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Viana P, Castillo-Flores S, Mora MMR, Cabral TDD, Martins PN, Kueht M, Faria I. Normothermic Machine Perfusion vs. Static Cold Storage in Liver Transplantation: A Systematic Review and Meta-Analysis. Artif Organs 2025; 49:945-954. [PMID: 39887468 DOI: 10.1111/aor.14960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/30/2024] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Normothermic machine perfusion (NMP) represents an alternative to prolong liver preservation and reduce organ discard rates. We performed an updated systematic review and meta-analysis to compare NMP with static cold storage (SCS) in liver transplantation. METHODS MEDLINE, Embase, and Cochrane were searched for randomized controlled trials (RCTs) or observational studies. Risk ratios (RR) and mean differences were calculated. p < 0.05 was considered significant. A random-effects model was applied for all outcomes. PROSPERO ID CRD42023486184. RESULTS We included 1295 patients from 5 RCTs and 6 observational studies from 2016 to 2023. 592 (45.7%) underwent NMP. A subgroup RCT analysis favored NMP for non-anastomotic strictures (RR 0.4; 95% CI 0.2, 0.9), postreperfusion syndrome (RR 0.4; 95% CI 0.27, 0.56), and early allograft dysfunction (RR 0.6; 95% CI 0.4, 0.9). NMP favored higher organ utilization rates (RR 1.1; 95% CI 1.02, 1.18). No significant differences between NMP and SCS were observed in graft survival or patient survival at 12 months, primary non-function, serious adverse events, overall biliary complications, AST, or bilirubin levels peak within the first 7 days, ICU or hospital length of stay. CONCLUSION Our findings suggest that NMP is associated with lower non-anastomotic biliary stricture rates, postreperfusion syndrome, early allograft dysfunction, and higher organ utilization in the RCT subgroup analysis, without increasing adverse events.
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Affiliation(s)
- Patricia Viana
- University of Extreme South of Santa Catarina, Criciuma, Brazil
| | | | - Maria M R Mora
- Univeristat Internacional de Catalunya, Barcelona, Spain
| | | | - Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, University of Massachusetts, Worcester, Massachusetts, USA
| | - Michael Kueht
- Division of Transplant Surgery, Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
| | - Isabella Faria
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
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Cresci GA, Liu Q, Sangwan N, Liu D, Grove D, Shapiro D, Ali K, Cazzaniga B, Prete LD, Miller C, Hashimoto K, Quintini C. The Impact of Liver Graft Preservation Method on Longitudinal Gut Microbiome Changes Following Liver Transplant: A Proof-of-concept Study. J Clin Transl Hepatol 2025; 13:284-294. [PMID: 40206278 PMCID: PMC11976440 DOI: 10.14218/jcth.2024.00352] [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: 09/21/2024] [Revised: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 04/11/2025] Open
Abstract
Background and Aims End-stage liver disease is associated with disruptions in gut microbiota composition and function, which may facilitate gut-to-liver bacterial translocation, impacting liver graft integrity and clinical outcomes following liver transplantation. This study aimed to assess the impact of two liver graft preservation methods on fecal microbiota and changes in fecal and breath organic acids following liver transplantation. Methods This single-center, non-randomized prospective pilot study enrolled liver transplant patients whose grafts were preserved using either static cold storage or ex situ normothermic machine perfusion (NMP). Fresh stool and breath samples were collected immediately before surgery and at postoperative months 3, 6, and 12. Stool microbiota was profiled via 16S rRNA gene sequencing, stool short-chain fatty acids were measured using gas chromatography/-mass spectrometry, and breath volatile organic compounds (VOCs) were analyzed with selected-ion flow-tube mass spectrometry. Results Both cohorts experienced a loss of microbiota diversity and dominance by single taxa. The NMP cohort demonstrated enrichment of several beneficial gut taxa, while the static cold storage cohort showed depletion of such taxa. Various gut bacteria were found to correlate with stool short-chain fatty acids (e.g., lactic acid, butyric acid) and several VOCs. Conclusions Fecal microbiota alterations associated with end-stage liver disease do not fully normalize to a healthy control profile following liver transplantation. However, notable differences in microbiota composition and function were observed between liver graft preservation methods. Future research with larger randomized cohorts is needed to explore whether the NMP-associated shift in gut microbiota impacts clinical outcomes and if breath VOCs could serve as biomarkers of the clinical trajectory in liver transplant patients.
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Affiliation(s)
- Gail A.M. Cresci
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland, OH, USA
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Qiang Liu
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Transplant Center, Cleveland Clinic, Cleveland, OH, USA
| | - Naseer Sangwan
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA
- Cardiovascular and Metabolic Sciences/Shared Laboratory Resources, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Darren Liu
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - David Grove
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - David Shapiro
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Khaled Ali
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Transplant Center, Cleveland Clinic, Cleveland, OH, USA
| | - Beatrice Cazzaniga
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Transplant Center, Cleveland Clinic, Cleveland, OH, USA
| | - Luca Del Prete
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Transplant Center, Cleveland Clinic, Cleveland, OH, USA
| | - Charles Miller
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Transplant Center, Cleveland Clinic, Cleveland, OH, USA
| | - Koji Hashimoto
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Transplant Center, Cleveland Clinic, Cleveland, OH, USA
| | - Cristiano Quintini
- Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates
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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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4
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Purssell A, Kumar D. Impact of machine perfusion on transplant infectious diseases: New challenges and opportunities. Transpl Infect Dis 2024; 26 Suppl 1:e14348. [PMID: 39078339 DOI: 10.1111/tid.14348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/30/2024] [Accepted: 07/09/2024] [Indexed: 07/31/2024]
Abstract
Preservation techniques that maintain the viability of an organ graft between retrieval from the donor and implantation into the recipient remain a critical aspect of solid organ transplantation. While traditionally preservation is accomplished with static cold storage, advances in ex vivo dynamic machine perfusion, both hypothermic and normothermic, have allowed for prolongation of organ viability and recovery of marginal organs effectively increasing the usable donor pool. However, the use of these novel machine perfusion technologies likely exposes the recipient to additional infectious risk either through clonal expansion of pathogens derived during organ recovery or de novo exogenous acquisition of pathogens while the organ remains on the machine perfusion circuit. There is a paucity of high-quality studies that have attempted to quantify infection risk, although it appears that prolonging the time on the machine perfusion circuit and normothermic parameters increases the risk of infection. Conversely, the use of ex vivo machine perfusion unlocks new opportunities to detect and treat donor-derived infections before implantation into the recipient. This review seeks to reveal how the use of ex vivo machine perfusion strategies may augment the risk of infection in the organ recipient as well as outline ways that this technology could be leveraged to enhance our ability to manage donor-derived infections.
