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Fan L, Xia H, Peng G, Wang W, Fu Z, Ye Q. A Novel Machine Perfusion System for Enhancing Hepatic Microcirculation Perfusion. Artif Organs 2025; 49:582-591. [PMID: 39740084 DOI: 10.1111/aor.14930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 11/19/2024] [Accepted: 12/09/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Machine perfusion is a promising strategy for safeguarding liver transplants donated after cardiac death (DCD). In this study, we developed and validated a novel machine perfusion approach for mitigating risk factors and salvaging severe DCD livers. METHODS A novel hypothermic oxygenated perfusion (HOPE) system was developed, incorporating two pumps and an elastic water sac to emulate the functionality of the cardiac cycle. Compared to conventional systems (HOPE S1 and S2), the novel HOPE system (HOPE S3) was evaluated in rats, utilizing healthy livers perfused with methylene blue diluted using Histidine-tryptophan-ketoglutarate (HTK) solution or DCD livers subjected to 60 min of warm ischemia without heparin administration. Liver perfusion outcomes were assessed through macroscopic and microscopic evaluations, molecular analyses, and orthotopic liver transplantation (OLT). RESULTS DCD livers subjected to HOPE systems' perfusion exhibited decreased injury and enhanced survival rates compared to static cold storage following 60 min of warm ischemia (DCD + SCS). The 4-week post-transplantation survival rates were 0%, 20%, and 33% in the DCD + SCS, HOPE S1, and HOPE S2 groups, respectively. HOPE S3 conferred protection against hepatocyte and non-parenchymal cell injury, resulting in a 67% animal survival rate following 60 min of warm donor ischemia (HOPE S3). Assessments of hepatic sinusoidal microcirculation, morphological changes, and molecular alterations in preserved livers further confirmed these findings. CONCLUSIONS The newly devised machine perfusion system can enhance and uniform liver perfusion and may become a promising tool for revitalizing DCD liver grafts afflicted with severe warm ischemic injuries.
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Affiliation(s)
- Lin Fan
- Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Hubei Key Laboratory of Medical Technology on Transplantation, National Quality Control Center for Donated Organ Procurement, Transplant Center of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Haoyang Xia
- Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Hubei Key Laboratory of Medical Technology on Transplantation, National Quality Control Center for Donated Organ Procurement, Transplant Center of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Guizhu Peng
- Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Hubei Key Laboratory of Medical Technology on Transplantation, National Quality Control Center for Donated Organ Procurement, Transplant Center of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Weiyu Wang
- Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Hubei Key Laboratory of Medical Technology on Transplantation, National Quality Control Center for Donated Organ Procurement, Transplant Center of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhen Fu
- Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Hubei Key Laboratory of Medical Technology on Transplantation, National Quality Control Center for Donated Organ Procurement, Transplant Center of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Qifa Ye
- Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Hubei Key Laboratory of Medical Technology on Transplantation, National Quality Control Center for Donated Organ Procurement, Transplant Center of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- National Health Commission Key Laboratory of Translational Research on Transplantation Medicine, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, China
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Elgosbi M, Kurt AS, Londoño MC, Caballero-Marcos A, Lim TY, Lozano JJ, Dave M, Heaton N, Sánchez-Fueyo A, Cortes-Cerisuelo M. Hypothermic oxygenated machine perfusion influences the immunogenicity of donor livers in humans. Liver Transpl 2025; 31:311-322. [PMID: 39172015 DOI: 10.1097/lvt.0000000000000461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 08/06/2024] [Indexed: 08/23/2024]
Abstract
Hypothermic oxygenated machine perfusion (HOPE) is an organ preservation strategy shown to reduce ischemia-reperfusion injury (IRI)-related complications following liver transplantation. In animal models, HOPE can also decrease alloimmune responses after transplantation, but this remains to be evaluated in humans. Our study, involving 27 patients undergoing liver transplantation enrolled in 2 randomized controlled trials comparing static cold storage with HOPE (14 HOPE-treated and 13 static cold storage-treated), delves into the impact of HOPE on the molecular profile of liver allografts and on the immune responses elicited after transplantation. Following HOPE treatment, fewer intrahepatic immune cells were observed in liver perfusates compared to static cold storage. Analysis of liver tissue transcriptome at reperfusion revealed an effect of HOPE on the reactive oxygen species pathway. Two weeks after transplantation, HOPE recipients exhibited increased circulating CD4+FOXP3+CD127lo regulatory T cells ( p < 0.01), which corresponded to a higher frequency of donor-specific regulatory T cells ( p < 0.01) and was followed by reduced alloreactivity index of CD8+ T cells 3 months after transplant. Our study provides novel mechanistic insight into the capacity of HOPE to influence liver ischemia-reperfusion injury and to modulate effector and regulatory donor-specific T-cell responses after transplantation. These findings, which confirm observations made in animal models, help explain the decreased rejection rates reported in patients receiving HOPE-treated allografts.
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Affiliation(s)
- Marwa Elgosbi
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
| | - Ada Sera Kurt
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
| | - Maria-Carlota Londoño
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
- Liver Unit, Hospital Clínic Barcelona, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelonna, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain
| | - Aranzazu Caballero-Marcos
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
| | - Tiong Yeng Lim
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
| | - Juan J Lozano
- Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Carlos III Health Institute, Barcelona, Spain
| | - Mona Dave
- Clinical Perfusion Service, Institute of Liver Studies, King's College Hospital, London, UK
| | - Nigel Heaton
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
- Department of Liver Transplant Surgery, Institute of Liver Studies, King's College Hospital, London, UK
| | - Alberto Sánchez-Fueyo
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
| | - Miriam Cortes-Cerisuelo
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences at King's College London University and Hospital, UK
- Department of Liver Transplant Surgery, Institute of Liver Studies, King's College Hospital, London, UK
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Morawski M, Zhylko A, Kubiszewski H, Rochoń J, Rykowski P, Staszewski M, Krasnodębski M, Figiel W, Krawczyk M, Grąt M. Normothermic Machine Perfusion in Orphan Liver Graft Viability Assessment. J Clin Med 2025; 14:777. [PMID: 39941448 PMCID: PMC11818235 DOI: 10.3390/jcm14030777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/31/2024] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Liver transplantation constitutes a well-established treatment for patients with end-stage liver disease and selected hepatic malignancies. The introduction of normothermic machine perfusion (NMP) offers a platform for both extracorporeal organ maintenance and viability assessment, especially for organs with suspicious malfunction. These organs, discarded by the majority of transplant centers (so-called 'orphan livers'), may help to safely expand the donor pool thanks to pre-transplant appraisal; Methods: We identified all grafts undergoing normothermic ma-chine perfusions performed in the Department of General, Transplant, and Liver Surgery between December 2022 and August 2023. Their perfusion characteristics and immediate postoperative periods, as well as complications that occurred in the 90-day postoperative periods, were analyzed; Results: There were eight orphan liver grafts that underwent NMP in our Department. Postoperative complications occurring in patients receiving grafts after NMP did not seem associated with the procedure. One patient required laparotomy within the 90-day postoperative period due to biliary fistula and underwent bile duct stenting due to both fistula and nonanastomotic stricture. In one patient we observed the occurrence of anastomotic biliary stricture more than 90 days after LTx; Conclusions: NMP allows for the viability assessment of grafts with suspicious prepreservation malfunction. Some of these organs may help to expand the donor pool.
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Affiliation(s)
- Marcin Morawski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.Z.); (H.K.); (J.R.); (P.R.); (M.S.); (M.K.); (W.F.); (M.K.); (M.G.)
