, Tuul M, Jiao C, Sun K, Fairchild RL, Quintini C, Fujiki M, Pinna AD, Miller C, Hashimoto K, Schlegel A. Impact of Back-to-Base Normothermic Machine Perfusion on Complications and Costs: A Multicenter, Real-World Risk-Matched Analysis. Ann Surg 2024; 280:300-310. [PMID: 38557793 DOI: 10.1097/sla.0000000000006291] [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: 04/04/2024]
Abstract
OBJECTIVE Assess cost and complication outcomes after liver transplantation (LT) using normothermic machine perfusion (NMP). BACKGROUND End-ischemic NMP is often used to aid logistics, yet its impact on outcomes after LT remains unclear, as does its true impact on costs associated with transplantation. METHODS Deceased donor liver recipients at 2 centers (January 1, 2019, to June 30, 2023) were included. Retransplants, splits, and combined grafts were excluded. End-ischemic NMP (OrganOx-Metra) was implemented in October 2022 for extended-criteria donation after brain death (DBDs), all donations after circulatory deaths (DCDs), and logistics. NMP cases were matched 1:2 with static cold storage controls (SCS) using the Balance-of-Risk [donation after brain death (DBD)-grafts] and UK-DCD Score (DCD-grafts). RESULTS Overall, 803 transplantations were included, 174 (21.7%) receiving NMP. Matching was achieved between 118 NMP-DBDs with 236 SCS; and 37 NMP-DCD with 74 corresponding SCS. For both graft types, median inpatient comprehensive complications index values were comparable between groups. DCD-NMP grafts experienced reduced cumulative 90-day comprehensive complications index (27.6 vs 41.9, P =0.028). NMP also reduced the need for early relaparotomy and renal replacement therapy, with subsequently less frequent major complications (Clavien-Dindo ≥IVa). This effect was more pronounced in DCD transplants. NMP had no protective effect on early biliary complications. Organ acquisition/preservation costs were higher with NMP, yet NMP-treated grafts had lower 90-day pretransplant costs in the context of shorter waiting list times. Overall costs were comparable for both cohorts. CONCLUSIONS This is the first risk-adjusted outcome and cost analysis comparing NMP and SCS. In addition to logistical benefits, NMP was associated with a reduction in relaparotomy and bleeding in DBD grafts, and overall complications and post-LT renal replacement for DCDs. While organ acquisition/preservation was more costly with NMP, overall 90-day health care costs-per-transplantation were comparable.
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Affiliation(s)
| | | | | | | | - Jamak Modaresi Esfeh
- Department of Gastroenterology and Transplant Hepatology, Cleveland Clinic, Cleveland, OH
| | - Teresa Diago-Uso
- Department of Liver Transplantation, Cleveland Clinic Abu Dhabi, Cleveland, OH
| | - Jaekeun Kim
- Transplantation Center, Cleveland Clinic, OH
| | | | | | - Khaled Ali
- Transplantation Center, Cleveland Clinic, OH
| | | | | | - Qiang Liu
- Transplantation Center, Cleveland Clinic, OH
| | - Sami Fares
- Transplantation Center, Cleveland Clinic, OH
| | - Hanna Hong
- Transplantation Center, Cleveland Clinic, OH
| | | | - Chunbao Jiao
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH
| | - Keyue Sun
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH
| | - Robert L Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH
| | - Cristiano Quintini
- Department of Liver Transplantation, Cleveland Clinic Abu Dhabi, Cleveland, OH
| | | | | | | | - Koji Hashimoto
- Transplantation Center, Cleveland Clinic, OH
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH
| | - Andrea Schlegel
- Transplantation Center, Cleveland Clinic, OH
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH
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11
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Risbey CWG, Lau NS, Niu A, Zhang WB, Crawford M, Pulitano C. Return of the cold: How hypothermic oxygenated machine perfusion is changing liver transplantation. Transplant Rev (Orlando) 2024; 38:100853. [PMID: 38581881 DOI: 10.1016/j.trre.2024.100853] [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: 03/04/2024] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 04/08/2024]
Abstract
Hypothermic Oxygenated machine PErfusion (HOPE) has recently emerged as a preservation technique which can reduce ischemic injury and improve clinical outcomes following liver transplantation. First developed with the advent solid organ transplantation techniques, hypothermic machine perfusion largely fell out of favour following the development of preservation solutions which can satisfactorily preserve grafts using the cheap and simple method, static cold storage (SCS). However, with an increasing need to develop techniques to reduce graft injury and better utilise marginal and donation after circulatory death (DCD) grafts, HOPE has emerged as a relatively simple and safe technique to optimise clinical outcomes following liver transplantation. Perfusing the graft with cold, acellular, oxygenated perfusate either via the portal vein (PV) alone, or via both the PV and hepatic artery (HA), HOPE is generally commenced for a period of 1-2 h immediately prior to implantation. The technique has been validated by multiple randomised control trials, and pre-clinical evidence suggests HOPE primarily reduces graft injury by decreasing the accumulation of harmful mitochondrial intermediates, and subsequently, the severity of post-reperfusion injury. HOPE can also facilitate real time graft assessment, most notably via the measurement of flavin mononucleotide (FMN) in the perfusate, allowing transplant teams to make better informed clinical decisions prior to transplantation. HOPE may also provide a platform to administer novel therapeutic agents to ex situ organs without risk of systemic side effects. As such, HOPE is uniquely positioned to revolutionise how liver transplantation is approached and facilitate optimised clinical outcomes for liver transplant recipients.
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Affiliation(s)
- Charles W G Risbey
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Central Clinical School, The University of Sydney, John Hopkins Dr, Camperdown 2050, NSW, Australia
| | - Ngee-Soon Lau
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia
| | - Anita Niu
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia
| | - Wesley B Zhang
- Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia
| | - Michael Crawford
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Central Clinical School, The University of Sydney, John Hopkins Dr, Camperdown 2050, NSW, Australia
| | - Carlo Pulitano
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Central Clinical School, The University of Sydney, John Hopkins Dr, Camperdown 2050, NSW, Australia.
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12
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Hofmann J, Meszaros AT, Butler A, Hann A, Hartog H, Kneifel F, Iype S, Crick K, Cardini B, Fiore B, Attia M, Pollok JM, Pascher A, Vogel T, Perera T, Watson CJE, Schneeberger S. Predictive value of early postoperative lactate (<6 h) during normothermic machine perfusion and outcome after liver transplantation: results from a multicentre study. Br J Surg 2024; 111:znae084. [PMID: 38875136 PMCID: PMC11177788 DOI: 10.1093/bjs/znae084] [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] [Received: 11/05/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND Biomarkers with strong predictive capacity towards transplantation outcome for livers undergoing normothermic machine perfusion (NMP) are needed. We investigated lactate clearing capacity as a basic function of liver viability during the first 6 h of NMP. METHODS A trial conducted in 6 high-volume transplant centres in Europe. All centres applied a back-to-base NMP approach with the OrganOx metra system. Perfusate lactate levels at start, 1, 2, 4 and 6 h of NMP were assessed individually and as area under the curve (AUC) and correlated with EAD (early allograft dysfunction), MEAF (model for early allograft function) and modified L-GrAFT (liver graft assessment following transplantation) scores. RESULTS A total of 509 livers underwent ≥6 h of NMP before transplantation in 6 centres in the UK, Germany and Austria. The donor age was 53 (40-63) years (median, i.q.r.).The total NMP time was 10.8 (7.9-15.7) h. EAD occurred in 26%, MEAF was 4.72 (3.54-6.05) and L-GrAFT10 -0.96 (-1.52--0.32). Lactate at 1, 2 and 6 h correlated with increasing robustness with MEAF. Rather than a binary assessment with a cut-off value at 2 h, the actual 2 h lactate level correlated with the MEAF (P = 0.0306 versus P = 0.0002, Pearson r = 0.01087 versus r = 0.1734). The absolute lactate concentration at 6 h, the AUC of 0-6 h and 1-6 h (P < 0.0001, r = 0.3176) were the strongest predictors of MEAF. CONCLUSION Lactate measured 1-6 h and lactate levels at 6 h correlate strongly with risk of liver allograft dysfunction upon transplantation. The robustness of predicting MEAF by lactate increases with perfusion duration. Monitoring lactate levels should be extended to at least 6 h of NMP routinely to improve clinical outcome.
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Affiliation(s)
- Julia Hofmann
- Department of Visceral, Transplant and Thoracic Surgery, Medical University
of Innsbruck, Innsbruck, Austria
| | - Andras T Meszaros
- Department of Visceral, Transplant and Thoracic Surgery, Medical University
of Innsbruck, Innsbruck, Austria
| | - Andrew Butler
- Department of Surgery, University of Cambridge,
Cambridge, UK
| | - Angus Hann
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS
Foundation Trust (UHBFT), Birmingham, UK
| | - Hermien Hartog
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS
Foundation Trust (UHBFT), Birmingham, UK
| | - Felicia Kneifel
- Department of General, Visceral and Transplant Surgery, University Hospital
of Münster (UKM), Münster, Germany
| | - Satheesh Iype
- Department of HPB and Liver Transplantation, The Royal Free
Hospital, Hampstead, London, UK
| | - Keziah Crick
- Department of HPB and Liver Transplantation, The Royal Free
Hospital, Hampstead, London, UK
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University
of Innsbruck, Innsbruck, Austria
| | - Barbara Fiore
- Liver Transplant Unit, Leeds Teaching Hospitals, NHS Foundation
Trust, Leeds, UK
| | - Magdy Attia
- Liver Transplant Unit, Leeds Teaching Hospitals, NHS Foundation
Trust, Leeds, UK
| | - Joerg-Matthias Pollok
- Department of HPB and Liver Transplantation, The Royal Free
Hospital, Hampstead, London, UK
- Division of Surgery and Interventional Science, University College
London, London, UK
| | - Andreas Pascher
- Department of General, Visceral and Transplant Surgery, University Hospital
of Münster (UKM), Münster, Germany
| | - Thomas Vogel
- Department of General, Visceral and Transplant Surgery, University Hospital
of Münster (UKM), Münster, Germany
| | - Thamara Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS
Foundation Trust (UHBFT), Birmingham, UK
| | | | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University
of Innsbruck, Innsbruck, Austria
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13
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Lindemann J, Yu J, Doyle MM. Normothermic machine perfusion for liver transplantation: current state and future directions. Curr Opin Organ Transplant 2024; 29:186-194. [PMID: 38483109 DOI: 10.1097/mot.0000000000001141] [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: 04/30/2024]
Abstract
PURPOSE OF REVIEW The number of patients on the liver transplant waitlist continues to grow and far exceeds the number of livers available for transplantation. Normothermic machine perfusion (NMP) allows for ex-vivo perfusion under physiologic conditions with the potential to significantly increase organ yield and expand the donor pool. RECENT FINDINGS Several studies have found increased utilization of donation after cardiac death and extended criteria brain-dead donor livers with implementation of NMP, largely due to the ability to perform viability testing during machine perfusion. Recently, proposed viability criteria include lactate clearance, maintenance of perfusate pH more than 7.2, ALT less than 6000 u/l, evidence of glucose metabolism and bile production. Optimization of liver grafts during NMP is an active area of research and includes interventions for defatting steatotic livers, preventing ischemic cholangiopathy and rejection, and minimizing ischemia reperfusion injury. SUMMARY NMP has resulted in increased organ utilization from marginal donors with acceptable outcomes. The added flexibility of prolonged organ storage times has the potential to improve time constraints and transplant logistics. Further research to determine ideal viability criteria and investigate ways to optimize marginal and otherwise nontransplantable liver grafts during NMP is warranted.