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Affiliation(s)
- Andrew Purssell
- Ajmera Transplant Centre, University Health Network, Toronto, Canada
| | - Deepali Kumar
- Ajmera Transplant Centre, University Health Network, Toronto, Canada
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5
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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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Semash K, Salimov U, Dzhanbekov T, Sabirov D. Liver Graft Machine Perfusion: From History Perspective to Modern Approaches in Transplant Surgery. EXP CLIN TRANSPLANT 2024; 22:497-508. [PMID: 39223808 DOI: 10.6002/ect.2024.0137] [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: 09/04/2024]
Abstract
The shortage of donor organs remains an unresolved issue in livertransplantation worldwide. Consequently, strategies for expanding the donor pool are currently being developed. Donors meeting extended criteria undergo thorough evaluation, as livers obtained from marginal donors yield poorer outcomes in recipients, including exacerbated reperfusion injury, acute kidney injury, early graft dysfunction, and primary nonfunctioning graft. However, the implementation of machine perfusion has shown excellent potential in preserving donor livers and improving their characteristics to achieve better outcomes for recipients. In this review, we analyzed the global experience of using machine perfusion in livertransplantation through the history ofthe development ofthis method to the latest trends and possibilities for increasing the number of liver transplants.
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7
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López-Martínez S, Simón C, Santamaria X. Normothermic Machine Perfusion Systems: Where Do We Go From Here? Transplantation 2024; 108:22-44. [PMID: 37026713 DOI: 10.1097/tp.0000000000004573] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Normothermic machine perfusion (NMP) aims to preserve organs ex vivo by simulating physiological conditions such as body temperature. Recent advancements in NMP system design have prompted the development of clinically effective devices for liver, heart, lung, and kidney transplantation that preserve organs for several hours/up to 1 d. In preclinical studies, adjustments to circuit structure, perfusate composition, and automatic supervision have extended perfusion times up to 1 wk of preservation. Emerging NMP platforms for ex vivo preservation of the pancreas, intestine, uterus, ovary, and vascularized composite allografts represent exciting prospects. Thus, NMP may become a valuable tool in transplantation and provide significant advantages to biomedical research. This review recaps recent NMP research, including discussions of devices in clinical trials, innovative preclinical systems for extended preservation, and platforms developed for other organs. We will also discuss NMP strategies using a global approach while focusing on technical specifications and preservation times.
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Affiliation(s)
- Sara López-Martínez
- Carlos Simon Foundation, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Carlos Simón
- Carlos Simon Foundation, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Department of Obstetrics and Gynecology, Universidad de Valencia, Valencia, Spain
- Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX
| | - Xavier Santamaria
- Carlos Simon Foundation, Centro de Investigación Príncipe Felipe, Valencia, Spain
- INCLIVA Biomedical Research Institute, Valencia, Spain
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8
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Durán M, Calleja R, Hann A, Clarke G, Ciria R, Nutu A, Sanabria-Mateos R, Ayllón MD, López-Cillero P, Mergental H, Briceño J, Perera MTPR. Machine perfusion and the prevention of ischemic type biliary lesions following liver transplant: What is the evidence? World J Gastroenterol 2023; 29:3066-3083. [PMID: 37346149 PMCID: PMC10280793 DOI: 10.3748/wjg.v29.i20.3066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/01/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
The widespread uptake of different machine perfusion (MP) strategies for liver transplant has been driven by an effort to minimize graft injury. Damage to the cholangiocytes during the liver donation, preservation, or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage. This problem continues to trouble clinicians, and may have catastrophic consequences for the graft and patient. Ischemic injury, as a result of compromised hepatic artery flow, is a well-known cause of biliary strictures, sepsis, and graft failure. However, very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions (ITBL) that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise. Both the warm and cold ischemic period duration appear to influence the onset of ITBL. All of the commonly used MP techniques deliver oxygen to the graft cells, and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL. As clinical experience and published evidence grows for these modalities, the impact they have on ITBL rates is important to consider. In this review, the evidence for the three commonly used MP strategies (abdominal normothermic regional perfusion [A-NRP], hypothermic oxygenated perfusion [HOPE], and normothermic machine perfusion [NMP] for ITBL prevention has been critically reviewed. Inconsistencies with ITBL definitions used in trials, coupled with variations in techniques of MP, make interpretation challenging. Overall, the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage. The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak.
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Affiliation(s)
- Manuel Durán
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Rafael Calleja
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - George Clarke
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Ruben Ciria
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Anisa Nutu
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | | | - María Dolores Ayllón
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Pedro López-Cillero
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Hynek Mergental
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Javier Briceño
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
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9
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Risbey CWG, Pulitano C. Normothermic Ex Vivo Machine Perfusion for Liver Transplantation: A Systematic Review of Progress in Humans. J Clin Med 2023; 12:jcm12113718. [PMID: 37297913 DOI: 10.3390/jcm12113718] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Liver transplantation is a lifesaving procedure for patients with end-stage liver disease (ESLD). However, many patients never receive a transplant due to insufficient donor supply. Historically, organs have been preserved using static cold storage (SCS). However, recently, ex vivo normothermic machine perfusion (NMP) has emerged as an alternative technique. This paper aims to investigate the clinical progress of NMP in humans. METHODS Papers evaluating the clinical outcomes of NMP for liver transplantation in humans were included. Lab-based studies, case reports, and papers utilizing animal models were excluded. Literature searches of MEDLINE and SCOPUS were conducted. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) and the risk of bias in nonrandomised studies for interventions (ROBINS-I) tools were used. Due to the heterogeneity of the included papers, a meta-analysis was unable to be completed. RESULTS In total, 606 records were identified, with 25 meeting the inclusion criteria; 16 papers evaluated early allograft dysfunction (EAD) with some evidence for lower rates using NMP compared to SCS; 19 papers evaluated patient or graft survival, with no evidence to suggest superior outcomes with either NMP or SCS; 10 papers evaluated utilization of marginal and donor after circulatory death (DCD) grafts, with good evidence to suggest NMP is superior to SCS. CONCLUSIONS There is good evidence to suggest that NMP is safe and that it likely affords clinical advantages to SCS. The weight of evidence supporting NMP is growing, and this review found the strongest evidence in support of NMP to be its capacity to increase the utilization rates of marginal and DCD allografts.