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Yu J, Yunhua T, Guo Y, Dong Y, Gong JL, Wang T, Chen Z, Chen M, Ju W, He X. Beyond graft function impairment after liver transplantation: the prolonged cold ischemia time impact on recurrence of hepatocellular carcinoma after liver transplantation-a single-center retrospective study. PeerJ 2024; 12:e18126. [PMID: 39376229 PMCID: PMC11457873 DOI: 10.7717/peerj.18126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 08/28/2024] [Indexed: 10/09/2024] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) is one of the malignant tumors responsible for high mortality and recurrence rates. Although liver transplantation (LT) is an effective treatment option for HCC, ischemia-reperfusion injury (IRI) is a contributor to HCC recurrence after LT. Moreover, prolonged cold ischemia time (CIT) is a risk factor for IRI during LT, and there is insufficient clinical evidence regarding the impact of CIT on HCC recurrence after LT. Patients and Methods This retrospective study analyzed 420 patients who underwent LT for HCC between February 2015 and November 2020 at The First Affiliated Hospital, Sun Yat-sen University. The duration of CIT was defined as the time from clamping of the donor aorta until portal reperfusion. Results A total of 133 patients (31.7%) experienced tumor recurrence after LT, and CIT > 568 min was the independent risk factor for HCC recurrence (OR, 2.406; 95% CI [1.371-4.220]; p = 0.002). Multivariate Cox's regression analysis revealed that the recipients' gender, exceeding Milan criteria, poor differentiation, and alpha-fetoprotein (AFP) ≥400 ng/ml in CIT > 568 min group were independent risk factors for disease-free survival. The peak 7-day postoperative alanine aminotransferase (ALT) level (p < 0.001), the peak 7-day postoperative aspartate aminotransferase (AST) level (p < 0.001), the peak 7-day postoperative peak total bilirubin (TBIL) level (p = 0.012), and the incidence of early allograft dysfunction (EAD) (p = 0.006) were significantly higher in the CIT > 568 min group compared to the CIT ≤ 568 min group. Moreover, the amount of fresh frozen plasma (FFP) infusion during the operation increased (p = 0.02), and the time of mechanical ventilation postoperative was longer (p = 0.045). Conclusion An effective strategy to improve the prognosis is to reduce CIT; this strategy lowers the recurrence of HCC in patients undergoing LT, especially those within the Milan criteria.
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Affiliation(s)
- Jia Yu
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
- The First Affiliated Hospital of University of South China, Hengyang, China
| | - Tang Yunhua
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Yiwen Guo
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Yuqi Dong
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | | | - Tielong Wang
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Zhitao Chen
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Weiqiang Ju
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Xiaoshun He
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
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Risbey CWG, Thomas C, Niu A, Liu K, Crawford M, Pulitano C. Hypothermic Oxygenated machine PErfusion for high-risk liver grafts for transplantation: A systematic review and meta-analysis. Artif Organs 2024; 48:1085-1099. [PMID: 39418539 DOI: 10.1111/aor.14814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/22/2024] [Accepted: 06/11/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Hypothermic Oxygenated machine PErfusion (HOPE) can reduce ischemic reperfusion injury and improve outcomes for liver transplant recipients. However, the effect of HOPE on high-risk extended criteria donor (ECD) and donation after circulatory death determination (DCDD) grafts is incomplete, despite the expectation that this cohort benefit maximally from HOPE. Accordingly, this paper aims to characterize the effect of HOPE on ECD and DCDD grafts. METHODS This study includes all papers comparing HOPE to static cold storage for high-risk ECD and DCDD grafts. Systematic searches of Medline, Embase, and Scopus were completed using the terms "HOPE" OR "hypothermic oxygenated machine perfusion" AND "liver transplantation". Data were extracted and analyzed using IBM SPSS to perform the meta-analysis. RESULTS A total of 2286 records were identified, with 10 meeting the inclusion criteria. Overall, the quality of evidence is heterogenous with many papers relying on retrospective controls. However, pooled analysis demonstrates HOPE to significantly reduce the rate of early allograft dysfunction, 12-month graft failure, re-transplantation, total biliary complications, and non-anastomotic strictures for high-risk grafts. CONCLUSIONS There is good evidence that HOPE improves outcomes following liver transplantation across a number of biochemical and clinical endpoints for high-risk grafts. Of note, the reduction in biliary complications and re-transplantation is particularly significant given the morbidity associated with these endpoints. However, further, high-quality prospective trials with contemporary controls and clinically relevant primary endpoints are needed to better define the impact of HOPE for this cohort of grafts.
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Affiliation(s)
- Charles W G Risbey
- Department of Transplant Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment, Repair, & Optimization (COARO), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Royal Prince Alfred Hospital Transplant Institute (RPATI), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Charles Thomas
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Anita Niu
- Department of Transplant Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment, Repair, & Optimization (COARO), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Royal Prince Alfred Hospital Transplant Institute (RPATI), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Ken Liu
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Australian National Liver Transplantation Unit (ANLTU), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Michael Crawford
- Department of Transplant Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment, Repair, & Optimization (COARO), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Royal Prince Alfred Hospital Transplant Institute (RPATI), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Australian National Liver Transplantation Unit (ANLTU), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Carlo Pulitano
- Department of Transplant Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Centre for Organ Assessment, Repair, & Optimization (COARO), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Royal Prince Alfred Hospital Transplant Institute (RPATI), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Australian National Liver Transplantation Unit (ANLTU), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
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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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De Goeij FHC, De Meijer V, Mergental H, Guarrera JV, Asthana S, Ghinolfi D, Boteon YL, Selzner N, Kalisvaart M, Pulitano C, Sonnenday C, Martins PN, Berlakovich G, Schlegel A. Challenges With the Implementation of Machine Perfusion in Clinical Liver Transplantation. Transplantation 2024; 108:1296-1307. [PMID: 38057969 DOI: 10.1097/tp.0000000000004872] [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: 12/08/2023]
Abstract
Dynamic organ preservation is a relatively old technique which has regained significant interest in the last decade. Machine perfusion (MP) techniques are applied in various fields of solid organ transplantation today. The first clinical series of ex situ MP in liver transplantation was presented in 2010. Since then, the number of research and clinical applications has substantially increased. Despite the notable beneficial effect on organ quality and recipient outcome, MP is still not routinely used in liver transplantation. Based on the enormous need to better preserve organs and the subsequent demand to continuously innovate and develop perfusion equipment further, this technology is also beneficial to test and deliver future therapeutic strategies to livers before implantation. This article summarizes the various challenges observed during the current shift from static to dynamic liver preservation in the clinical setting. The different organ perfusion strategies are discussed first, together with ongoing clinical trials and future study design. The current status of research and the impact of costs and regulations is highlighted next. Factors contributing to costs and other required resources for a worldwide successful implementation and reimbursement are presented third. The impact of research on cost-utility and effectivity to guide the tailored decision-making regarding the optimal perfusion strategy is discussed next. Finally, this article provides potential solutions to the challenging field of innovation in healthcare considering the various social and economic factors and the role of clinical, regulatory, and financial stakeholders worldwide.
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Affiliation(s)
- Femke H C De Goeij
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Vincent De Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Hynek Mergental
- The Liver Unit, Queen Elizabeth University Hospital, Birmingham, United Kingdom
- The Liver Unit, Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - James V Guarrera
- Division of Abdominal Transplant Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ
| | | | - Davide Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Yuri L Boteon
- Instituto Israelita de Ensino e Pesquisa Albert Einstein, Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, Brazil
| | - Nazia Selzner
- Ajmera Transplant Center, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Marit Kalisvaart
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Zurich, Switzerland
| | - Carlo Pulitano
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital and Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | | | - Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, University of Massachusetts Memorial Hospital, University of Massachusetts, Worcester, MA
| | - Gabriela Berlakovich
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Tian X, Wu L, Li X, Zheng W, Zuo H, Song H. Exosomes derived from bone marrow mesenchymal stem cells alleviate biliary ischemia reperfusion injury in fatty liver transplantation by inhibiting ferroptosis. Mol Cell Biochem 2024; 479:881-894. [PMID: 37243945 PMCID: PMC11016128 DOI: 10.1007/s11010-023-04770-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 05/15/2023] [Indexed: 05/29/2023]
Abstract
Fatty liver grafts are susceptible to ischemia reperfusion injury (IRI), increasing the risk of biliary complications after liver transplantation (LT). Ferroptosis, a newly recognized programmed cell death, is expected to be a novel therapeutic target for IRI. We investigated whether exosomes derived from heme oxygenase 1-modified bone marrow mesenchymal stem cells (HExos) relieve ferroptosis and protect biliary tracts from IRI in a rat fatty liver transplantation model. Rats were fed with a methionine choline deficient (MCD) diet for 2 weeks to induce severe hepatic steatosis. Steatotic grafts were implanted and HExos were administered after liver transplantation. A series of functional assays and pathological analysis were performed to assess ferroptosis and biliary IRI. The HExos attenuated IRI following liver transplantation, as demonstrated by less ferroptosis, improved liver function, less Kupffer and T cell activation, and less long-term biliary fibrosis. MicroRNA (miR)-204-5p delivered by HExos negatively regulated ferroptosis by targeting a key pro-ferroptosis enzyme, ACSL4. Ferroptosis contributes to biliary IRI in fatty liver transplantation. HExos protect steatotic grafts by inhibiting ferroptosis, and may become a promising strategy to prevent biliary IRI and expand the donor pool.