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Affiliation(s)
- Jessica Lindemann
- Department of Surgery, Section of Abdominal Organ Transplantation, Washington University School of Medicine, Saint Louis, Missouri, USA
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14
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Qureshi S, Elliott H, Noel A, Swift L, Fear C, Webster R, Brown NM, Gaurav R, Butler AJ, Watson CJE. Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy. Transplantation 2024; 108:1376-1382. [PMID: 38196099 PMCID: PMC11115456 DOI: 10.1097/tp.0000000000004897] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/23/2023] [Accepted: 10/01/2023] [Indexed: 01/11/2024]
Abstract
BACKGROUND Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted. CONCLUSIONS Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.
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Affiliation(s)
- Saeed Qureshi
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Heather Elliott
- Antimicrobial Reference Laboratory, Pathology Sciences Building, North Bristol NHS Trust, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom
| | - Alan Noel
- Antimicrobial Reference Laboratory, Pathology Sciences Building, North Bristol NHS Trust, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom
| | - Lisa Swift
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Corrina Fear
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Rachel Webster
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Nicholas M Brown
- Department of Microbiology, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Rohit Gaurav
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
| | - Andrew J Butler
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
- The Cambridge NIHR Biomedical Research Centre and the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, United Kingdom
| | - Christopher J E Watson
- The Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, United Kingdom
- The Cambridge NIHR Biomedical Research Centre and the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Cambridge, United Kingdom
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15
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Stevens LJ, van de Steeg E, Doppenberg JB, Alwayn IPJ, Knibbe CAJ, Dubbeld J. Ex vivo gut-hepato-biliary organ perfusion model to characterize oral absorption, gut-wall metabolism, pre-systemic hepatic metabolism and biliary excretion; application to midazolam. Eur J Pharm Sci 2024; 196:106760. [PMID: 38574899 DOI: 10.1016/j.ejps.2024.106760] [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: 12/11/2023] [Revised: 03/03/2024] [Accepted: 04/01/2024] [Indexed: 04/06/2024]
Abstract
To date, characterization of the first-pass effect of orally administered drugs consisting of local intestinal absorption and metabolism, portal vein transport and hepatobiliary processes remains challenging. Aim of this study was to explore the applicability of a porcine ex-vivo perfusion model to study oral absorption, gut-hepatobiliary metabolism and biliary excretion of midazolam. Slaughterhouse procured porcine en bloc organs (n = 4), were perfused via the aorta and portal vein. After 120 min of perfusion, midazolam, atenolol, antipyrine and FD4 were dosed via the duodenum and samples were taken from the systemic- and portal vein perfusate, intestinal faecal effluent and bile to determine drug and metabolite concentrations. Stable arterial and portal vein flow was obtained and viability of the perfused organs was confirmed. After intraduodenal administration, midazolam was rapidly detected in the portal vein together with 1-OH midazolam (EG-pv of 0.16±0.1) resulting from gut wall metabolism through oxidation. In the intestinal faecal effluent, 1-OH midazolam and 1-OH midazolam glucuronide (EG-intestine 0.051±0.03) was observed resulting from local gut glucuronidation. Biliary elimination of midazolam (0.04±0.01 %) and its glucuronide (0.01±0.01 %) only minimally contributed to the enterohepatic circulation. More extensive hepatic metabolism (FH 0.35±0.07) over intestinal metabolism (FG 0.78±0.11) was shown, resulting in oral bioavailability of 0.27±0.05. Ex vivo perfusion demonstrated to be a novel approach to characterize pre-systemic extraction of midazolam by measuring intestinal as well as hepatic extraction. The model can generate valuable insights into the absorption and metabolism of new drugs.
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Affiliation(s)
- L J Stevens
- Department of Surgery, Leiden University Medical Center (LUMC), Leiden, the Netherlands; LUMC Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands; Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - E van de Steeg
- Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - J B Doppenberg
- LUMC Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands
| | - I P J Alwayn
- Department of Surgery, Leiden University Medical Center (LUMC), Leiden, the Netherlands; LUMC Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
| | - C A J Knibbe
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research (LACDR), Leiden & Department of Clinical Pharmacy, St. Antonius Hospital Nieuwegein & Utrecht, Leiden University, the Netherlands
| | - J Dubbeld
- Department of Surgery, Leiden University Medical Center (LUMC), Leiden, the Netherlands; LUMC Transplant Center, Leiden University Medical Center (LUMC), Leiden, the Netherlands
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16
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Abbas SH, Ceresa CDL, Pollok JM. Steatotic Donor Transplant Livers: Preservation Strategies to Mitigate against Ischaemia-Reperfusion Injury. Int J Mol Sci 2024; 25:4648. [PMID: 38731866 PMCID: PMC11083584 DOI: 10.3390/ijms25094648] [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: 03/12/2024] [Revised: 04/21/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Liver transplantation (LT) is the only definitive treatment for end-stage liver disease, yet the UK has seen a 400% increase in liver disease-related deaths since 1970, constrained further by a critical shortage of donor organs. This shortfall has necessitated the use of extended criteria donor organs, including those with evidence of steatosis. The impact of hepatic steatosis (HS) on graft viability remains a concern, particularly for donor livers with moderate to severe steatosis which are highly sensitive to the process of ischaemia-reperfusion injury (IRI) and static cold storage (SCS) leading to poor post-transplantation outcomes. This review explores the pathophysiological predisposition of steatotic livers to IRI, the limitations of SCS, and alternative preservation strategies, including novel organ preservation solutions (OPS) and normothermic machine perfusion (NMP), to mitigate IRI and improve outcomes for steatotic donor livers. By addressing these challenges, the liver transplant community can enhance the utilisation of steatotic donor livers which is crucial in the context of the global obesity crisis and the growing need to expand the donor pool.
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Affiliation(s)
- Syed Hussain Abbas
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK;
| | - Carlo Domenico Lorenzo Ceresa
- Department of Hepatopancreatobiliary and Liver Transplant Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK;
| | - Joerg-Matthias Pollok
- Department of Hepatopancreatobiliary and Liver Transplant Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK;
- Division of Surgery & Interventional Science, University College London, Gower Street, London WC1E 6BT, UK
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17
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Westhaver LP, Nersesian S, Arseneau RJ, Hefler J, Hargreaves BK, Edgar A, Azizieh Y, Cuesta-Gomez N, Izquierdo DL, Shapiro AJ, Gala-Lopez BL, Boudreau JE. Mitochondrial DNA levels in perfusate and bile during ex vivo normothermic machine correspond with donor liver quality. Heliyon 2024; 10:e27122. [PMID: 38463874 PMCID: PMC10920371 DOI: 10.1016/j.heliyon.2024.e27122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 02/23/2024] [Indexed: 03/12/2024] Open
Abstract
Ex vivo normothermic machine perfusion (NMP) preserves donor organs and permits real-time assessment of allograft health, but the most effective indicators of graft viability are uncertain. Mitochondrial DNA (mtDNA), released consequent to traumatic cell injury and death, including the ischemia-reperfusion injury inherent in transplantation, may meet the need for a biomarker in this context. We describe a real time PCR-based approach to assess cell-free mtDNA during NMP as a universal biomarker of allograft quality. Measured in the perfusate fluid of 29 livers, the quantity of mtDNA correlated with metrics of donor liver health including International Normalized Ratio (INR), lactate, and warm ischemia time, and inversely correlated with inferior vena cava (IVC) flow during perfusion. Our findings endorse mtDNA as a simple and rapidly measured feature that can inform donor liver health, opening the possibility to better assess livers acquired from extended criteria donors to improve organ supply.
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Affiliation(s)
| | - Sarah Nersesian
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | | | - Joshua Hefler
- Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
| | | | - Alexander Edgar
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Yara Azizieh
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Nerea Cuesta-Gomez
- Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Dayne L. Izquierdo
- Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
| | - A.M. James Shapiro
- Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Boris L. Gala-Lopez
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
- Department of Surgery, Dalhousie University, Halifax, NS, Canada
| | - Jeanette E. Boudreau
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
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18
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Dondossola D, Lonati C, Battistin M, Vivona L, Zanella A, Maggioni M, Valentina V, Zizmare L, Trautwein C, Schlegel A, Gatti S. Twelve-hour normothermic liver perfusion in a rat model: characterization of the changes in the ex-situ bio-molecular phenotype and metabolism. Sci Rep 2024; 14:6040. [PMID: 38472309 DOI: 10.1038/s41598-024-56433-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 03/06/2024] [Indexed: 03/14/2024] Open
Abstract
The partial understanding of the biological events that occur during normothermic machine perfusion (NMP) and particularly during prolonged perfusion might hinder its deployment in clinical transplantation. The aim of our study was to implement a rat model of prolonged NMP to characterize the bio-molecular phenotype and metabolism of the perfused organs. Livers (n = 5/group) were procured and underwent 4 h (NMP4h) or 12 h (NMP12h) NMP, respectively, using a perfusion fluid supplemented with an acellular oxygen carrier. Organs that were not exposed to any procedure served as controls (Native). All perfused organs met clinically derived viability criteria at the end of NMP. Factors related to stress-response and survival were increased after prolonged perfusion. No signs of oxidative damage were detected in both NMP groups. Evaluation of metabolite profiles showed preserved mitochondrial function, activation of Cori cycle, induction of lipolysis, acetogenesis and ketogenesis in livers exposed to 12 h-NMP. Increased concentrations of metabolites involved in glycogen synthesis, glucuronidation, bile acid conjugation, and antioxidant response were likewise observed. In conclusion, our NMP12h model was able to sustain liver viability and function, thereby deeply changing cell homeostasis to maintain a newly developed equilibrium. Our findings provide valuable information for the implementation of optimized protocols for prolonged NMP.
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Affiliation(s)
- Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100, Milan, Italy.
- Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100, Milan, Italy.
| | - Caterina Lonati
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy
| | - Michele Battistin
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy
| | - Luigi Vivona
- Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy
| | - Alberto Zanella
- Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100, Milan, Italy
- Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy
| | - Marco Maggioni
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Vaira Valentina
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Laimdota Zizmare
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University of Tübingen, Röntgenweg 13, 72076, Tübingen, Germany
| | - Christoph Trautwein
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University of Tübingen, Röntgenweg 13, 72076, Tübingen, Germany
| | - Andrea Schlegel
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy
- Transplantation Center, Digestive Disease and Surgery Institute and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Stefano Gatti
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100, Milan, Italy
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19
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Watson CJ, Gaurav R, Butler AJ. Current Techniques and Indications for Machine Perfusion and Regional Perfusion in Deceased Donor Liver Transplantation. J Clin Exp Hepatol 2024; 14:101309. [PMID: 38274508 PMCID: PMC10806097 DOI: 10.1016/j.jceh.2023.101309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/27/2023] [Indexed: 01/27/2024] Open
Abstract
Since the advent of University of Wisconsin preservation solution in the 1980s, clinicians have learned to work within its confines. While affording improved outcomes, considerable limitations still exist and contribute to the large number of livers that go unused each year, often for fear they may never work. The last 10 years have seen the widespread availability of new perfusion modalities which provide an opportunity for assessing organ viability and prolonged organ storage. This review will discuss the role of in situ normothermic regional perfusion for livers donated after circulatory death. It will also describe the different modalities of ex situ perfusion, both normothermic and hypothermic, and discuss how they are thought to work and the opportunities afforded by them.