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Affiliation(s)
- Charles W G Risbey
- Department of Surgery, Royal Prince Alfred Hospital, Sydney 2050, Australia
- Centre for Organ Assessment, Repair & Optimization (COARO), Sydney 2050, Australia
- Central Clinical School, The University of Sydney, Sydney 2006, Australia
| | - Carlo Pulitano
- Centre for Organ Assessment, Repair & Optimization (COARO), Sydney 2050, Australia
- Central Clinical School, The University of Sydney, Sydney 2006, Australia
- Department of Transplant Surgery, Royal Prince Alfred Hospital, Sydney 2050, Australia
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10
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Sequential hypothermic and normothermic perfusion preservation and transplantation of expanded criteria donor livers. Surgery 2023; 173:846-854. [PMID: 36302699 DOI: 10.1016/j.surg.2022.07.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/02/2022] [Accepted: 07/20/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential benefits of graft viability preservation and assessment before liver transplantation. METHODS With the Food and Drug Administration and institutional review board approval, 17 expanded criteria donor livers underwent sequential hypothermic oxygenated perfusion and normothermic machine perfusion using our institutionally developed perfusion device. RESULTS Expanded criteria donor livers were from older donors, donors after cardiac death, with steatosis, hypertransaminasemia, or calcified arteries. Perfusion duration ranged between 1 and 2 hours for the hypothermic oxygenated perfusion phase and between 4 and 9 hours for the normothermic machine perfusion phase. Three livers were judged to be untransplantable during normothermic machine perfusion based on perfusate lactate, bile production, and macro-appearance. One liver was not transplanted because of recipient issue after anesthesia induction and failed reallocation. Thirteen livers were transplanted, including 9 donors after cardiac death livers (donor warm ischemia time 16-25 minutes) and 4 from donors after brain death. All livers had the standardized lactate clearance >60% (perfusate lactate cleared to <4.0 mmol/L) within 3 hours of normothermic machine perfusion. Bile production rate was 0.2 to 10.7 mL/h for donors after brain death livers and 0.3 to 6.1 mL/h for donors after cardiac death livers. After transplantation, 5 cases had early allograft dysfunction (3 donors after cardiac death and 2 donors after brain death livers). No graft failure or patient death has occurred during follow-up time of 6 to 13 months. Two livers developed ischemic cholangiopathy. Compared with our previous normothermic machine perfusion study, the bile duct had fewer inflammatory cells in histology, but the post-transplant outcomes had no difference. CONCLUSION Sequential hypothermic oxygenated perfusion and normothermic machine perfusion preservation is safe and feasible and has the potential benefits of preserving and evaluating expanded criteria donor livers.
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11
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Riveros S, Marino C, Ochoa G, Soto D, Alegría L, Zenteno MJ, San Martín S, Brañes A, Achurra P, Rebolledo R. Customized normothermic machine perfusion decreases ischemia-reperfusion injury compared with static cold storage in a porcine model of liver transplantation. Artif Organs 2023; 47:148-159. [PMID: 36007920 DOI: 10.1111/aor.14390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 07/20/2022] [Accepted: 08/09/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Liver transplantation has been demonstrated to be the best treatment for several liver diseases, while grafts are limited. This has caused an increase in waiting lists, making it necessary to find ways to expand the number of organs available for transplantation. Normothermic perfusion (NMP) of liver grafts has been established as an alternative to static cold storage (SCS), but only a small number of perfusion machines are commercially available. METHODS Using a customized ex situ machine perfusion, we compared the results between ex situ NMP and SCS preservation in a porcine liver transplant model. RESULTS During NMP, lactate concentrations were 80% lower after the 3-h perfusion period, compared with SCS. Bile production had a 2.5-fold increase during the NMP period. After transplantation, aspartate transaminase (AST) and alanine transaminase (ALT) levels were 35% less in the NMP group, compared to the SCS group. In pathologic analyses of grafts after transplant, tissue oxidation did not change between groups, but the ischemia-reperfusion injury score was lower in the NMP group. CONCLUSION NMP reduced hepatocellular damage and ischemia-reperfusion injury when compared to SCS using a customized perfusion machine. This could be an alternative for low-income countries to include machine perfusion in their therapeutic options.
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Affiliation(s)
- Sergio Riveros
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlo Marino
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gabriela Ochoa
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Dagoberto Soto
- Department of Intensive Care Unit, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leyla Alegría
- Department of Intensive Care Unit, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Sebastián San Martín
- Biomedical Research Center, School of Medicine, Universidad de Valparaíso, Valparaíso, Chile
| | - Alejandro Brañes
- Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
| | - Pablo Achurra
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rolando Rebolledo
- Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile.,Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
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12
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Outcomes of Liver Transplantation Using Machine Perfusion in Donation after Cardiac Death vs Brain Death in the US. J Am Coll Surg 2023; 236:73-80. [PMID: 36519910 DOI: 10.1097/xcs.0000000000000425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Liver transplant (LT) outcomes using machine perfusion (MP) in donation after brain death (DBD) is promising, but the LT outcomes of MP in donation after cardiac death (DCD) is limited in the US. The aim of this study was to compare LT outcomes of MP between DCD and DBD. STUDY DESIGN We analyzed data from the United Network for Organ Sharing between 2016 and 2021 among adult LT recipients. Propensity score matching was performed to assess the outcomes between DCD and DBD. RESULTS A total of 380 LTs (295 from DBD and 85 from DCD) were performed using MP. When compared with DBD, DCD group had older median recipient age (61 vs 58 years, p = 0.03), higher prevalence of diabetes (41% vs 28%, p = 0.02), lower model for end-stage liver disease score (17 vs 22, p < 0.01), longer wait time (276 vs 143 days, p < 0.01) and younger median donor age (40 vs 51 years, p < 0.01). The most common primary diagnosis was alcohol-related liver disease, and hepatocellular carcinoma was more common in the DCD group (22% vs 13%). On survival analysis, 1-year overall/graft survivals (DCD 95.4% vs DBD 92.1%, p = 0.54; DCD 91.7% vs DBD 89.8%, p = 0.86) were the same. After propensity score matching, overall/graft survivals were the same. In Cox regression analysis, DCD was not an independent risk factor of mortality (hazard ratio 0.80; 95% CI 0.25 to 2.52; p = 0.70) and graft failure (hazard ratio 0.58; 95% CI 0.17 to 1.97; p = 0.38). CONCLUSIONS In transplant recipients who underwent LT using MP, posttransplant outcomes of overall and graft survival were similar among DCD and DBD cohorts.