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Affiliation(s)
- Xuan Tian
- School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Longlong Wu
- School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Xiang Li
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Weiping Zheng
- Department of Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China
- NHC Key Laboratory of Critical Care Medicine, Tianjin, 300192, People's Republic of China
| | - Huaiwen Zuo
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Hongli Song
- Department of Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China.
- Tianjin Key Laboratory of Organ Transplantation, Tianjin, People's Republic of China.
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10
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Tang G, Zhang L, Xia L, Zhang J, Wei Z, Zhou R. Hypothermic oxygenated perfusion in liver transplantation: a meta-analysis of randomized controlled trials and matched studies. Int J Surg 2024; 110:464-477. [PMID: 37738017 PMCID: PMC10793758 DOI: 10.1097/js9.0000000000000784] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/10/2023] [Indexed: 09/23/2023]
Abstract
BACKGROUND Hypothermic oxygenated machine perfusion (HOPE) is a novel organ-preservation technology designed to optimize organ quality. However, the effects of HOPE on morbidity and mortality after liver transplantation remain unclear. This meta-analysis evaluated the potential benefits of HOPE in liver transplantation. MATERIALS AND METHODS The Embase, Web of Science, PubMed, Cochrane Library, and Scopus databases were searched for articles published up to 15 June 2023 (updated on 12 August 2023). Mean differences (MDs), risk ratios (RRs), and 95% confidence intervals were calculated. RESULTS Eleven studies encompassing five randomized controlled trials and six matched studies were included, with a total of 1000 patients. HOPE did not reduce the incidence of major postoperative complications (RR 0.80), primary non-function (PNF) (RR 0.54), reperfusion syndrome (RR 0.92), hepatic artery thrombosis (RR 0.92), renal replacement therapy (RR 0.98), length of hospital stay (MD, -1.38 days), 1-year recipient death (RR 0.67), or intensive care unit stay (MD, 0.19 days) after liver transplantation. HOPE reduced the incidence of biliary complications (RR 0.74), non-anastomotic biliary strictures (NAS) (RR 0.34), early allograft dysfunction (EAD) (RR 0.54), and acute rejection (RR 0.54). In addition, HOPE improved the retransplantation (RR 0.42) and 1-year graft loss rates (RR 0.38). CONCLUSIONS Compared with static cold storage (SCS), HOPE can reduce the incidence of biliary complications, NAS, EAD, and acute rejection and retransplantation rate after liver transplantation and improve the 1-year graft loss rate. These findings suggest that HOPE, when compared to SCS, can contribute to minimizing complications and enhancing graft survival in liver transplantation. Further research is needed to investigate long-term outcomes and confirm the promising advantages of HOPE in liver transplantation settings.
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Affiliation(s)
- Gang Tang
- Biliary Surgical Department of West China Hospital
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | | | - Lingying Xia
- Biliary Surgical Department of West China Hospital
- Center for Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan
| | - Jie Zhang
- Biliary Surgical Department of West China Hospital
| | - Zhengqiang Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
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11
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Panconesi R, Carvalho MF, Eden J, Fazi M, Ansari F, Mancina L, Navari N, Sousa Da Silva RX, Dondossola D, Borrego LB, Pietzke M, Peris A, Meierhofer D, Muiesan P, Galkin A, Marra F, Dutkowski P, Schlegel A. Mitochondrial injury during normothermic regional perfusion (NRP) and hypothermic oxygenated perfusion (HOPE) in a rodent model of DCD liver transplantation. EBioMedicine 2023; 98:104861. [PMID: 37924707 PMCID: PMC10660010 DOI: 10.1016/j.ebiom.2023.104861] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 10/15/2023] [Accepted: 10/16/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking. METHODS A rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 °C (NRP) or with oxygenated Belzer-MPS at 10 °C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury. FINDINGS Healthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mitochondrial injury and inflammation as measured by increased perfusate Lactate, FMN- and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%). INTERPRETATION High-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results. FUNDING Funding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.
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Affiliation(s)
- Rebecca Panconesi
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, 10124, Turin, Italy; Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | | | - Janina Eden
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Marilena Fazi
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fariha Ansari
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - Leandro Mancina
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Nadia Navari
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Richard Xavier Sousa Da Silva
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Centre of Preclinical Research, 20122, Italy
| | - Lucia Bautista Borrego
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Matthias Pietzke
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, 14195, Berlin, Germany
| | - Adriano Peris
- Tuscany Regional Transplant Authority, Centro Regionale Allocazione Organi e Tessuti (CRAOT), Florence, Italy
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, 14195, Berlin, Germany
| | - Paolo Muiesan
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - Alexander Galkin
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Center for Research, High Education and Transfer DENOThe, University of Florence, Florence, Italy
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Andrea Schlegel
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland; General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Centre of Preclinical Research, 20122, Italy; Transplantation Center, Digestive Disease and Surgery Institute and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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12
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Grąt M, Morawski M, Zhylko A, Rykowski P, Krasnodębski M, Wyporski A, Borkowski J, Lewandowski Z, Kobryń K, Stankiewicz R, Stypułkowski J, Hołówko W, Patkowski W, Mielczarek-Puta M, Struga M, Szczepankiewicz B, Górnicka B, Krawczyk M. Routine End-ischemic Hypothermic Oxygenated Machine Perfusion in Liver Transplantation From Donors After Brain Death: A Randomized Controlled Trial. Ann Surg 2023; 278:662-668. [PMID: 37497636 DOI: 10.1097/sla.0000000000006055] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
OBJECTIVE To assess whether end-ischemic hypothermic oxygenated machine perfusion (HOPE) is superior to static cold storage (SCS) in preserving livers procured from donors after brain death (DBD). BACKGROUND There is increasing evidence of the benefits of HOPE in liver transplantation, but predominantly in the setting of high-risk donors. METHODS In this randomized clinical trial, livers procured from DBDs were randomly assigned to either end-ischemic dual HOPE for at least 2 hours or SCS (1:3 allocation ratio). The Model for Early Allograft Function (MEAF) was the primary outcome measure. The secondary outcome measure was 90-day morbidity (ClinicalTrials. gov, NCT04812054). RESULTS Of the 104 liver transplantations included in the study, 26 were assigned to HOPE and 78 to SCS. Mean MEAF was 4.94 and 5.49 in the HOPE and SCS groups ( P =0.24), respectively, with the corresponding rates of MEAF >8 of 3.8% (1/26) and 15.4% (12/78; P =0.18). Median Comprehensive Complication Index was 20.9 after transplantations with HOPE and 21.8 after transplantations with SCS ( P =0.19). Transaminase activity, bilirubin concentration, and international normalized ratio were similar in both groups. In the case of donor risk index >1.70, HOPE was associated with significantly lower mean MEAF (4.92 vs 6.31; P =0.037) and lower median Comprehensive Complication Index (4.35 vs 22.6; P =0.050). No significant differences between HOPE and SCS were observed for lower donor risk index values. CONCLUSION Routine use of HOPE in DBD liver transplantations does not seem justified as the clinical benefits are limited to high-risk donors.