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Affiliation(s)
- Christopher J.E. Watson
- University of Cambridge Department of Surgery, Box 210, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
- The Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
| | - Rohit Gaurav
- The Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
| | - Andrew J. Butler
- University of Cambridge Department of Surgery, Box 210, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
- The Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
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20
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Rossignol G, Muller X, Brunet TA, Bidault V, Hervieu V, Clement Y, Ayciriex S, Mabrut JY, Salvador A, Mohkam K. Comprehensive bile acid pool analysis during ex-vivo liver perfusion in a porcine model of ischemia-reperfusion injury. Sci Rep 2024; 14:2384. [PMID: 38286808 PMCID: PMC10824768 DOI: 10.1038/s41598-024-52504-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 01/19/2024] [Indexed: 01/31/2024] Open
Abstract
Bile acids (BA) are key for liver regeneration and injury. This study aims at analyzing the changes in the BA pool induced by ischemia-reperfusion (IRI) and investigates the impact of hypothermic oxygenated perfusion (HOPE) on the BA pool compared to static cold storage (SCS). In a porcine model of IRI, liver grafts underwent 30 min of asystolic warm ischemia followed by 6 h of SCS (n = 6) ± 2 h of HOPE (n = 6) and 2 h of ex-situ warm reperfusion. The BA pool in bile samples was analyzed with liquid chromatography coupled with tandem mass spectrometry. We identified 16 BA and observed significant changes in response to ischemia-reperfusion, which were associated with both protective and injury mechanisms. Second, HOPE-treated liver grafts exhibited a more protective BA phenotype, characterized by a more hydrophilic BA pool compared to SCS. Key BA, such as GlycoCholic Acid, were identified and were associated with a decreased transaminase release and improved lactate clearance during reperfusion. Partial Least Square-Discriminant Analysis revealed a distinct injury profile for the HOPE group. In conclusion, the BA pool changes with liver graft IRI, and preservation with HOPE results in a protective BA phenotype compared to SCS.
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Affiliation(s)
- Guillaume Rossignol
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Lyon, France.
- Department of Pediatric Surgery and Liver Transplantation, Femme Mere Enfant University Hospital, Lyon, France.
- The Cancer Research Center of Lyon, INSERM U1052, Lyon, France.
- ED 340 BMIC, Claude Bernard Lyon 1 University, Villeurbanne, France.
- Institute of Analytical Sciences, CNRS UMR 5280, Claude Bernard University Lyon 1, Villeurbanne, France.
| | - Xavier Muller
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Lyon, France.
- The Cancer Research Center of Lyon, INSERM U1052, Lyon, France.
- ED 340 BMIC, Claude Bernard Lyon 1 University, Villeurbanne, France.
| | - Thomas Alexandre Brunet
- Institute of Analytical Sciences, CNRS UMR 5280, Claude Bernard University Lyon 1, Villeurbanne, France
| | - Valeska Bidault
- Department of Pediatric Surgery and Liver Transplantation, Femme Mere Enfant University Hospital, Lyon, France
| | - Valerie Hervieu
- Department of Pathology, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Villeurbanne, Lyon, France
| | - Yohann Clement
- Institute of Analytical Sciences, CNRS UMR 5280, Claude Bernard University Lyon 1, Villeurbanne, France
| | - Sophie Ayciriex
- Institute of Analytical Sciences, CNRS UMR 5280, Claude Bernard University Lyon 1, Villeurbanne, France
| | - Jean-Yves Mabrut
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Lyon, France
- The Cancer Research Center of Lyon, INSERM U1052, Lyon, France
| | - Arnaud Salvador
- Institute of Analytical Sciences, CNRS UMR 5280, Claude Bernard University Lyon 1, Villeurbanne, France
| | - Kayvan Mohkam
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Lyon, France
- Department of Pediatric Surgery and Liver Transplantation, Femme Mere Enfant University Hospital, Lyon, France
- The Cancer Research Center of Lyon, INSERM U1052, Lyon, France
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21
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Muller X, Rossignol G, Couillerot J, Breton A, Hervieu V, Lesurtel M, Mohkam K, Mabrut JY. A Single Preservation Solution for Static Cold Storage and Hypothermic Oxygenated Perfusion of Marginal Liver Grafts: A Preclinical Study. Transplantation 2024; 108:175-183. [PMID: 37410580 DOI: 10.1097/tp.0000000000004714] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Abstract
BACKGROUND Hypothermic oxygenated perfusion (HOPE) improves outcomes of marginal liver grafts. However, to date, no preservation solution exists for both static cold storage (SCS) and HOPE. METHODS After 30 min of asystolic warm ischemia, porcine livers underwent 6 h of SCS followed by 2 h of HOPE. Liver grafts were either preserved with a single preservation solution (IGL2) designed for SCS and HOPE (IGL2-Machine Perfusion Solution [MPS] group, n = 6) or with the gold-standard University of Wisconsin designed for for SCS and Belzer MPS designed for HOPE (MPS group, n = 5). All liver grafts underwent warm reperfusion with whole autologous blood for 2 h, and surrogate markers of hepatic ischemia-reperfusion injury (IRI) were assessed in the hepatocyte, cholangiocyte, vascular, and immunological compartments. RESULTS After 2 h of warm reperfusion, livers in the IGL2-MPS group showed no significant differences in transaminase release (aspartate aminotransferase: 65.58 versus 104.9 UI/L/100 g liver; P = 0.178), lactate clearance, and histological IRI compared with livers in the MPS group. There were no significant differences in biliary acid composition, bile production, and histological biliary IRI. Mitochondrial and endothelial damage was also not significantly different and resulted in similar hepatic inflammasome activation. CONCLUSIONS This preclinical study shows that a novel IGL2 allows for the safe preservation of marginal liver grafts with SCS and HOPE. Hepatic IRI was comparable with the current gold standard of combining 2 different preservation solutions (University of Wisconsin + Belzer MPS). These data pave the way for a phase I first-in-human study and it is a first step toward tailored preservation solutions for machine perfusion of liver grafts.
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Affiliation(s)
- Xavier Muller
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
- Hepatology Institute of Lyon, INSERM U1052, Lyon, France
- Ecole Doctorale 340, Biologie Moléculaire et Intégrative, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Guillaume Rossignol
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
- Hepatology Institute of Lyon, INSERM U1052, Lyon, France
- Ecole Doctorale 340, Biologie Moléculaire et Intégrative, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Joris Couillerot
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
- Hepatology Institute of Lyon, INSERM U1052, Lyon, France
| | - Antoine Breton
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
- Hepatology Institute of Lyon, INSERM U1052, Lyon, France
| | - Valérie Hervieu
- Department of Pathology, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Villeurbanne, Lyon, France
| | - Mickaël Lesurtel
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
| | - Kayvan Mohkam
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
- Hepatology Institute of Lyon, INSERM U1052, Lyon, France
| | - Jean-Yves Mabrut
- Department of General Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
- Hepatology Institute of Lyon, INSERM U1052, Lyon, France
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22
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Chapman WC, Barbas AS, D'Alessandro AM, Vianna R, Kubal CA, Abt P, Sonnenday C, Barth R, Alvarez-Casas J, Yersiz H, Eckhoff D, Cannon R, Genyk Y, Sher L, Singer A, Feng S, Roll G, Cohen A, Doyle MB, Sudan DL, Al-Adra D, Khan A, Subramanian V, Abraham N, Olthoff K, Tekin A, Berg L, Coussios C, Morris C, Randle L, Friend P, Knechtle SJ. Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States: A Randomized Controlled Trial. Ann Surg 2023; 278:e912-e921. [PMID: 37389552 DOI: 10.1097/sla.0000000000005934] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2023]
Abstract
OBJECTIVE To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)]. BACKGROUND The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death). METHODS Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function. RESULTS The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%). CONCLUSIONS NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.
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Affiliation(s)
- William C Chapman
- Department of Surgery, School of Medicine, Washington University, St. Louis
| | | | | | - Rodrigo Vianna
- Department of Surgery, University of Miami School of Medicine
| | | | - Peter Abt
- Department of Surgery, University of Pennsylvania School of Medicine
| | | | - Rolf Barth
- Department of Surgery, University of Chicago School of Medicine
| | | | - Hasan Yersiz
- Department of Surgery, David Geffen School of Medicine at UCLA
| | - Devin Eckhoff
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School
| | - Robert Cannon
- Department of Surgery, University of Alabama School of Medicine
| | - Yuri Genyk
- Department of Surgery, Keck School of Medicine of USC
| | - Linda Sher
- Department of Surgery, Keck School of Medicine of USC
| | | | - Sandy Feng
- Department of Surgery, UCSF School of Medicine
| | | | - Ari Cohen
- Department of Surgery, Ochsner Clinic
| | - Maria B Doyle
- Department of Surgery, School of Medicine, Washington University, St. Louis
| | - Debra L Sudan
- Department of Surgery, Duke University School of Medicine
| | - David Al-Adra
- Department of Surgery, School of Medicine, University of Wisconsin, Madison
| | - Adeel Khan
- Department of Surgery, School of Medicine, Washington University, St. Louis
| | | | - Nader Abraham
- Department of Surgery, Duke University School of Medicine
| | - Kim Olthoff
- Department of Surgery, University of Pennsylvania School of Medicine
| | - Akin Tekin
- Department of Surgery, University of Miami School of Medicine
| | - Lynn Berg
- Department of Surgery, School of Medicine, University of Wisconsin, Madison
| | | | - Chris Morris
- Department of Surgery, Ochsner Medical Center, New Orleans, LA
| | - Lucy Randle
- Department of Surgery, Ochsner Medical Center, New Orleans, LA
| | - Peter Friend
- Department of Surgery, Ochsner Medical Center, New Orleans, LA
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23
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Strobl F, Michelotto J, Muth V, Moosburner S, Knaub K, Zimmer M, Patel MS, Pratschke J, Sauer IM, Raschzok N, Gassner JMGV. Advancing Perfusion Models: Dual-Vessel Ex Vivo Rat Liver Perfusion Based on a Clinical Setup. Tissue Eng Part A 2023; 29:518-528. [PMID: 37498780 DOI: 10.1089/ten.tea.2023.0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023] Open
Abstract
Normothermic ex vivo liver machine perfusion (NEVLP) has been developed to address the increasing organ shortage in liver transplantation, through optimal preservation, assessment, and conditioning of grafts from extended criteria donors. There remains a need to establish simple and standardized animal models that simulate clinical NEVLP to test novel therapies. Liver grafts from 36 Sprague-Dawley rats were perfused for 6 h in a dual-vessel NEVLP system with a Dulbecco's modified Eagles medium-based perfusate supplemented with rat plasma and erythrocytes. Varying doses of the clinically used vasodilator epoprostenol, Kupffer cell inhibitor glycine, and a Steen™-based perfusate were assessed. Perfusion pressures and bile production were recorded, and perfusate was analyzed for transaminase secretion. Tissue samples were evaluated histologically, and levels of cytokines and 8-Isoprostane were measured. Increasing levels of epoprostenol and the addition of glycine resulted in a stepwise decrease of transaminase secretion and improved bile production. Steen further decreased transaminase release and interleukin 1 beta levels. Liver grafts perfused with the optimized Steen-based protocol exhibited lowest levels of oxidative stress and best-preserved liver integrity. In conclusion, epoprostenol seemed to ameliorate liver function and prevent cellular damage beyond its vasodilatory effect, with glycine acting synergistically. The anti-inflammatory and antioxidative properties of Steen further improved the outcome of perfusion. Our rodent NEVLP system may be used to rapidly test new agents for the pharmacologic conditioning of livers and help translate findings from bench-to-bedside.