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13
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Where are we today with machine perfusion of liver in donation after circulatory death liver transplantation? TRANSPLANTATION REPORTS 2022. [DOI: 10.1016/j.tpr.2022.100111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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14
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Ramírez-Del Val A, Guarrera J, Porte RJ, Selzner M, Spiro M, Raptis DA, Friend PJ, Nasralla D. Does machine perfusion improve immediate and short-term outcomes by enhancing graft function and recipient recovery after liver transplantation? A systematic review of the literature, meta-analysis and expert panel recommendations. Clin Transplant 2022; 36:e14638. [PMID: 35279883 DOI: 10.1111/ctr.14638] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/28/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent evidence supports the use of machine perfusion technologies (MP) for marginal liver grafts. Their effect on enhanced recovery, however, remains uncertain. OBJECTIVES To identify areas in which MP might contribute to an ERAS program and to provide expert panel recommendations. DATA SOURCES Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS Systematic review and meta-analysis following PRISMA guidelines and recommendations using the GRADE approach. CRD42021237713 RESULTS: Both hypothermic (HMP) and normothermic (NMP) machine perfusion demonstrated significant benefits in preventing postreperfusion syndrome (PRS) (HMP OR .33, .15-.75 CI; NMP OR .51, .29-.90 CI) and early allograft dysfunction (EAD) (HMP OR .51, .35-.75 CI; NMP OR .66, .45-.97 CI), while shortening LOS (HMP MD -3.9; NMP MD -12.41). Only NMP showed a significant decrease in the length of ICU stay (L-ICU) (MD -7.07, -8.76; -5.38 CI), while only HMP diminishes the likelihood of major complications. Normothermic regional perfusion (NRP) reduces EAD (OR .52, .38-.70 CI) and primary nonfunction (PNF) (OR .51, .27-.98 CI) without effect on L-ICU and LOS. CONCLUSIONS The use of HMP decreases PRS and EAD, specifically for marginal grafts. This is supported by a shorter LOS and a lower rate of major postoperative complications (QOE; moderate | Recommendation; Strong). NMP reduces the incidence of PRS and EAD with associated shortening in L-ICU for both DBD and DCD grafts (QOE; moderate | Recommendation; High) This technology also shortens the length of hospital stay (QOE; low | Recommendation; Strong). NRP decreases the likelihood of EAD (QOE; moderate) and the risk of PNF (QOE; low) when compared to both DBD and SRR-DCD grafts preserved in SCS. (Recommendation; Strong).
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Affiliation(s)
| | - James Guarrera
- Division of Liver Transplantation and Hepatobiliary Surgery at Rutgers, New Jersey Medical School, Newark, New Jersey, USA
| | - Robert J Porte
- Department of Surgery, University of Groningen, Groningen, The Netherlands
| | - Markus Selzner
- Department of Abdominal Transplant, Toronto General Hospital, Toronto, Ontario, Canada
| | - Michael Spiro
- Department of Anaesthesia and Intensive Care Medicine, Royal Free Hospital, London, UK.,Division of Surgery and Interventional Science, University College London, London, UK
| | - Dimitri Aristotle Raptis
- Division of Surgery and Interventional Science, University College London, London, UK.,Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London, UK
| | - Peter J Friend
- Transplant Unit, Churchill Hospital, Oxford University Hospitals, Oxford, UK.,Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - David Nasralla
- Division of Surgery and Interventional Science, University College London, London, UK.,Clinical Service of HPB Surgery and Liver Transplantation, Royal Free Hospital, London, UK
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15
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Jakubauskas M, Jakubauskiene L, Leber B, Strupas K, Stiegler P, Schemmer P. Machine Perfusion in Liver Transplantation: A Systematic Review and Meta-Analysis. Visc Med 2022; 38:243-254. [PMID: 36160822 PMCID: PMC9421699 DOI: 10.1159/000519788] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/12/2021] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Liver transplantation (LTx) is the only treatment option for patients with end-stage liver disease. Novel organ preservation techniques such as hypothermic machine perfusion (HMP) or normothermic machine perfusion (NMP) are under investigation in order to improve organ quality from extended criteria donors and donors after circulatory death. The aim of this study was to systematically review the literature reporting LTx outcomes using NMP or HMP compared to static cold storage (SCS). METHODS The following data were retrieved: graft primary nonfunction rate, early allograft dysfunction (EAD) rate, biliary complication rate, and 12-month graft and patient survival. A total of 15 studies were included (6 NMP and 9 HMP studies), and meta-analysis was performed only for HMP studies because NMP had considerable differences. RESULTS The systematic review showed the potential of NMP to reduce graft injury and lower the liver graft discard rate. The performed quantitative analyses showed that the use of HMP reduces the rate of EAD (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.34-0.76; p = 0.001; I 2 = 0%) and non-anastomotic biliary strictures (OR 0.34; 95% CI 0.17-0.67; p = 0.002; I 2 = 0%) compared to SCS. CONCLUSION Our systematic review and meta-analysis revealed that the use of HMP reduces the rate of EAD and non-anastomotic biliary strictures compared to SCS.