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Affiliation(s)
- Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Morawski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Andriy Zhylko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Paweł Rykowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Anya Wyporski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Jan Borkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Zbigniew Lewandowski
- Department of Epidemiology and Biostatistics, Medical University of Warsaw, Warsaw, Poland
| | - Konrad Kobryń
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Rafał Stankiewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Jan Stypułkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Wacław Hołówko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | | | - Marta Struga
- Department of Biochemistry, Medical University of Warsaw, Warsaw, Poland
| | | | - Barbara Górnicka
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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13
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Tingle SJ, Dobbins JJ, Thompson ER, Figueiredo RS, Mahendran B, Pandanaboyana S, Wilson C. Machine perfusion in liver transplantation. Cochrane Database Syst Rev 2023; 9:CD014685. [PMID: 37698189 PMCID: PMC10496129 DOI: 10.1002/14651858.cd014685.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Abstract
BACKGROUND Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box). OBJECTIVES To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation. SEARCH METHODS We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023. SELECTION CRITERIA We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence. MAIN RESULTS We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I2 = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I2 = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I2 = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies. AUTHORS' CONCLUSIONS In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.
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Affiliation(s)
- Samuel J Tingle
- NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle upon Tyne, UK
| | | | - Emily R Thompson
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK
| | | | | | - Sanjay Pandanaboyana
- HPB and Liver Transplant Surgery, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Colin Wilson
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK
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14
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Sakamoto S, Bochimoto H, Shibata K, Zin NKM, Fukai M, Nakamura K, Ishikawa T, Fujiyoshi M, Shimamura T, Taketomi A. Exploration of Optimal pH in Hypothermic Machine Perfusion for Rat Liver Grafts Retrieved after Circulatory Death. J Clin Med 2023; 12:jcm12113845. [PMID: 37298042 DOI: 10.3390/jcm12113845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
Ex vivo hypothermic machine perfusion (HMP) is a strategy for controlling ischemia-reperfusion injury in donation after circulatory death (DCD) liver transplantation. The pH of blood increases with a decrease in temperature and water dissociation, leading to a decrease in [H+]. This study aimed to verify the optimal pH of HMP for DCD livers. Rat livers were retrieved 30 min post-cardiac arrest and subjected to 3-h cold storage (CS) in UW solution (CS group) or HMP with UW-gluconate solution (machine perfusion [MP] group) of pH 7.4 (original), 7.6, 7.8, and 8.0 (MP-pH 7.6, 7.8, 8.0 groups, respectively) at 7-10 °C. The livers were subjected to normothermic perfusion to simulate reperfusion after HMP. All HMP groups showed greater graft protection compared to the CS group due to the lower levels of liver enzymes in the former. The MP-pH 7.8 group showed significant protection, evidenced by bile production, diminished tissue injury, and reduced flavin mononucleotide leakage, and further analysis by scanning electron microscopy revealed a well-preserved structure of the mitochondrial cristae. Therefore, the optimum pH of 7.8 enhanced the protective effect of HMP by preserving the structure and function of the mitochondria, leading to reduced reperfusion injury in the DCD liver.
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Affiliation(s)
- Sodai Sakamoto
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Hiroki Bochimoto
- Department of Cell Physiology, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Kengo Shibata
- Gastroenterological Surgery 1, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Nur Khatijah Mohd Zin
- Department of Cell Physiology, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Kosei Nakamura
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Takahisa Ishikawa
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Masato Fujiyoshi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo 060-0815, Japan
- Gastroenterological Surgery 1, Hokkaido University Hospital, Sapporo 060-8648, Japan
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15
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Luo J, Hu Y, Qiao Y, Li H, Huang J, Xu K, Jiang L, Wu H, Hu X, Jia J, Zhou L, Xie H, Li J, Zheng S. Hypothermic Oxygenated Machine Perfusion Promotes Mitophagy Flux against Hypoxia-Ischemic Injury in Rat DCD Liver. Int J Mol Sci 2023; 24:ijms24065403. [PMID: 36982476 PMCID: PMC10049087 DOI: 10.3390/ijms24065403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 03/14/2023] Open
Abstract
Hypothermic oxygenated machine perfusion (HOPE) can enhance organ preservation and protect mitochondria from hypoxia-ischemic injury; however, an understanding of the underlying HOPE mechanism that protects mitochondria is somewhat lacking. We hypothesized that mitophagy may play an important role in HOPE mitochondria protection. Experimental rat liver grafts were exposed to 30 min of in situ warm ischemia. Then, grafts were procured, followed by cold storage for 3 or 4 h to mimic the conventional preservation and transportation time in donation after circulatory death (DCD) in clinical contexts. Next, the grafts underwent hypothermic machine perfusion (HMP) or HOPE for 1 h through portal vein only perfusion. The HOPE-treated group showed a better preservation capacity compared with cold storage and HMP, preventing hepatocyte damage, nuclear injury, and cell death. HOPE can increase mitophagy marker expression, promote mitophagy flux via the PINK1/Parkin pathway to maintain mitochondrial function, and reduce oxygen free radical generation, while the inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect. HOPE-treated DCD liver also demonstrated more changes in the expression of genes responsible for bile metabolism, mitochondrial dynamics, cell survival, and oxidative stress. Overall, HOPE attenuates hypoxia-ischemic injury in DCD liver by promoting mitophagy flux to maintain mitochondrial function and protect hepatocytes. Mitophagy could pave the way for a protective approach against hypoxia-ischemic injury in DCD liver.
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Affiliation(s)
- Jia Luo
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Yiqing Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Yinbiao Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Haoyu Li
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Jiacheng Huang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Kangdi Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Li Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hao Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Xiaoyi Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Jianhui Li
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310015, China
- The Organ Repair and Regeneration Medicine Institute of Hangzhou, Hangzhou 310003, China
- Correspondence: (J.L.); (S.Z.); Tel./Fax: +86-571-87236466 (J.L. & S.Z.)
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310015, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
- Correspondence: (J.L.); (S.Z.); Tel./Fax: +86-571-87236466 (J.L. & S.Z.)
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16
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Hughes CB, Nigmet Y, Villanueva FS, Chen X, Demetris AJ, Stolz DB, Pacella JJ, Humar A. Ultrasound-Targeted Microbubble Cavitation During Machine Perfusion Reduces Microvascular Thrombi and Graft Injury in a Rat Liver Model of Donation After Circulatory Death. Transplant Proc 2023; 55:485-495. [PMID: 36878745 DOI: 10.1016/j.transproceed.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/15/2023] [Accepted: 02/02/2023] [Indexed: 03/07/2023]
Abstract
BACKGROUND Ischemic cholangiopathy is a process of bile duct injury that might result from peribiliary vascular plexus (PBP) thrombosis and remains a dreaded complication in liver transplantation from donors after circulatory death (DCD). The aim of this study was to propose a mechanical method of clot destruction to clear microvascular thrombi in DCD livers before transplantation. METHODS Sonothrombolysis (STL) is a process by which inertial cavitation of circulating microbubbles entering an ultrasound field create a high-energy shockwave at a microbubble-thrombus interface, causing mechanical clot destruction. The effectiveness of STL in DCD liver treatment remains unclear. We carried out STL treatment during normothermic, oxygenated, ex vivo machine perfusion (NMP), introducing microbubbles into the perfusate with the liver enveloped in an ultrasound field. RESULTS The STL livers showed reduction in hepatic arterial and PBP thrombus and decreases in hepatic arterial and portal venous flow resistance, reduced parenchymal injury as measured by aspartate transaminase release and oxygen consumption, and improved cholangiocyte function. Light and electron microscopy showed reduction of hepatic arterial and PBP thrombus in STL livers compared with controls and preserved hepatocyte structure, sinusoid endothelial morphology, and biliary epithelial microvilli. CONCLUSION In this model, STL improved flow and functional measures in DCD livers undergoing NMP. These data suggest a novel therapeutic approach to treat PBP injury in DCD livers, which may ultimately increase the pool of grafts available to patients awaiting liver transplantation.