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Affiliation(s)
- Felix Strobl
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Julian Michelotto
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Vanessa Muth
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Moosburner
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Kristina Knaub
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Maximilian Zimmer
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Madhukar S Patel
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Johann Pratschke
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Igor M Sauer
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nathanael Raschzok
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Joseph M G V Gassner
- Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
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24
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Richards JA, Gaurav R, Upponi SS, Swift L, Fear C, Webb GJ, Allison MED, Watson CJE, Butler AJ. Outcomes of livers from donation after circulatory death donors with extended agonal phase and the adjunct of normothermic regional perfusion. Br J Surg 2023; 110:1112-1115. [PMID: 37079886 PMCID: PMC10416677 DOI: 10.1093/bjs/znad099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/18/2023] [Accepted: 03/27/2023] [Indexed: 04/22/2023]
Abstract
The liver performs important functions that are essential for life. If the liver fails, patients will die unless they receive a new liver from a donor (transplant). Unfortunately, there are not enough livers for everyone and some patients die while waiting for a suitable organ. This article describes a novel technique that allows resuscitation and testing of a potential donor liver so that more patients can safely receive a transplant.
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Affiliation(s)
- James A Richards
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- University of Cambridge Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK
- NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), Cambridge, UK
- National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
- HPB and Liver Transplant Surgery, Royal Free Hospital, London, UK
| | - Rohit Gaurav
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
| | - Sara S Upponi
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
- Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
| | - Lisa Swift
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
| | - Corrina Fear
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
| | - Gwilym J Webb
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- Department of Medicine, Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge, UK
| | - Michael E D Allison
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
- Department of Medicine, Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge, UK
| | - Christopher J E Watson
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- University of Cambridge Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK
- NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), Cambridge, UK
- National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
| | - Andrew J Butler
- Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- University of Cambridge Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK
- NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), Cambridge, UK
- National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
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25
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Huwyler F, Eden J, Binz J, Cunningham L, Sousa Da Silva RX, Clavien P, Dutkowski P, Tibbitt MW, Hefti M. A Spectrofluorometric Method for Real-Time Graft Assessment and Patient Monitoring. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301537. [PMID: 37265001 PMCID: PMC10427358 DOI: 10.1002/advs.202301537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/03/2023] [Indexed: 06/03/2023]
Abstract
Biomarkers are powerful clinical diagnostics and predictors of patient outcome. However, robust measurements often require time and expensive laboratory equipment, which is insufficient to track rapid changes and limits direct use in the operating room. Here, this study presents a portable spectrophotometric device for continuous real-time measurements of fluorescent and non-fluorescent biomarkers at the point of care. This study measures the mitochondrial damage biomarker flavin mononucleotide (FMN) in 26 extended criteria human liver grafts undergoing hypothermic oxygenated perfusion to guide clinical graft assessment. Real-time data identified seven organs unsuitable for transplant that are discarded. The remaining grafts are transplanted and FMN values correlated with post-transplant indicators of liver function and patient recovery. Further, this study shows how this device can be used to monitor dialysis patients by measuring creatinine in real-time. Our approach provides a simple method to monitor biomarkers directly within biological fluids to improve organ assessment, patient care, and biomarker discovery.
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Affiliation(s)
- Florian Huwyler
- Macromolecular Engineering Lab, Department of Mechanical and Process EngineeringETH ZurichZurich8092Switzerland
- Department of Surgery and Transplantation, Swiss Hepato‐Pancreato‐Biliary (HPB) and Transplant CenterUniversity Hospital ZurichZurich8091Switzerland
- Wyss Zurich Translational CenterETH Zurich and University of ZurichZurich8092Switzerland
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss Hepato‐Pancreato‐Biliary (HPB) and Transplant CenterUniversity Hospital ZurichZurich8091Switzerland
| | - Jonas Binz
- Macromolecular Engineering Lab, Department of Mechanical and Process EngineeringETH ZurichZurich8092Switzerland
| | - Leslie Cunningham
- Macromolecular Engineering Lab, Department of Mechanical and Process EngineeringETH ZurichZurich8092Switzerland
- Department of Surgery and Transplantation, Swiss Hepato‐Pancreato‐Biliary (HPB) and Transplant CenterUniversity Hospital ZurichZurich8091Switzerland
- Wyss Zurich Translational CenterETH Zurich and University of ZurichZurich8092Switzerland
| | - Richard X. Sousa Da Silva
- Department of Surgery and Transplantation, Swiss Hepato‐Pancreato‐Biliary (HPB) and Transplant CenterUniversity Hospital ZurichZurich8091Switzerland
- Wyss Zurich Translational CenterETH Zurich and University of ZurichZurich8092Switzerland
| | - Pierre‐Alain Clavien
- Department of Surgery and Transplantation, Swiss Hepato‐Pancreato‐Biliary (HPB) and Transplant CenterUniversity Hospital ZurichZurich8091Switzerland
- Wyss Zurich Translational CenterETH Zurich and University of ZurichZurich8092Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss Hepato‐Pancreato‐Biliary (HPB) and Transplant CenterUniversity Hospital ZurichZurich8091Switzerland
| | - Mark W. Tibbitt
- Macromolecular Engineering Lab, Department of Mechanical and Process EngineeringETH ZurichZurich8092Switzerland
- Wyss Zurich Translational CenterETH Zurich and University of ZurichZurich8092Switzerland
| | - Max Hefti
- Wyss Zurich Translational CenterETH Zurich and University of ZurichZurich8092Switzerland
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26
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Clatworthy MR, Watson CJE. Understanding the Immunology of Normothermic Machine Perfusion. Transpl Int 2023; 36:11670. [PMID: 37538137 PMCID: PMC10395750 DOI: 10.3389/ti.2023.11670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 07/07/2023] [Indexed: 08/05/2023]
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27
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De Carlis R, Paolo Muiesan, Taner B. Donation after circulatory death: Novel strategies to improve the liver transplant outcome. J Hepatol 2023; 78:1169-1180. [PMID: 37208104 DOI: 10.1016/j.jhep.2023.04.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 05/21/2023]
Abstract
In many countries, donation after circulatory death (DCD) liver grafts are used to overcome organ shortages; however, DCD grafts have been associated with an increased risk of complications and even graft loss after liver transplantation. The increased risk of complications is thought to correlate with prolonged functional donor warm ischaemia time. Stringent donor selection criteria and utilisation of in situ and ex situ organ perfusion technologies have led to improved outcomes. Additionally, the increased use of novel organ perfusion strategies has led to the possibility of reconditioning marginal DCD liver grafts. Moreover, these technologies enable the assessment of liver function before implantation, thus providing valuable data that can guide more precise graft-recipient selection. In this review, we first describe the different definitions of functional warm donor ischaemia time and its role as a determinant of outcomes after DCD liver transplantation, with a focus on the thresholds proposed for graft acceptance. Next, organ perfusion strategies, namely normothermic regional perfusion, hypothermic oxygenated perfusion, and normothermic machine perfusion are discussed. For each technique, clinical studies reporting on the transplant outcome are described, together with a discussion on the possible protective mechanisms involved and the functional criteria adopted for graft selection. Finally, we review multimodal preservation protocols involving a combination of more than one perfusion technique and potential future directions in the field.
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Affiliation(s)
- Riccardo De Carlis
- Division of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Ph.D. Course in Clinical and Experimental Sciences, University of Padua, Padua, Italy
| | - Paolo Muiesan
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Centre of Preclinical Research, 20122, Italy
| | - Burcin Taner
- Department of Transplant, Mayo Clinic Florida, Jacksonville, United States.
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28
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Staubli SM, Ceresa CDL, Pollok JM. The Current Role and Future Applications of Machine Perfusion in Liver Transplantation. Bioengineering (Basel) 2023; 10:bioengineering10050593. [PMID: 37237663 DOI: 10.3390/bioengineering10050593] [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: 03/08/2023] [Revised: 04/07/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
The relative paucity of donor livers suitable for transplantation has sparked innovations to preserve and recondition organs to expand the pool of transplantable organs. Currently, machine perfusion techniques have led to the improvement of the quality of marginal livers and to prolonged cold ischemia time and have allowed for the prediction of graft function through the analysis of the organ during perfusion, improving the rate of organ use. In the future, the implementation of organ modulation might expand the scope of machine perfusion beyond its current usage. The aim of this review was to provide an overview of the current clinical use of machine perfusion devices in liver transplantation and to provide a perspective for future clinical use, including therapeutic interventions in perfused donor liver grafts.
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Affiliation(s)
- Sebastian M Staubli
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
| | - Carlo D L Ceresa
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
- Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxfordshire OX3 9DU, UK
| | - Joerg M Pollok
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
- Division of Surgery & Interventional Science, University College London, London WC1E 6BT, UK
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29
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Li J, Lu H, Zhang J, Li Y, Zhao Q. Comprehensive Approach to Assessment of Liver Viability During Normothermic Machine Perfusion. J Clin Transl Hepatol 2023; 11:466-479. [PMID: 36643041 PMCID: PMC9817053 DOI: 10.14218/jcth.2022.00130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 06/14/2022] [Accepted: 08/10/2022] [Indexed: 01/18/2023] Open
Abstract
Liver transplantation is the most effective treatment of advanced liver disease, and the use of extended criteria donor organs has broadened the source of available livers. Although normothermic machine perfusion (NMP) has become a useful tool in liver transplantation, there are no consistent criteria that can be used to evaluate the viability of livers during NMP. This review summarizes the criteria, indicators, and methods used to evaluate liver viability during NMP. The shape, appearance, and hemodynamics of the liver can be analyzed at a macroscopic level, while markers of liver injury, indicators of liver and bile duct function, and other relevant indicators can be evaluated by biochemical analysis. The liver can also be assessed by tissue biopsy at the microscopic level. Novel methods for assessment of liver viability are introduced. The limitations of evaluating liver viability during NMP are discussed and suggestions for future clinical practice are provided.