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Affiliation(s)
- Matas Jakubauskas
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Lina Jakubauskiene
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Bettina Leber
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | | | - Philipp Stiegler
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Peter Schemmer
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
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16
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Croome KP, Mao S, Taner CB. The Current Landscape of Liver Transplantation After Ex Situ Machine Perfusion and Normothermic Regional Perfusion in the United States. Liver Transpl 2022; 28:1108-1112. [PMID: 35000268 DOI: 10.1002/lt.26404] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/17/2021] [Accepted: 12/27/2021] [Indexed: 12/23/2022]
Affiliation(s)
| | - Shennen Mao
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
| | - C Burcin Taner
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
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17
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De Simone P, Ghinolfi D. Hospital-Based Health Technology Assessment of Machine Perfusion Systems for Human Liver Transplantation. Transpl Int 2022; 35:10405. [PMID: 35692735 PMCID: PMC9184439 DOI: 10.3389/ti.2022.10405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 05/05/2022] [Indexed: 01/14/2023]
Abstract
Based on published data, we have carried out a hospital-based health technology assessment of machine perfusion in adult liver transplantation using cold storage as a comparator, and within the perspective of a national health system-based hospital practice and disease-related group reimbursement policy. A systematic literature review on machine perfusion for adult liver transplantation was conducted exploring the Pubmed, CINAHL, Scopus, Embase, and Cochrane databases. The literature was analyzed with the intent to provide information on 6 dimensions and 19 items of the hospital-based health technology assessment framework derived from previous studies. Out of 705 references, 47 (6.7%) were retained for current analysis. Use of machine perfusion was associated with advantages over cold storage, i.e., a 10%–50% reduced risk for early allograft dysfunction, 7%–15% less ischemia reperfusion injury; 7%–50% fewer ischemic biliary complications, comparable or improved 1-year graft and patient survival, and up to a 50% lower graft discard rate. Hospital stay was not longer, and technical failures were anecdotal. Information on costs of machine perfusion is limited, but this technology is projected to increase hospital costs while cost-effectiveness analysis requires data over the transplant patient lifetime. No hospital-based health technology assessment study on machine perfusion in liver transplantation was previously conducted. From the hospital perspective, there is evidence of the clinical advantages of this novel technology, but strategies to counterbalance the increased costs of liver transplantation are urgently needed. Further studies should focus on the ethical, social, and organizational issues related to machine perfusion.
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Affiliation(s)
- Paolo De Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
- Department of Surgical, Medical, Biomolecular Pathology and Intensive Care Unit, University of Pisa, Pisa, Italy
- *Correspondence: Paolo De Simone,
| | - Davide Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
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18
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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: 28] [Impact Index Per Article: 9.3] [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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19
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Abraham N, Zhang M, Cray P, Gao Q, Samy KP, Neill R, Cywinska G, Migaly J, Kahan R, Pontula A, Halpern SE, Rush C, Penaflor J, Kesseli SJ, Krischak M, Song M, Hartwig MG, Pollara JJ, Barbas AS. Two Compartment Evaluation of Liver Grafts During Acellular Room Temperature Machine Perfusion (acRTMP) in a Rat Liver Transplant Model. Front Med (Lausanne) 2022; 9:804834. [PMID: 35280912 PMCID: PMC8907827 DOI: 10.3389/fmed.2022.804834] [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: 10/29/2021] [Accepted: 01/25/2022] [Indexed: 11/24/2022] Open
Abstract
Background Subnormothermic machine perfusion (SNMP) of liver grafts is currently less clinically developed than normothermic and hypothermic approaches, but may have logistical advantages. At intermediate temperatures, the oxygen demand of the graft is low enough to be satisfied with an acellular perfusate, obviating the need for oxygen carrying molecules. This intermediate metabolic rate, however, is sufficient to support the production of bile, which is emerging as an important indicator of graft injury and viability. In this study, we hypothesized that the biliary compartment would be more sensitive than perfusate in detecting graft injury during SNMP. Methods To test this hypothesis in a rat model, we performed liver transplants with DCD and control liver grafts after 1 h of acellular room temperature machine perfusion (acRTMP) or static cold storage (SCS). Point of care liver function tests were measured in biliary and perfusate samples after 1 h of machine perfusion. Following transplantation, rats were sacrificed at 24 h for assessment of post-transplant graft function and histology. Results All point-of-care liver function tests were significantly more concentrated in the biliary compartment than the perfusate compartment during acRTMP. DCD liver grafts could be distinguished from control liver grafts by significantly higher markers of hepatocyte injury (AST, ALT) in the biliary compartment, but not in the perfusate compartment. Classical markers of cholangiocyte injury, such as gammy-glut amyl transferase (GGT), amylase (AML), and alkaline phosphatase were detectable in the biliary compartment, but not in the perfusate compartment. In comparison to SCS, graft preservation by acRTMP produced a significant survival benefit in DCD liver transplantation (75 vs. 0%, p < 0.0030). Conclusion Together, these findings demonstrate that during acRTMP, the biliary compartment may be a more sensitive indicator of graft injury than the perfusate compartment. Moreover, acRTMP provides superior graft preservation to SCS in rat DCD liver transplantation.
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Affiliation(s)
- Nader Abraham
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Min Zhang
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Paul Cray
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Qimeng Gao
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Kannan P Samy
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Ryan Neill
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Greta Cywinska
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - JonCarlo Migaly
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Riley Kahan
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Arya Pontula
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Samantha E Halpern
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Caroline Rush
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Jude Penaflor
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Samuel J Kesseli
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Madison Krischak
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Mingqing Song
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Matthew G Hartwig
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Justin J Pollara
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| | - Andrew S Barbas
- Duke Ex-Vivo Organ Lab (DEVOL) - Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
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20
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Quintini C, Del Prete L, Simioni A, Del Angel L, Diago Uso T, D'Amico G, Hashimoto K, Aucejo F, Fujiki M, Eghtesad B, Sasaki K, Kwon CHD, Cywinski J, Bennett A, Bilancini M, Miller C, Liu Q. Transplantation of declined livers after normothermic perfusion. Surgery 2022; 171:747-756. [PMID: 35065791 DOI: 10.1016/j.surg.2021.10.056] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/29/2021] [Accepted: 10/27/2021] [Indexed: 01/07/2023]
Abstract