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Affiliation(s)
- Christopher B Hughes
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | - Yermek Nigmet
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Flordeliza S Villanueva
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh Medical, Pittsburgh, Pennsylvania
| | - Xucai Chen
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh Medical, Pittsburgh, Pennsylvania
| | - Anthony J Demetris
- Division of Transplant Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Donna B Stolz
- Center for Biological Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - John J Pacella
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh Medical, Pittsburgh, Pennsylvania
| | - Abhinav Humar
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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17
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Muth V, Gassner JMGV, Moosburner S, Lurje G, Michelotto J, Strobl F, Knaub K, Engelmann C, Tacke F, Selzner M, Pratschke J, Sauer IM, Raschzok N. Ex Vivo Liver Machine Perfusion: Comprehensive Review of Common Animal Models. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:10-27. [PMID: 35848526 DOI: 10.1089/ten.teb.2022.0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The most common preservation technique for liver grafts is static cold storage. Due to the organ shortage for liver transplantation (LT), extended criteria donor (ECD) allografts are increasingly used-despite the higher risk of inferior outcome after transplantation. Ex vivo liver machine perfusion (MP) has been developed to improve the outcome of transplantation, especially with ECD grafts, and is currently under evaluation in clinical trials. We performed a literature search on PubMed and ISI Web of Science to assemble an overview of rodent and porcine animal models of ex vivo liver MP for transplantation, which is essential for the present and future development of clinical liver MP. Hypothermic, subnormothermic, and normothermic MP systems have been successfully used for rat and pig LT. In comparison with hypothermic systems, normothermic perfusion often incorporates a dialysis unit. Moreover, it enables metabolic assessment of liver grafts. Allografts experiencing warm ischemic time have a superior survival rate after MP compared with cold storage alone, irrespective of the temperature used for perfusion. Furthermore, ex vivo MP improves the outcome of regular and ECD liver grafts in animal models. Small and large animal models of ex vivo liver MP are available to foster the further development of this new technology. Impact Statement Ex vivo machine perfusion is an important part of current research in the field of liver transplantation. While evidence for improve storage is constantly rising, the development of future applications such as quality assessment and therapeutic interventions necessitates robust animal models. This review is intended to provide an overview of this technology in common large and small animal models and to give an outlook on future applications. Moreover, we describe developmental steps that can be followed by others, and which can help to decrease the number of animals used for experiments based on the replace, reduce, refine concept.
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Affiliation(s)
- Vanessa Muth
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Joseph M G V Gassner
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Moosburner
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Julian Michelotto
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Felix Strobl
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Kristina Knaub
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Markus Selzner
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, Canada
| | - Johann Pratschke
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Igor M Sauer
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nathanael Raschzok
- Department of Surgery, Experimental Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Clinician Scientist Program, BIH Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
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18
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A Meta-Analysis and Systematic Review of Normothermic and Hypothermic Machine Perfusion in Liver Transplantation. J Clin Med 2022; 12:jcm12010235. [PMID: 36615037 PMCID: PMC9820958 DOI: 10.3390/jcm12010235] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The gap between the demand and supply of donor livers is still a considerable challenge. Since static cold storage is not sufficient in marginal livers, machine perfusion is being explored as an alternative. The objective of this study was to assess (dual) hypothermic oxygenated machine perfusion (HOPE/D-HOPE) and normothermic machine perfusion (NMP) in contrast to static cold storage (SCS). METHODS Three databases were searched to identify studies about machine perfusion. Graft and patient survival and postoperative complications were evaluated using the random effects model. RESULTS the incidence of biliary complications was lower in HOPE vs. SCS (OR: 0.59, 95% CI: 0.36-0.98, p = 0.04, I2: 0%). There was no significant difference in biliary complications between NMP and SCS (OR: 0.76, 95% CI: 0.41-1.40, p = 0.38, I2: 55%). Graft and patient survival were significantly better in HOPE than in SCS (HR: 0.40, 95% CI: 0.23-0.71, p = 0.002, I2: 0%) and (pooled HR: 0.43, 95% CI: 0.20-0.93, p = 0.03, I2: 0%). Graft and patient survival were not significantly different between NMP and SCS. CONCLUSION HOPE/D-HOPE and NMP are promising alternatives to SCS for donor liver preservation. They may help address the widening gap between the demand for and availability of donor livers by enabling the rescue and transplantation of marginal livers.
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19
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Sousa Da Silva RX, Weber A, Dutkowski P, Clavien PA. Machine perfusion in liver transplantation. Hepatology 2022; 76:1531-1549. [PMID: 35488496 DOI: 10.1002/hep.32546] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/24/2022] [Accepted: 02/24/2022] [Indexed: 12/29/2022]
Abstract
Although liver transplantation is a true success story, many patients still die awaiting an organ. The increasing need for liver grafts therefore remains an unsolved challenge to the transplant community. To address this, transplant donor criteria have been expanded and, for example, more liver grafts with significant steatosis or from donors with circulatory death are being used. These marginal grafts, however, carry an increased risk of graft-associated complications, such as primary nonfunction, delayed graft function, or late biliary injuries. Therefore, reliable assessment of graft viability before use is essential for further success. To achieve this, machine liver perfusion, a procedure developed more than 50 years ago but almost forgotten at the end of the last century, is again of great interest. We describe in this review the clinical most applied machine perfusion techniques, their mechanistic background, and a novel concept of combining immediate organ assessment during hypothermic oxygenated perfusion, followed by an extended phase of normothermic machine perfusion, with simultaneous ex situ treatment of the perfused liver. Such a new approach may allow the pool of usable livers to dramatically increase and improve outcomes for recipients.
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Affiliation(s)
- Richard X Sousa Da Silva
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary and Transplant Center, University Hospital Zurich, Zurich, Switzerland.,Wyss Zurich Translational Center, Swiss Federal Institute of Technology ETH Zurich/University of Zurich, Zurich, Switzerland
| | - Achim Weber
- Department of Pathology and Molecular Pathology, Institute of Molecular Cancer Research, University Hospital Zurich and University Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary and Transplant Center, University Hospital Zurich, Zurich, Switzerland
| | - Pierre-Alain Clavien
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary and Transplant Center, University Hospital Zurich, Zurich, Switzerland.,Wyss Zurich Translational Center, Swiss Federal Institute of Technology ETH Zurich/University of Zurich, Zurich, Switzerland
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20
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Parente A, Flores Carvalho M, Eden J, Dutkowski P, Schlegel A. Mitochondria and Cancer Recurrence after Liver Transplantation-What Is the Benefit of Machine Perfusion? Int J Mol Sci 2022; 23:9747. [PMID: 36077144 PMCID: PMC9456431 DOI: 10.3390/ijms23179747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor recurrence after liver transplantation has been linked to multiple factors, including the recipient's tumor burden, donor factors, and ischemia-reperfusion injury (IRI). The increasing number of livers accepted from extended criteria donors has forced the transplant community to push the development of dynamic perfusion strategies. The reason behind this progress is the urgent need to reduce the clinical consequences of IRI. Two concepts appear most beneficial and include either the avoidance of ischemia, e.g., the replacement of cold storage by machine perfusion, or secondly, an endischemic organ improvement through perfusion in the recipient center prior to implantation. While several concepts, including normothermic perfusion, were found to reduce recipient transaminase levels and early allograft dysfunction, hypothermic oxygenated perfusion also reduced IRI-associated post-transplant complications and costs. With the impact on mitochondrial injury and subsequent less IRI-inflammation, this endischemic perfusion was also found to reduce the recurrence of hepatocellular carcinoma after liver transplantation. Firstly, this article highlights the contributing factors to tumor recurrence, including the surgical and medical tissue trauma and underlying mechanisms of IRI-associated inflammation. Secondly, it focuses on the role of mitochondria and associated interventions to reduce cancer recurrence. Finally, the role of machine perfusion technology as a delivery tool and as an individual treatment is discussed together with the currently available clinical studies.