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Affiliation(s)
| | | | | | | | - Qiang Zhao
- Correspondence to: Qiang Zhao, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. ORCID: https://orcid.org/0000-0002-6369-1393. Tel: +86-15989196835, E-mail:
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30
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Schlegel A, Mueller M, Muller X, Eden J, Panconesi R, von Felten S, Steigmiller K, Sousa Da Silva RX, de Rougemont O, Mabrut JY, Lesurtel M, Cerisuelo MC, Heaton ND, Allard MA, Adam R, Monbaliu D, Jochmans I, Haring MPD, Porte RJ, Parente A, Muiesan P, Kron P, Attia M, Kollmann D, Berlakovich G, Rogiers X, Petterson K, Kranich AL, Amberg S, Müllhaupt B, Clavien PA, Dutkowski P. A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation. J Hepatol 2023; 78:783-793. [PMID: 36681160 DOI: 10.1016/j.jhep.2022.12.030] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 11/18/2022] [Accepted: 12/12/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND & AIMS Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear. METHODS In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints. RESULTS Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015). CONCLUSIONS HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events. IMPACT AND IMPLICATIONS This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies.
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Affiliation(s)
- Andrea Schlegel
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland; The Liver Unit, Queen Elizabeth University Hospital Birmingham, UK
| | - Matteo Mueller
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland
| | - Xavier Muller
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland; Department of Surgery and Liver Transplantation, Croix Rousse University Hospital, Hepatology Institute of Lyon, INSERM 1052, Lyon, France
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland
| | - Rebecca Panconesi
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Italy
| | - Stefanie von Felten
- Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Klaus Steigmiller
- Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Richard X Sousa Da Silva
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland
| | - Olivier de Rougemont
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland
| | - Jean-Yves Mabrut
- Department of Surgery and Liver Transplantation, Croix Rousse University Hospital, Hepatology Institute of Lyon, INSERM 1052, Lyon, France
| | - Mickaël Lesurtel
- Department of Surgery and Liver Transplantation, Croix Rousse University Hospital, Hepatology Institute of Lyon, INSERM 1052, Lyon, France
| | | | - Nigel D Heaton
- Liver Transplant Surgery, Institute of Liver Studies, Kings College Hospital, London, UK
| | - Marc Antoine Allard
- AP-HP Hôpital Paul Brousse, Research Unit "Chronotherapy, Cancers and Transplantation", Univ Paris-Saclay, Villejuif, France
| | - Rene Adam
- AP-HP Hôpital Paul Brousse, Research Unit "Chronotherapy, Cancers and Transplantation", Univ Paris-Saclay, Villejuif, France
| | - Diethard Monbaliu
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Belgium; Department of Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Ina Jochmans
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Belgium; Department of Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Martijn P D Haring
- 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
| | | | - Paolo Muiesan
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, UK; General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, 20122, Italy
| | - Philipp Kron
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland; Department of Transplantation and Hepatobiliary Surgery, Leeds Teaching Hospitals Trust, UK
| | - Magdy Attia
- Department of Transplantation and Hepatobiliary Surgery, Leeds Teaching Hospitals Trust, UK
| | - Dagmar Kollmann
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Gabriela Berlakovich
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Xavier Rogiers
- Department of General and Hepatobiliary Surgery, Liver Transplantation Service, Ghent University Hospital Medical School, Ghent, Belgium
| | - Karin Petterson
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland
| | - Anne L Kranich
- ODC BV, Keizersgracht 62-64, 1015, Amsterdam EBC, the Netherlands
| | - Stefanie Amberg
- ODC BV, Keizersgracht 62-64, 1015, Amsterdam EBC, the Netherlands
| | - Beat Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Switzerland
| | - Pierre-Alain Clavien
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Center, University Hospital Zurich, Switzerland.
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31
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Yuta T, Tian T, Chiba Y, Miyazaki K, Funada K, Mizuta K, Fu Y, Kawahara J, Iwamoto T, Takahashi I, Fukumoto S, Yoshizaki K. Development of a novel ex vivo organ culture system to improve preservation methods of regenerative tissues. Sci Rep 2023; 13:3354. [PMID: 36849572 PMCID: PMC9971270 DOI: 10.1038/s41598-023-29629-2] [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: 09/01/2022] [Accepted: 02/08/2023] [Indexed: 03/01/2023] Open
Abstract
Recent advances in regenerative technology have made the regeneration of various organs using pluripotent stem cells possible. However, a simpler screening method for evaluating regenerated organs is required to apply this technology to clinical regenerative medicine in the future. We have developed a simple evaluation method using a mouse tooth germ culture model of organs formed by epithelial-mesenchymal interactions. In this study, we successfully established a simple method that controls tissue development in a temperature-dependent manner using a mouse tooth germ ex vivo culture model. We observed that the development of the cultured tooth germ could be delayed by low-temperature culture and resumed by the subsequent culture at 37 °C. Furthermore, the optimal temperature for the long-term preservation of tooth germ was 25 °C, a subnormothermic temperature that maintains the expression of stem cell markers. We also found that subnormothermic temperature induces the expression of cold shock proteins, such as cold-inducible RNA-binding protein, RNA-binding motif protein 3, and serine and arginine rich splicing factor 5. This study provides a simple screening method to help establish the development of regenerative tissue technology using a tooth organ culture model. Our findings may be potentially useful for making advances in the field of regenerative medicine.
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Affiliation(s)
- Tomomi Yuta
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Tian Tian
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Yuta Chiba
- grid.177174.30000 0001 2242 4849Dento-Craniofacial Development and Regeneration Research Center, Kyushu University Faculty of Dental Science, Fukuoka, Japan ,grid.177174.30000 0001 2242 4849Section of Pediatric Dentistry, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Kanako Miyazaki
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Keita Funada
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Kanji Mizuta
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Yao Fu
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Jumpei Kawahara
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Tsutomu Iwamoto
- grid.265073.50000 0001 1014 9130Department of Pediatric Dentistry/Special Needs Dentistry, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ichiro Takahashi
- grid.177174.30000 0001 2242 4849Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan
| | - Satoshi Fukumoto
- Dento-Craniofacial Development and Regeneration Research Center, Kyushu University Faculty of Dental Science, Fukuoka, Japan. .,Section of Pediatric Dentistry, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan. .,Division of Pediatric Dentistry, Department of Community Social Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan.
| | - Keigo Yoshizaki
- Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, Japan. .,Dento-Craniofacial Development and Regeneration Research Center, Kyushu University Faculty of Dental Science, Fukuoka, Japan.
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Hypothermic Oxygenated Machine Perfusion (HOPE) Prior to Liver Transplantation Mitigates Post-Reperfusion Syndrome and Perioperative Electrolyte Shifts. J Clin Med 2022; 11:jcm11247381. [PMID: 36555997 PMCID: PMC9786550 DOI: 10.3390/jcm11247381] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
(1) Background: Post-reperfusion syndrome (PRS) and electrolyte shifts (ES) represent considerable challenges during liver transplantation (LT) being associated with significant morbidity. We aimed to investigate the impact of hypothermic oxygenated machine perfusion (HOPE) on PRS and ES in LT. (2) Methods: In this retrospective study, we compared intraoperative parameters of 100 LTs, with 50 HOPE preconditioned liver grafts and 50 grafts stored in static cold storage (SCS). During reperfusion phase, prospectively registered serum parameters and vasopressor administration were analyzed. (3) Results: Twelve percent of patients developed PRS in the HOPE cohort vs. 42% in the SCS group (p = 0.0013). Total vasopressor demand in the first hour after reperfusion was lower after HOPE pretreatment, with reduced usage of norepinephrine (−26%; p = 0.122) and significant reduction of epinephrine consumption (−52%; p = 0.018). Serum potassium concentration dropped by a mean of 14.1% in transplantations after HOPE, compared to a slight decrease of 1% (p < 0.001) after SCS. The overall incidence of early allograft dysfunction (EAD) was reduced by 44% in the HOPE group (p = 0.04). (4) Conclusions: Pre-transplant graft preconditioning with HOPE results in higher hemodynamic stability during reperfusion and lower incidence of PRS and EAD. HOPE has the potential to mitigate ES by preventing hyperpotassemic complications that need to be addressed in LT with HOPE-pre-treated grafts.
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Hyperspectral Imaging for Viability Assessment of Human Liver Allografts During Normothermic Machine Perfusion. Transplant Direct 2022; 8:e1420. [PMID: 36406899 PMCID: PMC9671746 DOI: 10.1097/txd.0000000000001420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 09/27/2022] [Accepted: 10/03/2022] [Indexed: 01/24/2023] Open
Abstract
UNLABELLED Normothermic machine perfusion (NMP) is nowadays frequently utilized in liver transplantation. Despite commonly accepted viability assessment criteria, such as perfusate lactate and perfusate pH, there is a lack of predictive organ evaluation strategies to ensure graft viability. Hyperspectral imaging (HSI)-as an optical imaging modality increasingly applied in the biomedical field-might provide additional useful data regarding allograft viability and performance of liver grafts during NMP. METHODS Twenty-five deceased donor liver allografts were included in the study. During NMP, graft viability was assessed conventionally and by means of HSI. Images of liver parenchyma were acquired at 1, 2, and 4 h of NMP, and subsequently analyzed using a specialized HSI acquisition software to compute oxygen saturation, tissue hemoglobin index, near-infrared perfusion index, and tissue water index. To analyze the association between HSI parameters and perfusate lactate as well as perfusate pH, we performed simple linear regression analysis. RESULTS Perfusate lactate at 1, 2, and 4 h NMP was 1.5 [0.3-8.1], 0.9 [0.3-2.8], and 0.9 [0.1-2.2] mmol/L. Perfusate pH at 1, 2, and 4 h NMP was 7.329 [7.013-7.510], 7.318 [7.081-7.472], and 7.265 [6.967-7.462], respectively. Oxygen saturation predicted perfusate lactate at 1 and 2 h NMP (R2 = 0.1577, P = 0.0493; R2 = 0.1831, P = 0.0329; respectively). Tissue hemoglobin index predicted perfusate lactate at 1, 2, and 4 h NMP (R2 = 0.1916, P = 0.0286; R2 = 0.2900, P = 0.0055; R2 = 0.2453, P = 0.0139; respectively). CONCLUSIONS HSI may serve as a noninvasive tool for viability assessment during NMP. Further evaluation and validation of HSI parameters are warranted in larger sample sizes.
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Muller X, Rossignol G, Mohkam K, Mabrut JY. Novel strategies in liver graft preservation - The French perspective. J Visc Surg 2022; 159:389-398. [PMID: 36109331 DOI: 10.1016/j.jviscsurg.2022.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Given the increasing graft shortage, the transplant community is forced to use so called marginal liver grafts with a higher susceptibility to ischemia-reperfusion injury. This exposes the recipient to a higher risk of graft failure and post-transplant complications. While static cold storage remains the gold standard in low-risk transplant scenarios, dynamic preservation strategies may allow to improve outcomes after transplantation of marginal liver grafts. Two dynamic preservation strategies, end-ischemic hypothermic oxygenated perfusion (HOPE) and continuous normothermic machine perfusion (cNMP), have been evaluated in randomized clinical trials. The results show improved preservation of liver grafts after cNMP and reduction of post-transplant biliary complications after HOPE. In comparison to cNMP, HOPE has the advantage of requiring less logistics and expertise with the possibility to return to default static cold storage. Both strategies allow to assess graft viability prior to transplantation and may thus contribute to optimizing graft selection and reducing discard rates. The use of dynamic preservation is rapidly increasing in France and results from a national randomized trial on the use of HOPE in marginal grafts will soon be available. Future applications should focus on controlled donation after circulatory death liver grafts, split grafts and graft treatment during perfusion. The final aim of dynamic liver graft preservation is to improve post-transplant outcomes, increase the number of transplanted grafts and allow expansion of transplant indications.