BACKGROUND The persistent shortage of liver allografts contributes to significant waitlist mortality despite efforts to increase organ donation. Normothermic machine perfusion holds the potential to enhance graft preservation, extend viability, and allow liver function evaluation in organs previously discarded because considered too high-risk for transplant. METHODS Discarded livers from other transplant centers were transplanted after assessment and reconditioning with our institutionally developed normothermic machine perfusion device. We report here our preliminary data. RESULTS Twenty-one human livers declined for transplantation were enrolled for assessment with normothermic machine perfusion. Six livers (28.5%) were ultimately discarded after normothermic machine perfusion because of insufficient lactate clearance (>4.1 mmol/L after 4 hours), limited bile production (<0.5 mI/h), or moderate macrosteatosis, whereas 15 (71.5%) were considered suitable for transplantation. Normothermic machine perfusion duration was from 3 hours, 49 minutes to 10 hours, 29 minutes without technical problems or adverse events. No intraoperative or major early postoperative complications occurred in all transplanted recipients. No primary nonfunction occurred after transplantation. Seven livers had early allograft dysfunction with fast recovery, and 1 patient developed ischemic cholangiopathy after 4 months treated with biliary stents. All other patients had good liver function with a follow-up time of 8 weeks to 14 months. CONCLUSION In total, 71.5% of discarded livers subjected to ex vivo normothermic machine perfusion were successfully transplanted after organ perfusion and assessment using an institutionally built device. This study challenges the current viability criteria reported in the literature and calls for a standardization of viability markers collection, an essential condition for the advancement of the field.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Masato Fujiki
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | | | | | | | - Ana Bennett
- Transplantation Center, Cleveland Clinic, Cleveland, OH
| | | | | | - Qiang Liu
- Transplantation Center, Cleveland Clinic, Cleveland, OH
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21
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Liu Q, Del Prete L, Hassan A, Pezzati D, Bilancini M, D'Amico G, Diago Uso T, Hashimoto K, Aucejo F, Fujiki M, Sasaki K, Kwon CHD, Eghtesad B, Miller C, Quintini C. Two pumps or one pump? A comparison of human liver normothermic machine perfusion devices for transplantation. Artif Organs 2021; 46:859-866. [PMID: 34904245 DOI: 10.1111/aor.14150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Normothermic machine perfusion provides continuous perfusion to ex situ hepatic grafts through the portal vein and the hepatic artery. Because the portal vein has high flow with low pressure and the hepatic artery has low flow with high pressure, different types of perfusion machines have been employed to match the two vessels' infusion hemodynamics. METHODS We compared transplanted human livers perfused through a 2-pump (n = 9) versus a 1-pump perfusion system (n = 6) where a C-clamp is used as a tubing constrictor to regulate hemodynamics. RESULTS There was no significant difference between groups in portal vein or hepatic artery flow rate. The 1-pump group had more hemoglobin in the perfusate. However, there was no significant difference in plasma hemoglobin between the 2-pump and 1-pump groups at each time point or in the change in levels, proving no hemolysis occurred due to C-clamp tube constriction. After transplantation, the 2-pump group had two cases of early allograft dysfunction (EAD), whereas the 1-pump group had no EAD. There was no graft failure or patient death in either group during follow-up ranging from 20-52 months. CONCLUSIONS Our data show that the 1-pump design provided the same hemodynamic output as the 2-pump design, with no additional hemolytic risk, but with the benefits of lower costs, easier transport and faster and simpler setting.
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Affiliation(s)
- Qiang Liu
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Luca Del Prete
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Ahmed Hassan
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Daniele Pezzati
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Mary Bilancini
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | | | | | - Koji Hashimoto
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Federico Aucejo
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Masato Fujiki
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kazunari Sasaki
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Bijan Eghtesad
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Charles Miller
- Transplantation Center, Cleveland Clinic, Cleveland, Ohio, USA
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22
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Liew B, Nasralla D, Iype S, Pollok JM, Davidson B, Raptis DA. Liver transplant outcomes after ex vivo machine perfusion: a meta-analysis. Br J Surg 2021; 108:1409-1416. [PMID: 34791070 DOI: 10.1093/bjs/znab364] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/15/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND The pressure on liver-transplant programmes has expanded the usage of extended-criteria allografts. Machine perfusion may be better than conventional static cold storage (SCS) in alleviating ischaemia-reperfusion injury in this setting. Recipient outcomes with hypothermic or normothermic machine perfusion were assessed against SCS here. METHODS A search in MEDLINE, EMBASE and Scopus was conducted in February 2021. Primary studies investigating ex vivo machine perfusion were assessed for the following outcomes: morbidity, ICU and hospital stay, graft and patient survival rates and relative costs. Meta-analysis was performed to obtain pooled summary measures. RESULTS Thirty-four articles involving 1742 patients were included, of which 20 were used for quantitative synthesis. Odds ratios favoured hypothermic machine perfusion (over SCS) with less early allograft dysfunction, ischaemic cholangiopathy, non-anastomotic strictures and graft loss. Hypothermic machine perfusion was associated with a shorter hospital stay and normothermic machine perfusion with reduced graft injury. Two randomized clinical trials found normothermic machine perfusion reduced major complication risks. CONCLUSION Machine perfusion assists some outcomes with potential cost savings.
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Affiliation(s)
- Belle Liew
- Division of Surgery & Interventional Science, University College London, London, UK
| | - David Nasralla
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Satheesh Iype
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Joerg-Matthias Pollok
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Brian Davidson
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Dimitri A Raptis
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
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23
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Riveros S, Marino C, Ochoa G, Morales E, Soto D, Alegría L, Zenteno MJ, Brañes A, Achurra P, Rebolledo RA. Implementation and design of customized ex vivo machine perfusion. Analysis of its first results. Artif Organs 2021; 46:210-218. [PMID: 34519358 DOI: 10.1111/aor.14060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 12/14/2022]
Abstract
The lack of organs available for transplantation is a global problem. The high mortality rates on the waiting list and the high number of discarded livers are reasons to develop new tools in the preservation and transplantation process. New tools should also be available for low-income countries. This article reports the development of customized normothermic machine perfusion (NMP). An ex vivo dual perfusion machine was designed, composed of a common reservoir organ box (CRO), a centrifugal pump (portal system, low pressure), and a roller pump (arterial system, high pressure). Porcine livers (n = 5) were perfused with an oxygenated normothermic (37℃) strategy for 3 hours. Hemodynamic variables, metabolic parameters, and bile production during preservation were analyzed. Arterial and portal flow remain stable during perfusion. Total bilirubin production was 11.25 mL (4-14.5) at 180 minutes. The median pH value reached 7.32 (7.25-7.4) at 180 minutes. Lactate values decreased progressively to normalization at 120 minutes. This perfusion setup was stable and able to maintain the metabolic activity of a liver graft in a porcine animal model. Design and initial results from this customized NMP are promising for a future clinical application in low-income countries.