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Affiliation(s)
- Alessandro Parente
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham B15 2GW, UK
| | - Mauricio Flores Carvalho
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Andrea Schlegel
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
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21
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Schlegel A, Porte R, Dutkowski P. Protective mechanisms and current clinical evidence of hypothermic oxygenated machine perfusion (HOPE) in preventing post-transplant cholangiopathy. J Hepatol 2022; 76:1330-1347. [PMID: 35589254 DOI: 10.1016/j.jhep.2022.01.024] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/10/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
The development of cholangiopathies after liver transplantation impacts on the quality and duration of graft and patient survival, contributing to higher costs as numerous interventions are required to treat strictures and infections at the biliary tree. Prolonged donor warm ischaemia time in combination with additional cold storage are key risk factors for the development of biliary strictures. Based on this, the clinical implementation of dynamic preservation strategies is a current hot topic in the field of donation after circulatory death (DCD) liver transplantation. Despite various retrospective studies reporting promising results, also regarding biliary complications, there are only a few randomised-controlled trials on machine perfusion. Recently, the group from Groningen has published the first randomised-controlled trial on hypothermic oxygenated perfusion (HOPE), demonstrating a significant reduction of symptomatic ischaemic cholangiopathies with the use of a short period of HOPE before DCD liver implantation. The most likely mechanism for this important effect, also shown in several experimental studies, is based on mitochondrial reprogramming under hypothermic aerobic conditions, e.g. exposure to oxygen in the cold, with a controlled and slow metabolism of ischaemically accumulated succinate and simultaneous ATP replenishment. This unique feature prevents mitochondrial oxidative injury and further downstream tissue inflammation. HOPE treatment therefore supports livers by protecting them from ischaemia-reperfusion injury (IRI), and thereby also prevents the development of post-transplant biliary injury. With reduced IRI-associated inflammation, recipients are also protected from activation of the innate immune system, with less acute rejections seen after HOPE.
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Affiliation(s)
- Andrea Schlegel
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland; General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy
| | - Robert Porte
- Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland.
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22
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Delivering siRNA Compounds During HOPE to Modulate Organ Function: A Proof-of-Concept Study in a Rat Liver Transplant Model. Transplantation 2022; 106:1565-1576. [PMID: 35581683 DOI: 10.1097/tp.0000000000004175] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Apoptosis contributes to the severity of ischemia-reperfusion injury (IRI), limiting the use of extended criteria donors in liver transplantation (LT). Machine perfusion has been proposed as a platform to administer specific therapies to improve graft function. Alternatively, the inhibition of genes associated with apoptosis during machine perfusion could alleviate IRI post-LT. The aim of the study was to investigate whether inhibition of an apoptosis-associated gene (FAS) using a small interfering RNA (siRNA) approach could alleviate IRI in a rat LT model. METHODS In 2 different experimental protocols, FASsiRNA (500 µg) was administered to rat donors 2 h before organ procurement, followed by 22 h of static cold storage, (SCS) or was added to the perfusate during 1 h of ex situ hypothermic oxygenated perfusion (HOPE) to livers previously preserved for 4 h in SCS. RESULTS Transaminase levels were significantly lower in the SCS-FASsiRNA group at 24 h post-LT. Proinflammatory cytokines (interleukin-2, C-X-C motif chemokine 10, tumor necrosis factor alpha, and interferon gamma) were significantly decreased in the SCS-FASsiRNA group, whereas the interleukin-10 anti-inflammatory cytokine was significantly increased in the HOPE-FASsiRNA group. Liver absorption of FASsiRNA after HOPE session was demonstrated by confocal microscopy; however, no statistically significant differences on the apoptotic index, necrosis levels, and FAS protein transcription between treated and untreated groups were observed. CONCLUSIONS FAS inhibition through siRNA therapy decreases the severity of IRI after LT in a SCS protocol; however the association of siRNA therapy with a HOPE perfusion model is very challenging. Future studies using better designed siRNA compounds and appropriate doses are required to prove the siRNA therapy effectiveness during liver HOPE liver perfusion.
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23
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Parente A, Tirotta F, Ronca V, Schlegel A, Muiesan P. Donation after Circulatory Death Liver Transplantation in Paediatric Recipients. TRANSPLANTOLOGY 2022; 3:91-102. [DOI: 10.3390/transplantology3010009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024] Open
Abstract
Waiting list mortality together, with limited availability of organs, are one of the major challenges in liver transplantation (LT). Especially in the paediatric population, another limiting factor is the scarcity of transplantable liver grafts due to additional concerns regarding graft size matching. In adults, donation after circulatory death (DCD) liver grafts have been used to expand the donor pool with satisfactory results. Although several studies suggest that DCD livers could also be used in paediatric recipients with good outcomes, their utilisation in children is still limited to a small number of reports. Novel organ perfusion strategies could be used to improve organ quality and help to increase the number of DCD grafts utilised for children. With the current manuscript, we present the available literature of LT using DCD grafts in paediatric recipients, discussing current challenges with the use of these livers in children and how machine perfusion technologies could be of impact in the future.
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Affiliation(s)
| | - Fabio Tirotta
- Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK
| | - Vincenzo Ronca
- Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Andrea Schlegel
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico and University of Milan, 20122 Milan, Italy
- Swiss HPB and Transplant Center, Department of Visceral Surgery and Transplantation, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Paolo Muiesan
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico and University of Milan, 20122 Milan, Italy
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24
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Han Y, Black S, Gong Z, Chen Z, Ko JK, Zhou Z, Xia T, Fang D, Yang D, Gu D, Zhang Z, Ren H, Duan X, Reader BF, Chen P, Li Y, Kim JL, Li Z, Xu X, Guo L, Zhou X, Haggard E, Zhu H, Tan T, Chen K, Ma J, Zeng C. Membrane-delimited signaling and cytosolic action of MG53 preserve hepatocyte integrity during drug-induced liver injury. J Hepatol 2022; 76:558-567. [PMID: 34736969 DOI: 10.1016/j.jhep.2021.10.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 09/20/2021] [Accepted: 10/18/2021] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.
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Affiliation(s)
- Yu Han
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Sylvester Black
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Zhengfan Gong
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Zhi Chen
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Jae-Kyun Ko
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Zhongshu Zhou
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Tianyang Xia
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Dandong Fang
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Donghai Yang
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Daqian Gu
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Ziyue Zhang
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Hongmei Ren
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Xudong Duan
- Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China
| | - Brenda F Reader
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Ping Chen
- Department of Hepatobiliary Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Yongsheng Li
- Clinical Medicine Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jung-Lye Kim
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Zhongguang Li
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Laboratory of Cell Biology, Genetics and Developmental Biology, Shannxi Normal University College of Life Sciences, Xi'an, China
| | - Xuehong Xu
- Laboratory of Cell Biology, Genetics and Developmental Biology, Shannxi Normal University College of Life Sciences, Xi'an, China
| | - Li Guo
- Clinical Medicine Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Xinyu Zhou
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Erin Haggard
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Hua Zhu
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Tao Tan
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Ken Chen
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China.
| | - Jianjie Ma
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China.
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Ishii D, Matsuno N, Gochi M, Iwata H, Shonaka T, Nishikawa Y, Obara H, Yokoo H, Furukawa H. Beneficial effects of end-ischemic oxygenated machine perfusion preservation for split-liver transplantation in recovering graft function and reducing ischemia-reperfusion injury. Sci Rep 2021; 11:22608. [PMID: 34799598 PMCID: PMC8604979 DOI: 10.1038/s41598-021-01467-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 10/25/2021] [Indexed: 02/08/2023] Open
Abstract
This study examined the efficacy of end-ischemic hypothermic oxygenated machine perfusion preservation (HOPE) using an originally developed machine perfusion system for split-liver transplantation. Porcine split-liver grafts were created via 75% liver resection after 10 min of warm ischemia. In Group 1, grafts were preserved by simple cold storage (CS) for 8 h (CS group; n = 4). In Group 2, grafts were preserved by simple CS for 6 h and end-ischemic HOPE for 2 h (HOPE group; n = 5). All grafts were evaluated using an isolated ex vivo reperfusion model with autologous blood for 2 h. Biochemical markers (aspartate aminotransferase and lactate dehydrogenase levels) were significantly better immediately after reperfusion in the HOPE group than in the CS group. Furthermore, the HOPE group had a better histological score. The levels of inflammatory cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1β, and interleukin-10) were significantly lower after reperfusion in the HOPE group. Therefore, we concluded that end-ischemic HOPE for split-liver transplantation can aid in recovering the graft function and reducing ischemia-reperfusion injury. HOPE, using our originally developed machine perfusion system, is safe and can improve graft function while attenuating liver injury due to preservation.