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Affiliation(s)
- X Muller
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France; ED 340 BMIC, Claude-Bernard Lyon 1 University, 69622 Villeurbanne, France.
| | - G Rossignol
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France; ED 340 BMIC, Claude-Bernard Lyon 1 University, 69622 Villeurbanne, France; Department of Pediatric Surgery and Liver Transplantation, Femme-Mère-Enfant University Hospital, Hospices Civils de Lyon, Lyon, France
| | - K Mohkam
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France; Department of Pediatric Surgery and Liver Transplantation, Femme-Mère-Enfant University Hospital, Hospices Civils de Lyon, Lyon, France
| | - J Y Mabrut
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France
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35
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Abstract
PURPOSE OF REVIEW Viability assessment is one of the main indications for machine perfusion (MP) in liver transplantation. This review summarizes the rationale, evolution and limitations of proposed viability criteria and suggests a framework for future studies. RECENT FINDINGS Liver viability is most frequently assessed during normothermic MP by combining parameters relative to perfusate and bile composition, vascular flows and macroscopic aspect. Assessment protocols are largely heterogeneous and have significantly evolved over time, also within the same group, reflecting the ongoing evolution of the subject. Several recent preclinical studies using discarded human livers or animal models have explored other approaches to viability assessment. During hypothermic MP, perfusate flavin mononucleotide has emerged as a promising biomarker of mitochondrial injury and function. Most studies on the subject suffer from limitations, including low numbers, lack of multicenter validation, and subjective interpretation of some viability parameters. SUMMARY MP adds a further element of complexity in the process of assessing the quality of a liver graft. Understanding the physiology of the parameters included in the different assessment protocols is necessary for their correct interpretation. Despite the possibility of assessing liver viability during MP, the importance of donor-recipient matching and operational variables should not be disregarded.
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Affiliation(s)
- Damiano Patrono
- General Surgery 2U - Liver Transplant Unit. Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino - University of Turin, Turin
| | - Caterina Lonati
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Renato Romagnoli
- General Surgery 2U - Liver Transplant Unit. Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino - University of Turin, Turin
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36
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Widmer J, Eden J, Carvalho MF, Dutkowski P, Schlegel A. Machine Perfusion for Extended Criteria Donor Livers: What Challenges Remain? J Clin Med 2022; 11:jcm11175218. [PMID: 36079148 PMCID: PMC9457017 DOI: 10.3390/jcm11175218] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 08/30/2022] [Indexed: 11/28/2022] Open
Abstract
Based on the renaissance of dynamic preservation techniques, extended criteria donor (ECD) livers reclaimed a valuable eligibility in the transplantable organ pool. Being more vulnerable to ischemia, ECD livers carry an increased risk of early allograft dysfunction, primary non-function and biliary complications and, hence, unveiled the limitations of static cold storage (SCS). There is growing evidence that dynamic preservation techniques—dissimilar to SCS—mitigate reperfusion injury by reconditioning organs prior transplantation and therefore represent a useful platform to assess viability. Yet, a debate is ongoing about the advantages and disadvantages of different perfusion strategies and their best possible applications for specific categories of marginal livers, including organs from donors after circulatory death (DCD) and brain death (DBD) with extended criteria, split livers and steatotic grafts. This review critically discusses the current clinical spectrum of livers from ECD donors together with the various challenges and posttransplant outcomes in the context of standard cold storage preservation. Based on this, the potential role of machine perfusion techniques is highlighted next. Finally, future perspectives focusing on how to achieve higher utilization rates of the available donor pool are highlighted.
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Affiliation(s)
- Jeannette Widmer
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
| | - Mauricio Flores Carvalho
- Hepatobiliary Unit, Department of Clinical and Experimental Medicine, University of Florence, AOU Careggi, 50139 Florence, Italy
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
| | - Andrea Schlegel
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
- Correspondence:
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37
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Kim J, Yang Y, Hong SK, Zielonka J, Dash RK, Audi SH, Kumar SN, Joshi A, Zimmerman MA, Hong JC. Fluorescein clearance kinetics in blood and bile indicates hepatic ischemia-reperfusion injury in rats. Am J Physiol Gastrointest Liver Physiol 2022; 323:G126-G133. [PMID: 35700191 DOI: 10.1152/ajpgi.00038.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Quantitative measurement of the degree of hepatic ischemia-reperfusion injury (IRI) is crucial for developing therapeutic strategies for its treatment. We hypothesized that clearance of fluorescent dye through bile metabolism may reflect the degree of hepatic IRI. In this study, we investigated sodium fluorescein clearance kinetics in blood and bile for quantifying the degree of hepatic IRI. Warm ischemia times (WITs) of 0, 30, or 60 min followed by 1 h or 4 h of reperfusion, were applied to the median and lateral lobes of the liver in Sprague-Dawley rats. Subsequently, 2 mg/kg of sodium fluorescein was injected intravenously, and blood and bile samples were collected over 60 min to measure fluorescence intensities. The bile-to-plasma fluorescence ratios demonstrated an inverse correlation with WIT and were distinctly lower in the 60-min WIT group than in the control or 30-min WIT groups. Bile-to-plasma fluorescence ratios displayed superior discriminability for short versus long WITs when measured 1 h after reperfusion versus 4 h. We conclude that the bile-to-blood ratio of fluorescence after sodium fluorescein injection has the potential to enable the quantification of hepatic IRI severity.NEW & NOTEWORTHY Previous attempts to use fluorophore clearance to test liver function have relied on a single source of data. However, the kinetics of substrate processing via bile metabolism include decreasing levels in blood and increasing levels in bile. Thus, we analyzed data from blood and bile to better reflect fluorescein clearance kinetics.
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Affiliation(s)
- Joohyun Kim
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Yongqiang Yang
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Seung-Keun Hong
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jacek Zielonka
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ranjan K Dash
- Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.,Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Said H Audi
- Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.,Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Suresh N Kumar
- Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Amit Joshi
- Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.,Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Johnny C Hong
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
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38
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Tessier SN, de Vries RJ, Pendexter CA, Cronin SEJ, Ozer S, Hafiz EOA, Raigani S, Oliveira-Costa JP, Wilks BT, Lopera Higuita M, van Gulik TM, Usta OB, Stott SL, Yeh H, Yarmush ML, Uygun K, Toner M. Partial freezing of rat livers extends preservation time by 5-fold. Nat Commun 2022; 13:4008. [PMID: 35840553 PMCID: PMC9287450 DOI: 10.1038/s41467-022-31490-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 06/20/2022] [Indexed: 02/04/2023] Open
Abstract
The limited preservation duration of organs has contributed to the shortage of organs for transplantation. Recently, a tripling of the storage duration was achieved with supercooling, which relies on temperatures between -4 and -6 °C. However, to achieve deeper metabolic stasis, lower temperatures are required. Inspired by freeze-tolerant animals, we entered high-subzero temperatures (-10 to -15 °C) using ice nucleators to control ice and cryoprotective agents (CPAs) to maintain an unfrozen liquid fraction. We present this approach, termed partial freezing, by testing gradual (un)loading and different CPAs, holding temperatures, and storage durations. Results indicate that propylene glycol outperforms glycerol and injury is largely influenced by storage temperatures. Subsequently, we demonstrate that machine perfusion enhancements improve the recovery of livers after freezing. Ultimately, livers that were partially frozen for 5-fold longer showed favorable outcomes as compared to viable controls, although frozen livers had lower cumulative bile and higher liver enzymes.
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Affiliation(s)
- Shannon N. Tessier
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Reinier J. de Vries
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,grid.7177.60000000084992262Department of Surgery, Amsterdam University Medical Centers – location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Casie A. Pendexter
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,Present Address: Sylvatica Biotech Inc., North Charleston, SC USA
| | - Stephanie E. J. Cronin
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Sinan Ozer
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Ehab O. A. Hafiz
- grid.420091.e0000 0001 0165 571XDepartment of Electron Microscopy Research, Theodor Bilharz Research Institute, Giza, Egypt
| | - Siavash Raigani
- grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,grid.32224.350000 0004 0386 9924Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA USA
| | - Joao Paulo Oliveira-Costa
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.38142.3c000000041936754XDepartment of Medicine and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA USA
| | - Benjamin T. Wilks
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Manuela Lopera Higuita
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Thomas M. van Gulik
- grid.7177.60000000084992262Department of Surgery, Amsterdam University Medical Centers – location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Osman Berk Usta
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Shannon L. Stott
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.38142.3c000000041936754XDepartment of Medicine and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA USA
| | - Heidi Yeh
- grid.32224.350000 0004 0386 9924Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA USA
| | - Martin L. Yarmush
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA ,grid.430387.b0000 0004 1936 8796Department of Biomedical Engineering, Rutgers University, Piscataway, NJ USA
| | - Korkut Uygun
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
| | - Mehmet Toner
- grid.38142.3c000000041936754XCenter for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA USA ,grid.415829.30000 0004 0449 5362Shriners Hospitals for Children Boston, Boston, MA USA
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Panconesi R, Flores Carvalho M, Dondossola D, Muiesan P, Dutkowski P, Schlegel A. Impact of Machine Perfusion on the Immune Response After Liver Transplantation – A Primary Treatment or Just a Delivery Tool. Front Immunol 2022; 13:855263. [PMID: 35874758 PMCID: PMC9304705 DOI: 10.3389/fimmu.2022.855263] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 05/31/2022] [Indexed: 12/12/2022] Open
Abstract
The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion techniques are therefore frequently discussed with an ever-increasing number of experimental and clinical studies. Two main approaches, hypothermic and normothermic perfusion, are the leading strategies to be introduced in clinical practice in many western countries today. Despite this success, the number of studies, which provide robust data on the underlying mechanisms of protection conveyed through this technology remains scarce, particularly in context of different stages of ischemia-reperfusion-injury (IRI). Prior to a successful clinical implementation of machine perfusion, the concept of IRI and potential key molecules, which should be addressed to reduce IRI-associated inflammation, requires a better exploration. During ischemia, Krebs cycle metabolites, including succinate play a crucial role with their direct impact on the production of reactive oxygen species (ROS) at mitochondrial complex I upon reperfusion. Such features are even more pronounced under normothermic conditions and lead to even higher levels of downstream inflammation. The direct consequence appears with an activation of the innate immune system. The number of articles, which focus on the impact of machine perfusion with and without the use of specific perfusate additives to modulate the inflammatory cascade after transplantation is very small. This review describes first, the subcellular processes found in mitochondria, which instigate the IRI cascade together with proinflammatory downstream effects and their link to the innate immune system. Next, the impact of currently established machine perfusion strategies is described with a focus on protective mechanisms known for the different perfusion approaches. Finally, the role of such dynamic preservation techniques to deliver specific agents, which appear currently of interest to modulate this posttransplant inflammation, is discussed together with future aspects in this field.