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Affiliation(s)
- Sergio Riveros
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlo Marino
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gabriela Ochoa
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Emilio Morales
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Dagoberto Soto
- Department of Intensive Care, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leyla Alegría
- Department of Intensive Care, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Alejandro Brañes
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
| | - Pablo Achurra
- Department of Digestive Surgery, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rolando A Rebolledo
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.,Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río, Santiago, Chile
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24
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van Beekum CJ, Vilz TO, Glowka TR, von Websky MW, Kalff JC, Manekeller S. Normothermic Machine Perfusion (NMP) of the Liver - Current Status and Future Perspectives. Ann Transplant 2021; 26:e931664. [PMID: 34426566 PMCID: PMC8400594 DOI: 10.12659/aot.931664] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/21/2021] [Indexed: 12/24/2022] Open
Abstract
A shortage of available organs for liver transplantation has led transplant surgeons and researchers to seek for innovative approaches in hepatoprotection and improvement of marginal allografts. The most exciting development in the past decade has been continuous mechanical perfusion of livers with blood or preservation solution to mitigate ischemia-reperfusion injury in contrast to the current standard of static cold storage. Two variations of machine perfusion have emerged in clinical practice. During hypothermic oxygenated perfusion the liver is perfused using a red blood cell-free perfusate at 2-10°C. In contrast, normothermic machine perfusion mimics physiologic liver perfusion using a red blood cell-based solution at 35.5-037.5°C, offering a multitude of potential advantages. Putative effects of normothermic perfusion include abrogation of hyperfibrinolysis after reperfusion and inflammation, glycogen repletion, and regeneration of adenosine triphosphate. Research in normothermic machine perfusion focuses on development of biomarkers predicting allograft quality and susceptibility to ischemia-reperfusion injury. Moreover, normothermic perfusion of marginal allografts allows for application of a variety of therapeutic interventions potentially enhancing organ quality. Both methods need to be subjected to translational investigation and evaluation in clinical trials. A clear advantage is transformation of an emergency procedure at night into a planned daytime surgery. Current clinical trials suggest that normothermic perfusion not only increases the use of hepatic allografts but is also associated with milder ischemia-reperfusion injury, resulting in a reduced risk of early allograft dysfunction and less biliary complications, including ischemic cholangiopathy, compared to static cold storage. The aim of this review is to give a concise overview of normothermic machine perfusion and its current applications, benefits, and possible advances in the future.
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25
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Koritzinsky EH, Tsuda H, Fairchild RL. Endogenous memory T cells with donor-reactivity: early post-transplant mediators of acute graft injury in unsensitized recipients. Transpl Int 2021; 34:1360-1373. [PMID: 33963616 PMCID: PMC8389524 DOI: 10.1111/tri.13900] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/15/2021] [Accepted: 05/03/2021] [Indexed: 11/29/2022]
Abstract
The pretransplant presence of endogenous donor-reactive memory T cells is an established risk factor for acute rejection and poorer transplant outcomes. A major source of these memory T cells in unsensitized recipients is heterologously generated memory T cells expressing reactivity to donor allogeneic MHC molecules. Multiple clinical studies have shown that the pretransplant presence of high numbers of circulating endogenous donor-reactive memory T cells correlates with higher incidence of acute rejection and decreased graft function during the first-year post-transplant. These findings have spurred investigation in preclinical models to better understand mechanisms underlying endogenous donor-reactive memory T-cell-mediated allograft injury in unsensitized graft recipients. These studies have led to the identification of unique mechanisms underlying the activation of these memory T cells within allografts at early times after transplant. In particular, optimal activation to mediate acute allograft injury is dependent on the intensity of ischaemia-reperfusion injury. Therapeutic strategies directed at the recruitment and activation of endogenous donor-reactive memory T cells are effective in attenuating acute injury in allografts experiencing increased ischaemia-reperfusion injury in preclinical models and should be translatable to clinical transplantation.
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Affiliation(s)
- Erik H. Koritzinsky
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Hidetoshi Tsuda
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Robert L. Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Transplant Center, Cleveland Clinic, Cleveland, OH
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
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26
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Martins PN, Rizzari MD, Ghinolfi D, Jochmans I, Attia M, Jalan R, Friend PJ. Design, Analysis, and Pitfalls of Clinical Trials Using Ex Situ Liver Machine Perfusion: The International Liver Transplantation Society Consensus Guidelines. Transplantation 2021; 105:796-815. [PMID: 33760791 DOI: 10.1097/tp.0000000000003573] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Recent trials in liver machine perfusion (MP) have revealed unique challenges beyond those seen in most clinical studies. Correct trial design and interpretation of data are essential to avoid drawing conclusions that may compromise patient safety and increase costs. METHODS The International Liver Transplantation Society, through the Special Interest Group "DCD, Preservation and Machine Perfusion," established a working group to write consensus statements and guidelines on how future clinical trials in liver perfusion should be designed, with particular focus on relevant clinical endpoints and how different techniques of liver perfusion should be compared. Protocols, abstracts, and full published papers of clinical trials using liver MP were reviewed. The use of a simplified Grading of Recommendations Assessment, Development, and Evaluation working group (GRADE) system was attempted to assess the level of evidence. The working group presented its conclusions at the International Liver Transplantation Society consensus conference "DCD, Liver Preservation, and Machine Perfusion" held in Venice, Italy, on January 31, 2020. RESULTS Twelve recommendations were proposed with the main conclusions that clinical trials investigating the effect of MP in liver transplantation should (1) make the protocol publicly available before the start of the trial, (2) be adequately powered, and (3) carefully consider timing of randomization in function of the primary outcome. CONCLUSIONS There are issues with using accepted primary outcomes of liver transplantation trials in the context of MP trials, and no ideal endpoint could be defined by the working group. The setup of an international registry was considered vital by the working group.
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Affiliation(s)
- Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, University of Massachusetts Memorial Hospital, University of Massachusetts, Worcester, MA
| | - Michael D Rizzari
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, MI
| | - Davide Ghinolfi
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Ina Jochmans
- Transplantation Research Group, Lab of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium
- Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Magdy Attia
- Department of Hepatobiliary & Transplantation Surgery, Leeds Teaching Hospitals Trust, Leeds, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, London, United Kingdom
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
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27
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Current review of machine perfusion in liver transplantation from the Japanese perspective. Surg Today 2021; 52:359-368. [PMID: 33754175 DOI: 10.1007/s00595-021-02265-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 02/21/2021] [Indexed: 12/11/2022]
Abstract
In light of the present evidence, machine perfusion is opening up new horizons in the field of liver transplantation. Although many advances have been made in liver transplantation, organ preservation methods have so far changed very little. Static cold storage is universally used for graft preservation in liver transplantation; however, there is a need for better preservation methods, such as ex vivo machine perfusion, to improve the outcomes by decreasing warm ischemic damage. Based on the findings of basic and clinical trials, hypothermic and normothermic machine perfusion techniques are now commercially available and include the OrganOx metra, Liver Assist, Cleveland NMP device, Organ Care System, and LifePort Liver. Recent clinical trials have provided further evidence for the potential role of normothermic machine perfusion to resuscitate and subsequently improve utilization of marginal or currently discarded livers. Further studies are required to explore the longer-term outcomes, late biliary complications, outcomes in specific high-risk groups, viability biomarkers, optimum and maximum perfusion duration, perfusate composition, and liver-directed therapeutic interventions during normothermic machine perfusion. The use of organs from marginal donors after brain death, such as fatty livers and the livers from elderly donors with multiple comorbidities, may be accepted for machine perfusion in Japan in the near future.