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Affiliation(s)
- Daisuke Ishii
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Naoto Matsuno
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
| | - Mikako Gochi
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Hiroyoshi Iwata
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Tatsuya Shonaka
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Yuji Nishikawa
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiromichi Obara
- Department of Mechanical Engineering, Tokyo Metropolitan University, Tokyo, Japan
| | - Hideki Yokoo
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Hiroyuki Furukawa
- Department of Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
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Mitochondrial respiratory chain and Krebs cycle enzyme function in human donor livers subjected to end-ischaemic hypothermic machine perfusion. PLoS One 2021; 16:e0257783. [PMID: 34710117 PMCID: PMC8553115 DOI: 10.1371/journal.pone.0257783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/09/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Marginal human donor livers are highly susceptible to ischaemia reperfusion injury and mitochondrial dysfunction. Oxygenation during hypothermic machine perfusion (HMP) was proposed to protect the mitochondria but the mechanism is unclear. Additionally, the distribution and uptake of perfusate oxygen during HMP are unknown. This study aimed to examine the feasibility of mitochondrial function analysis during end-ischaemic HMP, assess potential mitochondrial viability biomarkers, and record oxygenation kinetics. METHODS This was a randomised pilot study using human livers retrieved for transplant but not utilised. Livers (n = 38) were randomised at stage 1 into static cold storage (n = 6), hepatic artery HMP (n = 7), and non-oxygen supplemented portal vein HMP (n = 7) and at stage 2 into oxygen supplemented and non-oxygen supplemented portal vein HMP (n = 11 and 7, respectively). Mitochondrial parameters were compared between the groups and between low- and high-risk marginal livers based on donor history, organ steatosis and preservation period. The oxygen delivery efficiency was assessed in additional 6 livers using real-time measurements of perfusate and parenchymal oxygen. RESULTS The change in mitochondrial respiratory chain (complex I, II, III, IV) and Krebs cycle enzyme activity (aconitase, citrate synthase) before and after 4-hour preservation was not different between groups in both study stages (p > 0.05). Low-risk livers that could have been used clinically (n = 8) had lower complex II-III activities after 4-hour perfusion, compared with high-risk livers (73 nmol/mg/min vs. 113 nmol/mg/min, p = 0.01). Parenchymal pO2 was consistently lower than perfusate pO2 (p ≤ 0.001), stabilised in 28 minutes compared to 3 minutes in perfusate (p = 0.003), and decreased faster upon oxygen cessation (75 vs. 36 minutes, p = 0.003). CONCLUSIONS Actively oxygenated and air-equilibrated end-ischaemic HMP did not induce oxidative damage of aconitase, and respiratory chain complexes remained intact. Mitochondria likely respond to variable perfusate oxygen levels by adapting their respiratory function during end-ischaemic HMP. Complex II-III activities should be further investigated as viability biomarkers.
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Jia D, Pan Q, Zhang Y, Yu Y, Song Z, Liu YF, Jia Z, Guo S, Cheng Y. Ischemic postconditioning improves the outcome of organs from donors after cardiac death in a pig liver transplantation model and provides synergistic protection with hypothermic machine perfusion. Clin Transplant 2021; 35:e14417. [PMID: 34231926 DOI: 10.1111/ctr.14417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/29/2021] [Accepted: 07/02/2021] [Indexed: 12/18/2022]
Abstract
AIM This study investigated whether ischemic postconditioning (IPO) improved the outcome of organs from donors after cardiac death and had a synergistic effect with hypothermic machine perfusion (HMP) in a pig liver transplantation model. METHODS A donor after cardiac death (DCD) model was developed in 48 healthy Bama miniature pigs randomly divided into four groups: simple cold storage group (SCS group), IPO group, HMP group, HMP-IPO group. The levels of serum alanine aminotransferase (ALT), total bilirubin, histopathological findings, apoptotic activity of hepatocytes, international normalized ratio (INR), tumor necrosis factor-α (TNF-α), and Malondialdehyde (MDA) were compared. RESULTS All recipients in the SCS group died within 6 h after transplantation. The livers of the recipients in the IPO had 50% survival on day 5. HMP allowed 83.3% survival and HMP-IPO allowed 100% survival. After reperfusion, the recipients in the IPO and HMP-IPO group had lower ALT and total bilirubin levels, less Suzuki score, less apoptosis, and less injury to hepatocytes and biliary ducts and attenuated inflammatory response and oxidative load. CONCLUSIONS IPO improved the outcome of organs from donors after cardiac death and had a synergistic effect with HMP in the pig liver transplantation model.
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Affiliation(s)
- Degong Jia
- Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
| | - Qi Pan
- Department of Organ Transplantation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yijie Zhang
- Department of Organ Transplantation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yang Yu
- Department of Organ Transplantation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhanyu Song
- Department of Organ Transplantation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yong Feng Liu
- Department of Organ Transplantation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhixing Jia
- Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
| | - Shanshan Guo
- School of Anesthesiology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Ying Cheng
- Department of Organ Transplantation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Bonaccorsi-Riani E, Gillooly A, Brüggenwirth IMA, Martins PN. Delivery of genetic load during ex situ liver machine perfusion with potential for CRISPR-Cas9 gene editing: An innovative strategy for graft treatment. Hepatobiliary Pancreat Dis Int 2021; 20:503-505. [PMID: 33958293 DOI: 10.1016/j.hbpd.2021.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 04/13/2021] [Indexed: 02/05/2023]
Affiliation(s)
- Eliano 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; Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA
| | - Andrew Gillooly
- Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA
| | - Isabel M A Brüggenwirth
- Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA; Department of Surgery, Section of hepatobiliary surgery and liver transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Paulo N Martins
- Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA.
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Patrono D, Roggio D, Mazzeo AT, Catalano G, Mazza E, Rizza G, Gambella A, Rigo F, Leone N, Elia V, Dondossola D, Lonati C, Fanelli V, Romagnoli R. Clinical assessment of liver metabolism during hypothermic oxygenated machine perfusion using microdialysis. Artif Organs 2021; 46:281-295. [PMID: 34516020 PMCID: PMC9292750 DOI: 10.1111/aor.14066] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/17/2021] [Accepted: 09/05/2021] [Indexed: 12/12/2022]
Abstract
Background While growing evidence supports the use of hypothermic oxygenated machine perfusion (HOPE) in liver transplantation, its effects on liver metabolism are still incompletely understood. Methods To assess liver metabolism during HOPE using microdialysis (MD), we conducted an open‐label, observational pilot study on 10 consecutive grafts treated with dual‐HOPE (D‐HOPE). Microdialysate and perfusate levels of glucose, lactate, pyruvate, glutamate, and flavin mononucleotide (FMN) were measured during back table preparation and D‐HOPE and correlated to graft function and patient outcome. Results Median (IQR) MD and D‐HOPE time was 228 (210, 245) and 116 (103, 143) min. Three grafts developed early allograft dysfunction (EAD), with one requiring retransplantation. During D‐HOPE, MD glucose and lactate levels increased (ANOVA = 9.88 [p = 0.01] and 3.71 [p = 0.08]). Their 2nd‐hour levels were higher in EAD group and positively correlated with L‐GrAFT score. 2nd‐hour MD glucose and lactate were also positively correlated with cold ischemia time, macrovesicular steatosis, weight gain during D‐HOPE, and perfusate FMN. These correlations were not apparent when perfusate levels were considered. In contrast, MD FMN levels invariably dropped steeply after D‐HOPE start, whereas perfusate FMN was higher in dysfunctioning grafts. Conclusion MD glucose and lactate during D‐HOPE are markers of hepatocellular injury and could represent additional elements of the viability assessment.