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Affiliation(s)
- Rebecca Panconesi
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della, Scienza di Torino, University of Turin, Turin, Italy
| | - Mauricio Flores Carvalho
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Paolo Muiesan
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | - Andrea Schlegel
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
- *Correspondence: Andrea Schlegel,
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40
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Utilization of dielectric properties for assessment of liver ischemia-reperfusion injury in vivo and during machine perfusion. Sci Rep 2022; 12:11183. [PMID: 35778457 PMCID: PMC9249774 DOI: 10.1038/s41598-022-14817-3] [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: 01/22/2022] [Accepted: 06/13/2022] [Indexed: 11/20/2022] Open
Abstract
There is a shortage of donor livers and patients consequently die on waiting lists worldwide. Livers are discarded if they are clinically judged to have a high risk of non-function following transplantation. With the aim of extending the pool of available donor livers, we assessed the condition of porcine livers by monitoring the microwave dielectric properties. A total of 21 livers were divided into three groups: control with no injury (CON), biliary injury by hepatic artery occlusion (AHEP), and overall hepatic injury by static cold storage (SCS). All were monitored for four hours in vivo, followed by ex vivo plurithermic machine perfusion (PMP). Permittivity data was modeled with a two-pole Cole–Cole equation, and dielectric properties from one-hour intervals were analyzed during in vivo and normothermic machine perfusion (NMP). A clear increasing trend in the conductivity was observed in vivo in the AHEP livers compared to the control livers. After four hours of NMP, separations in the conductivity were observed between the three groups. Our results indicate that dielectric relaxation spectroscopy (DRS) can be used to detect and differentiate liver injuries, opening for a standardized and reliable point of evaluation for livers prior to transplantation.
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41
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Schlegel A, Porte R, Dutkowski P. Protective mechanisms and current clinical evidence of hypothermic oxygenated machine perfusion (HOPE) in preventing post-transplant cholangiopathy. J Hepatol 2022; 76:1330-1347. [PMID: 35589254 DOI: 10.1016/j.jhep.2022.01.024] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/10/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
The development of cholangiopathies after liver transplantation impacts on the quality and duration of graft and patient survival, contributing to higher costs as numerous interventions are required to treat strictures and infections at the biliary tree. Prolonged donor warm ischaemia time in combination with additional cold storage are key risk factors for the development of biliary strictures. Based on this, the clinical implementation of dynamic preservation strategies is a current hot topic in the field of donation after circulatory death (DCD) liver transplantation. Despite various retrospective studies reporting promising results, also regarding biliary complications, there are only a few randomised-controlled trials on machine perfusion. Recently, the group from Groningen has published the first randomised-controlled trial on hypothermic oxygenated perfusion (HOPE), demonstrating a significant reduction of symptomatic ischaemic cholangiopathies with the use of a short period of HOPE before DCD liver implantation. The most likely mechanism for this important effect, also shown in several experimental studies, is based on mitochondrial reprogramming under hypothermic aerobic conditions, e.g. exposure to oxygen in the cold, with a controlled and slow metabolism of ischaemically accumulated succinate and simultaneous ATP replenishment. This unique feature prevents mitochondrial oxidative injury and further downstream tissue inflammation. HOPE treatment therefore supports livers by protecting them from ischaemia-reperfusion injury (IRI), and thereby also prevents the development of post-transplant biliary injury. With reduced IRI-associated inflammation, recipients are also protected from activation of the innate immune system, with less acute rejections seen after HOPE.
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Affiliation(s)
- Andrea Schlegel
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland; General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy
| | - Robert Porte
- Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland.
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Hann A, Nutu A, Clarke G, Patel I, Sneiders D, Oo YH, Hartog H, Perera MTPR. Normothermic Machine Perfusion—Improving the Supply of Transplantable Livers for High-Risk Recipients. Transpl Int 2022; 35:10460. [PMID: 35711320 PMCID: PMC9192954 DOI: 10.3389/ti.2022.10460] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022]
Abstract
The effectiveness of liver transplantation to cure numerous diseases, alleviate suffering, and improve patient survival has led to an ever increasing demand. Improvements in preoperative management, surgical technique, and postoperative care have allowed increasingly complicated and high-risk patients to be safely transplanted. As a result, many patients are safely transplanted in the modern era that would have been considered untransplantable in times gone by. Despite this, more gains are possible as the science behind transplantation is increasingly understood. Normothermic machine perfusion of liver grafts builds on these gains further by increasing the safe use of grafts with suboptimal features, through objective assessment of both hepatocyte and cholangiocyte function. This technology can minimize cold ischemia, but prolong total preservation time, with particular benefits for suboptimal grafts and surgically challenging recipients. In addition to more physiological and favorable preservation conditions for grafts with risk factors for poor outcome, the extended preservation time benefits operative logistics by allowing a careful explant and complicated vascular reconstruction when presented with challenging surgical scenarios. This technology represents a significant advancement in graft preservation techniques and the transplant community must continue to incorporate this technology to ensure the benefits of liver transplant are maximized.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research and NIHR Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Anisa Nutu
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - George Clarke
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research and NIHR Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Ishaan Patel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Dimitri Sneiders
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Ye H. Oo
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research and NIHR Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Hermien Hartog
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - M. Thamara P. R. Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research and NIHR Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- *Correspondence: M. Thamara P. R. Perera,
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Fodor M, Lanser L, Hofmann J, Otarashvili G, Pühringer M, Cardini B, Oberhuber R, Resch T, Weissenbacher A, Maglione M, Margreiter C, Zelger P, Pallua JD, Öfner D, Sucher R, Hautz T, Schneeberger S. Hyperspectral Imaging as a Tool for Viability Assessment During Normothermic Machine Perfusion of Human Livers: A Proof of Concept Pilot Study. Transpl Int 2022; 35:10355. [PMID: 35651880 PMCID: PMC9150258 DOI: 10.3389/ti.2022.10355] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/22/2022] [Indexed: 11/23/2022]
Abstract
Normothermic machine perfusion (NMP) allows for ex vivo viability and functional assessment prior to liver transplantation (LT). Hyperspectral imaging represents a suitable, non-invasive method to evaluate tissue morphology and organ perfusion during NMP. Liver allografts were subjected to NMP prior to LT. Serial image acquisition of oxygen saturation levels (StO2), organ hemoglobin (THI), near-infrared perfusion (NIR) and tissue water indices (TWI) through hyperspectral imaging was performed during static cold storage, at 1h, 6h, 12h and at the end of NMP. The readouts were correlated with perfusate parameters at equivalent time points. Twenty-one deceased donor livers were included in the study. Seven (33.0%) were discarded due to poor organ function during NMP. StO2 (p < 0.001), THI (p < 0.001) and NIR (p = 0.002) significantly augmented, from static cold storage (pre-NMP) to NMP end, while TWI dropped (p = 0.005) during the observational period. At 12-24h, a significantly higher hemoglobin concentration (THI) in the superficial tissue layers was seen in discarded, compared to transplanted livers (p = 0.036). Lactate values at 12h NMP correlated negatively with NIR perfusion index between 12 and 24h NMP and with the delta NIR perfusion index between 1 and 24h (rs = -0.883, p = 0.008 for both). Furthermore, NIR and TWI correlated with lactate clearance and pH. This study provides first evidence of feasibility of hyperspectral imaging as a potentially helpful contact-free organ viability assessment tool during liver NMP.
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Affiliation(s)
- Margot Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Lukas Lanser
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Julia Hofmann
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Giorgi Otarashvili
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Marlene Pühringer
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Thomas Resch
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Philipp Zelger
- Department for Hearing, Speech, and Voice Disorders, Medical University of Innsbruck, Innsbruck, Austria
| | - Johannes D. Pallua
- University Hospital for Orthopedics and Traumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Robert Sucher
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Clinic, Leipzig, Germany
| | - Theresa Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria,OrganLife, Organ Regeneration Center of Excellence, Innsbruck, Austria,*Correspondence: Stefan Schneeberger,
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44
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Normothermic Machine Perfusion as a Tool for Safe Transplantation of High-Risk Recipients. TRANSPLANTOLOGY 2022. [DOI: 10.3390/transplantology3020018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Normothermic machine perfusion (NMP) should no longer be considered a novel liver graft preservation strategy, but rather viewed as the standard of care for certain graft–recipient scenarios. The ability of NMP to improve the safe utilisation of liver grafts has been demonstrated in several publications, from numerous centres. This is partly mediated by its ability to limit the cold ischaemic time while also extending the total preservation period, facilitating the difficult logistics of a challenging transplant operation. Viability assessment of both the hepatocytes and cholangiocytes with NMP is much debated, with numerous different parameters and thresholds associated with a reduction in the incidence of primary non-function and biliary strictures. Maximising the utilisation of liver grafts is important as many patients require transplantation on an urgent basis, the waiting list is long, and significant morbidity and mortality is experienced by patients awaiting transplants. If applied in an appropriate manner, NMP has the ability to expand the pool of grafts available for even the sickest and most challenging of recipients. In addition, this is the group of patients that consume significant healthcare resources and, therefore, justify the additional expense of NMP. This review describes, with case examples, how NMP can be utilised to salvage suboptimal grafts, and our approach of transplanting them into high-risk recipients.
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Patrono D, Cussa D, Sciannameo V, Montanari E, Panconesi R, Berchialla P, Lepore M, Gambella A, Rizza G, Catalano G, Mirabella S, Tandoi F, Lupo F, Balagna R, Salizzoni M, Romagnoli R. Outcome of liver transplantation with grafts from brain-dead donors treated with dual hypothermic oxygenated machine perfusion, with particular reference to elderly donors. Am J Transplant 2022; 22:1382-1395. [PMID: 35150050 PMCID: PMC9303789 DOI: 10.1111/ajt.16996] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/21/2021] [Accepted: 01/12/2022] [Indexed: 01/25/2023]
Abstract
Prompted by the utilization of extended criteria donors, dual hypothermic oxygenated machine perfusion (D-HOPE) was introduced in liver transplantation to improve preservation. When donors after neurological determination of death (DBD) are used, D-HOPE effect on graft outcomes is unclear. To assess D-HOPE value in this setting and to identify ideal scenarios for its use, data on primary adult liver transplant recipients from January 2014 to April 2021 were analyzed using inverse probability of treatment weighting, comparing outcomes of D-HOPE-treated grafts (n = 121) with those preserved by static cold storage (n = 723). End-ischemic D-HOPE was systematically applied since November 2017 based on donor and recipient characteristics and transplant logistics. D-HOPE use was associated with a significant reduction of early allograft failure (OR: 0.24; 0.83; p = .024), grade ≥3 complications (OR: 0.57; p = .046), comprehensive complication index (-7.20 points; p = .003), and improved patient and graft survival. These results were confirmed in the subset of elderly donors (>75-year-old). Although D-HOPE did not reduce the incidence of biliary complications, its use was associated with a reduced severity of ischemic cholangiopathy. In conclusion, D-HOPE improves postoperative outcomes and reduces early allograft loss in extended criteria DBD grafts.