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28
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Michelotto J, Gassner JMGV, Moosburner S, Muth V, Patel MS, Selzner M, Pratschke J, Sauer IM, Raschzok N. Ex vivo machine perfusion: current applications and future directions in liver transplantation. Langenbecks Arch Surg 2021; 406:39-54. [PMID: 33216216 PMCID: PMC7870621 DOI: 10.1007/s00423-020-02014-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Liver transplantation is the only curative treatment option for end-stage liver disease; however, its use remains limited due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation, as a means to expand the donor organ pool. PURPOSE To present a systematic review of prospective clinical studies on ex vivo liver machine perfusion, in order to assess current applications and highlight future directions. METHODS A systematic literature search of both PubMed and ISI web of science databases as well as the ClinicalTrials.gov registry was performed. RESULTS Twenty-one articles on prospective clinical trials on ex vivo liver machine perfusion were identified. Out of these, eight reported on hypothermic, eleven on normothermic, and two on sequential perfusion. These trials have demonstrated the safety and feasibility of ex vivo liver machine perfusion in both standard and expanded criteria donors. Currently, there are twelve studies enrolled in the clinicaltrials.gov registry, and these focus on use of ex vivo perfusion in extended criteria donors and declined organs. CONCLUSION Ex vivo liver machine perfusion seems to be a suitable strategy to expand the donor pool for liver transplantation and holds promise as a platform for reconditioning diseased organs.
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Affiliation(s)
- Julian Michelotto
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Joseph M G V Gassner
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Simon Moosburner
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Vanessa Muth
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Madhukar S Patel
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, ON, Canada
| | - Markus Selzner
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, ON, Canada
| | - Johann Pratschke
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Igor M Sauer
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Nathanael Raschzok
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany.
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, ON, Canada.
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29
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Gao J, He K, Xia Q, Zhang J. Research progress on hepatic machine perfusion. Int J Med Sci 2021; 18:1953-1959. [PMID: 33850464 PMCID: PMC8040389 DOI: 10.7150/ijms.56139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/12/2021] [Indexed: 01/08/2023] Open
Abstract
Nowadays, liver transplantation is the most effective treatment for end-stage liver disease. However, the increasing imbalance between growing demand for liver transplantation and the shortage of donor pool restricts the development of liver transplantation. How to expand the donor pool is a significant problem to be solved clinically. Many doctors have devoted themselves to marginal grafting, which introduces livers with barely passable quality but a high risk of transplant failure into the donor pool. However, existing common methods of preserving marginal grafts lead to both high risk of postoperative complications and high mortality. The application of machine perfusion allows surgeons to make marginal livers meet the standard criteria for transplant, which shows promising prospect in preserving and repairing donor livers and improving ischemia reperfusion injury. This review summarizes the progress of recent researches on hepatic machine perfusion.
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Affiliation(s)
- Junda Gao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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30
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Bonaccorsi-Riani E, Brüggenwirth IMA, Buchwald JE, Iesari S, Martins PN. Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials. Semin Liver Dis 2020; 40:264-281. [PMID: 32557478 DOI: 10.1055/s-0040-1713118] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.
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Affiliation(s)
- E Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.,Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium
| | - I M A Brüggenwirth
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J E Buchwald
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
| | - S Iesari
- Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - P N Martins
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
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31
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Jia J, Nie Y, Li J, Xie H, Zhou L, Yu J, Zheng SS. A Systematic Review and Meta-Analysis of Machine Perfusion vs. Static Cold Storage of Liver Allografts on Liver Transplantation Outcomes: The Future Direction of Graft Preservation. Front Med (Lausanne) 2020; 7:135. [PMID: 32528963 PMCID: PMC7247831 DOI: 10.3389/fmed.2020.00135] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/30/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Machine perfusion (MP) and static cold storage (CS) are two prevalent methods for liver allograft preservation. However, the preferred method remains controversial. Aim: To conduct a meta-analysis on the impact of MP preservation on liver transplant outcome. Methods: PubMed, EMBASE, and Cochrane Library databases were systematically searched to identify relevant trials comparing the efficacy of MP vs. CS. Odds ratios (OR) and fixed-effects models were calculated to compare the pooled data. Results: Ten prospective cohort studies and two randomized controlled trials (RCTs) were included (MP livers vs. CS livers = 315:489). Machine perfusion demonstrated superior outcomes in posttransplantation aspartate aminotransferase levels compared to CS (P < 0.05). The overall incidence of early allograft dysfunction (EAD) was significantly reduced with MP preservation than CS [OR = 0.46; 95% confidence interval (CI) = 0.31–0.67; P < 0.0001]. The incidence of total biliary complications (OR = 0.53; 95% CI = 0.34–0.83; P = 0.006) and that of ischemic cholangiopathy (OR = 0.39; 95% CI = 0.18–0.85; P = 0.02) were significantly lower in recipients with MP preservation compared with CS preservation. Hypothermic machine perfusion (HMP) but not normothermic machine perfusion (NMP) was found to significantly protect grafts from total biliary complications and ischemic cholangiopathy (P < 0.05). However, no significant differences could be detected utilizing either HMP or NMP in primary nonfunction, hepatic artery thrombosis, postreperfusion syndrome, 1-year patient survival, or 1-year graft survival (P > 0.05). Conclusions: Machine perfusion is superior to CS on improving short-term outcomes for human liver transplantation, with a less clear effect in the longer term. Hypothermic machine perfusion but not NMP conducted significantly protective effects on EAD and biliary complications. Further RCTs are warranted to confirm MP's superiority and applications.
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Affiliation(s)
- Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Yu Nie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Jianhui Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Jun Yu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, College of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
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