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Affiliation(s)
- Damiano Patrono
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Davide Cussa
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | | | - Elena Montanari
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Rebecca Panconesi
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Paola Berchialla
- Department of Clinical and Biological SciencesUniversity of TurinTurinItaly
| | - Mirella Lepore
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | | | - Giorgia Rizza
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Giorgia Catalano
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Stefano Mirabella
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Francesco Tandoi
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Francesco Lupo
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Roberto Balagna
- Anesthesia Department 2A.O.U. Città della Salute e della Scienza di TorinoTurinItaly
| | - Mauro Salizzoni
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
| | - Renato Romagnoli
- General Surgery 2U ‐ Liver Transplant UnitA.O.U. Città della Salute e della Scienza di TorinoUniversity of TurinTurinItaly
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46
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Brüggenwirth IMA, van Leeuwen OB, Porte RJ, Martins PN. The Emerging Role of Viability Testing During Liver Machine Perfusion. Liver Transpl 2022; 28:876-886. [PMID: 33963657 DOI: 10.1002/lt.26092] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 04/30/2021] [Indexed: 12/23/2022]
Abstract
The transplant community continues to be challenged by the disparity between the need for liver transplantation and the shortage of suitable donor organs. At the same time, the number of unused donor livers continues to increase, most likely attributed to the worsening quality of these organs. To date, there is no reliable marker of liver graft viability that can predict good posttransplant outcomes. Ex situ machine perfusion offers additional data to assess the viability of donor livers before transplantation. Hence, livers initially considered unsuitable for transplantation can be assessed during machine perfusion in terms of appearance and consistency, hemodynamics, and metabolic and excretory function. In addition, postoperative complications such as primary nonfunction or posttransplant cholangiopathy may be predicted and avoided. A variety of viability criteria have been used in machine perfusion, and to date there is no widely accepted composition of criteria for clinical use. This review discusses potential viability markers for hepatobiliary function during machine perfusion, describes current limitations, and provides future recommendations for the use of viability criteria in clinical liver transplantation.
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Affiliation(s)
- Isabel M A Brüggenwirth
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Division of Organ Transplantation, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, MA
| | - Otto B van Leeuwen
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Robert J Porte
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, MA
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47
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Weissenbacher A, Bogensperger C, Oberhuber R, Meszaros A, Gasteiger S, Ulmer H, Berchtold V, Krendl FJ, Fodor M, Messner F, Hautz T, Otarashvili G, Resch T, Margreiter C, Maglione M, Irsara C, Griesmacher A, Raynaud M, Breitkopf R, Troppmair J, Öfner D, Cardini B, Schneeberger S. Perfusate Enzymes and Platelets Indicate Early Allograft Dysfunction After Transplantation of Normothermically Preserved Livers. Transplantation 2022; 106:792-805. [PMID: 34144552 DOI: 10.1097/tp.0000000000003857] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) has become a clinically established tool to preserve livers in a near-physiological environment. However, little is known about the predictive value of perfusate parameters toward the outcomes after transplantation. METHODS Fifty-five consecutive NMP livers between 2018 and 2019 were included. All of the livers were perfused on the OrganOx metra device according to an institutional protocol. Transplant and perfusion data were collected prospectively. RESULTS Forty-five livers were transplanted after NMP. Five livers stem from donors after circulatory death and 31 (68.9%) from extended criteria donors. Mean (SD) cold ischemia time was 6.4 (2.3) h; mean (SD) total preservation time was 21.4 (7.1) h. Early allograft dysfunction (EAD) occurred in 13 of 45 (28.9%) patients. Perfusate aspartate aminotransferase (P = 0.008), alanine aminotransferase (P = 0.006), lactate dehydrogenase (P = 0.007) and their development over time, alkaline phosphatase (P = 0.013), and sodium (P = 0.016) correlated with EAD. Number of perfusate platelets correlated with cold ischemia time duration and were indicative for the occurrence of EAD. Moreover, von Willebrand Factor antigen was significantly higher in perfusates of EAD livers (P < 0.001), and Δ von Willebrand factor antigen correlated with EAD. Although perfusate lactate and glucose had no predictive value, EAD was more likely to occur in livers with lower perfusate pH (P = 0.008). ΔPerfusate alkaline phosphatase, Δperfusate aspartate aminotransferase, Δperfusate alanine aminotransferase, and Δperfusate lactate dehydrogenase correlated closely with model for early allograft function but not liver graft assessment following transplantation risk score. Bile parameters correlated with extended criteria donor and donor risk index. CONCLUSIONS Biomarker assessment during NMP may help to predict EAD after liver transplantation. The increase of transaminases and lactate dehydrogenase over time as well as platelets and vWF antigen are important factors indicative for EAD.
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Affiliation(s)
- Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christina Bogensperger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Andras Meszaros
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Silvia Gasteiger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Hanno Ulmer
- Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria
| | - Valeria Berchtold
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix J Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Margot Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Franka Messner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Theresa Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Giorgi Otarashvili
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Resch
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Irsara
- Central Institute for Medical and Chemical Laboratory Diagnosis, Medical University of Innsbruck, Innsbruck, Austria
| | - Andrea Griesmacher
- Central Institute for Medical and Chemical Laboratory Diagnosis, Medical University of Innsbruck, Innsbruck, Austria
| | - Marc Raynaud
- Paris Translational Research Center for Organ Transplantation, INSERM, UMR-S970, Paris, France
| | - Robert Breitkopf
- Department of Anesthesia, Medical University of Innsbruck, Innsbruck, Austria
| | - Jakob Troppmair
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
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48
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Verstraeten L, Jochmans I. Sense and Sensibilities of Organ Perfusion as a Kidney and Liver Viability Assessment Platform. Transpl Int 2022; 35:10312. [PMID: 35356401 PMCID: PMC8958413 DOI: 10.3389/ti.2022.10312] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/26/2022] [Indexed: 12/13/2022]
Abstract
Predicting organ viability before transplantation remains one of the most challenging and ambitious objectives in transplant surgery. Waitlist mortality is high while transplantable organs are discarded. Currently, around 20% of deceased donor kidneys and livers are discarded because of “poor organ quality”, Decisions to discard are still mainly a subjective judgement since there are only limited reliable tools predictive of outcome available. Organ perfusion technology has been posed as a platform for pre-transplant organ viability assessment. Markers of graft injury and function as well as perfusion parameters have been investigated as possible viability markers during ex-situ hypothermic and normothermic perfusion. We provide an overview of the available evidence for the use of kidney and liver perfusion as a tool to predict posttransplant outcomes. Although evidence shows post-transplant outcomes can be predicted by both injury markers and perfusion parameters during hypothermic kidney perfusion, the predictive accuracy is too low to warrant clinical decision making based upon these parameters alone. In liver, further evidence on the usefulness of hypothermic perfusion as a predictive tool is needed. Normothermic perfusion, during which the organ remains fully metabolically active, seems a more promising platform for true viability assessment. Although we do not yet fully understand “on-pump” organ behaviour at normothermia, initial data in kidney and liver are promising. Besides the need for well-designed (registry) studies to advance the field, the catch-22 of selection bias in clinical studies needs addressing.
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Affiliation(s)
- Laurence Verstraeten
- Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Ina Jochmans
- Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
- *Correspondence: Ina Jochmans,
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49
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Liver Transplantation Outcomes From Controlled Circulatory Death Donors: Static cold storage vs in situ normothermic regional perfusion vs ex situ normothermic machine perfusion. Ann Surg 2022; 275:1156-1164. [PMID: 35258511 DOI: 10.1097/sla.0000000000005428] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To compare the outcomes of livers donated after circulatory death (DCD) and undergoing either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion (NMP) with livers undergoing static cold storage (SCS). SUMMARY OF BACKGROUND DATA DCD livers are associated with increased risk of primary nonfunction, poor function, and nonanastomotic strictures (NAS), leading to underutilization. METHODS A single center, retrospective analysis of prospectively collected data on 233 DCD liver transplants performed using SCS, NRP, or NMP between January 2013 and October 2020. RESULTS Ninety-seven SCS, 69 NRP, and 67 NMP DCD liver transplants were performed, with 6-month and 3-year transplant survival (graft survival noncensored for death) rates of 87%, 94%, 90%, and 76%, 90%, and 76%, respectively. NRP livers had a lower 6-month risk-adjusted Cox proportional hazard for transplant failure compared to SCS (hazard ratio 0.30, 95%CI 0.08-1.05, P = 0.06). NRP and NMP livers had a risk-adjusted estimated reduction in the mean model for early allograft function score of 1.52 (P < 0.0001) and 1.19 (P < 0.001) respectively compared to SCS. Acute kidney injury was more common with SCS (55% vs 39% NRP vs 40% NMP; P = 0.08), with a lower risk-adjusted peak-to-baseline creatinine ratio in the NRP (P = 0.02). No NRP liver had clinically significant NAS in contrast to SCS (14%) and NMP (11%, P = 0.009), with lower risk-adjusted odds of overall NAS development compared to SCS (odds ratio = 0.2, 95%CI 0.06-0.72, P = 0.01). CONCLUSION NRP and NMP were associated with better early liver function compared to SCS, whereas NRP was associated with superior preservation of the biliary system.
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50
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Coagulation Factors Accumulate During Normothermic Liver Machine Perfusion Regardless of Donor Type and Severity of Ischemic Injury. Transplantation 2022; 106:510-518. [PMID: 33756546 DOI: 10.1097/tp.0000000000003763] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Coagulation factors may inform on liver function during normothermic machine perfusion (NMP). We investigated whether graft ischemic injury impairs the accumulation of anticoagulation factors during NMP of porcine and human livers. METHODS Dynamics of FV, FVII, FVIII, FIX, and FX during NMP and their correlation with graft injury was investigated in porcine livers with minimal (no warm ischemia, n = 5) or severe injury (60 min warm ischemia, n = 5). Next, FV, FVIII, FIX, fibrinogen, and antithrombin were measured in 35 matched human liver NMPs from the COPE trial. Correlation of these factors with outcomes was explored. Livers were categorized in to 4 groups depending on donor type and posttransplant peak aspartate aminotransferase (AST) as surrogate of minimal (peak < 500 IU/L) or moderate injury (peak > 1000 IU/L). RESULTS Factor concentrations increased significantly during NMP regardless of severity of injury. In porcine livers, factor concentrations were 2- to 6-fold lower in severely injured grafts (all P < 0.05). All factors negatively correlated with AST (coefficient range: from -0.50 to -0.93; all P < 0.05) and lactate (range: from -0.51 to -0.67; all P < 0.05). In human livers, no difference in factor accumulation rates and no correlation with other markers were observed. One graft with primary nonfunction had low rate of factor accumulation. CONCLUSIONS Anticoagulation factors accumulate during NMP regardless of donor type and severity of injury. In pigs, severe ischemic injury resulted in significantly lower factor concentrations. In human livers with life-sustaining function, they do not correlate with hepatic injury. Whether low concentrations predict nonfunction in high-risk livers with severe injury requires further investigation.
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