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Affiliation(s)
- Damiano Patrono
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Dorotea Roggio
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Anna Teresa Mazzeo
- Anaesthesia, Critical Care and Emergency, A.O.U. Department of Surgical Sciences, Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.,Anesthesia and Intensive Care, Department of Adult and Pediatric Pathology, University of Messina, Messina, Italy
| | - Giorgia Catalano
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Elena Mazza
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Giorgia Rizza
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Alessandro Gambella
- Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Federica Rigo
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Nicola Leone
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Vincenzo Elia
- Anaesthesia, Critical Care and Emergency, A.O.U. Department of Surgical Sciences, Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi of Milan, Milan, Italy
| | - Caterina Lonati
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Vito Fanelli
- Anaesthesia, Critical Care and Emergency, A.O.U. Department of Surgical Sciences, Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Renato Romagnoli
- General Surgery 2U - Liver Transplant Unit, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
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Liu H, Man K. New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation. Int J Mol Sci 2021; 22:ijms22158210. [PMID: 34360975 PMCID: PMC8348697 DOI: 10.3390/ijms22158210] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.
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Masior Ł, Grąt M. Methods of Attenuating Ischemia-Reperfusion Injury in Liver Transplantation for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:8229. [PMID: 34360995 PMCID: PMC8347959 DOI: 10.3390/ijms22158229] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent indications for liver transplantation. However, the transplantation is ultimately associated with the occurrence of ischemia-reperfusion injury (IRI). It affects not only the function of the graft but also significantly worsens the oncological results. Various methods have been used so far to manage IRI. These include the non-invasive approach (pharmacotherapy) and more advanced options encompassing various types of liver conditioning and machine perfusion. Strategies aimed at shortening ischemic times and better organ allocation pathways are still under development as well. This article presents the mechanisms responsible for IRI, its impact on treatment outcomes, and strategies to mitigate it. An extensive review of the relevant literature using MEDLINE (PubMed) and Scopus databases until September 2020 was conducted. Only full-text articles written in English were included. The following search terms were used: "ischemia reperfusion injury", "liver transplantation", "hepatocellular carcinoma", "preconditioning", "machine perfusion".
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Affiliation(s)
- Łukasz Masior
- Department of General, Vascular and Oncological Surgery, Medical University of Warsaw, Stępińska Street 19/25, 00-739 Warsaw, Poland
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha Street 1A, 02-097 Warsaw, Poland;
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Hypothermic Oxygenated Machine Perfusion (HOPE) Reduces Early Allograft Injury and Improves Post-Transplant Outcomes in Extended Criteria Donation (ECD) Liver Transplantation from Donation After Brain Death (DBD): Results from a Multicenter Randomized Controlled Trial (HOPE ECD-DBD). Ann Surg 2021; 274:705-712. [PMID: 34334635 DOI: 10.1097/sla.0000000000005110] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD). BACKGROUND HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT). METHODS Between 09/2017-09/2020 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n=23) or SCS (n=23). Peak-ALT levels within seven days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications (Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)), length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD). RESULTS Demographics were equally distributed between both groups (donor age: 72 [IQR:59-78] years, recipient age: 62 [IQR:55-65] years, labMELD: 15 [IQR:9-25], 38 male and 8 female recipients). HOPE resulted in a 47% decrease in serum peak ALT (418 [IQR: 221-828] vs. 796 [IQR:477-1195] IU/L, p=0.030), a significant reduction in 90-day complications (44% vs. 74% CD grade ≥3, p=0.036; 32 [IQR:12-56] vs. 52 [IQR:35-98] CCI, p=0.021), and shorter ICU- and hospital-stays (5 [IQR:4-8] vs. 8 [IQR:5-18] days, p=0.045; 20 [IQR:16-27] vs. 36 [IQR:23-62] days, p=0.002) compared to SCS. A trend towards reduced EAD was observed for HOPE (17% vs. 35%; p=0.314). CONCLUSION This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.
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Tingle SJ, Thompson ER, Figueiredo RS, Mahendran B, Pandanaboyana S, Wilson CH. Machine perfusion in liver transplantation: a network meta-analysis. Hippokratia 2021. [DOI: 10.1002/14651858.cd014685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Samuel J Tingle
- NIHR Blood and Transplant Research Unit; Newcastle University and Cambridge University; Newcastle upon Tyne UK
| | - Emily R Thompson
- Institute of Transplantation; The Freeman Hospital; Newcastle upon Tyne UK
| | | | | | - Sanjay Pandanaboyana
- HPB and Liver Transplant Surgery; Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust; Newcastle upon Tyne UK
| | - Colin H Wilson
- Institute of Transplantation; The Freeman Hospital; Newcastle upon Tyne UK
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Franzin R, Stasi A, Fiorentino M, Simone S, Oberbauer R, Castellano G, Gesualdo L. Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials. Front Immunol 2021; 12:673562. [PMID: 34295329 PMCID: PMC8290413 DOI: 10.3389/fimmu.2021.673562] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022] Open
Abstract
Donor organ shortage still remains a serious obstacle for the access of wait-list patients to kidney transplantation, the best treatment for End-Stage Kidney Disease (ESKD). To expand the number of transplants, the use of lower quality organs from older ECD or DCD donors has become an established routine but at the price of increased incidence of Primary Non-Function, Delay Graft Function and lower-long term graft survival. In the last years, several improvements have been made in the field of renal transplantation from surgical procedure to preservation strategies. To improve renal outcomes, research has focused on development of innovative and dynamic preservation techniques, in order to assess graft function and promote regeneration by pharmacological intervention before transplantation. This review provides an overview of the current knowledge of these new preservation strategies by machine perfusions and pharmacological interventions at different timing possibilities: in the organ donor, ex-vivo during perfusion machine reconditioning or after implementation in the recipient. We will report therapies as anti-oxidant and anti-inflammatory agents, senolytics agents, complement inhibitors, HDL, siRNA and H2S supplementation. Renal delivery of pharmacologic agents during preservation state provides a window of opportunity to treat the organ in an isolated manner and a crucial route of administration. Even if few studies have been reported of transplantation after ex-vivo drugs administration, targeting the biological pathway associated to kidney failure (i.e. oxidative stress, complement system, fibrosis) might be a promising therapeutic strategy to improve the quality of various donor organs and expand organ availability.
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Affiliation(s)
- Rossana Franzin
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Simona Simone
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, University Clinic for Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
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Haque OJ, Roth EM, Fleishman A, Eckhoff DE, Khwaja K. Long-Term Outcomes of Early Experience in Donation After Circulatory Death Liver Transplantation: Outcomes at 10 Years. Ann Transplant 2021; 26:e930243. [PMID: 33875633 PMCID: PMC8067669 DOI: 10.12659/aot.930243] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Donation after circulatory death (DCD) livers remain an underutilized pool of transplantable organs due to concerns of inferior long-term patient survival (PS) and graft survival (GS), which factors greatly into clinician decision-making and patient expectations. MATERIAL AND METHODS This retrospective study used SRTR data to assess 33 429 deceased-donor liver transplants (LT) and compared outcomes between DCD and donation after brain death (DBD) LT recipients in the United States. Data were collected from 2002 to 2008 to obtain 10 years of follow-up (2012-2018) in the era of MELD implementation. Propensity scores for donor type (DCD vs DBD) were estimated using logistic regression, and the association of donor type with 10-year outcomes was evaluated after adjustment using stabilized inverse probability of treatment weights. RESULTS After adjusting for confounders, patient survival for DBD recipients at 10 years was 60.7% versus 57.5% for DCD recipients (P=0.24). Incorporating retransplants, 10-year adjusted patient survival was 60.2% for DBD recipients versus 55.5% for DCD recipients (P=0.07). Adjusted 10-year graft survival for DBD recipients was 56.4% versus 45.4% for DCD recipients (P<0.001). Surprisingly, however, 1 year after LT, DBD and DCD graft failure rates converged to 7.5% over the remaining 9 years. CONCLUSIONS These data reveal inferior 10-year DCD graft survival, but only in the first year after LT, and similar 10-year patient survival in DCD LT recipients compared to DBD recipients. Our results show the stability and longevity of DCD grafts, which should encourage the increased utilization of these livers for transplantation.
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Affiliation(s)
- Omar J Haque
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Eve M Roth
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Aaron Fleishman
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Devin E Eckhoff
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Khalid Khwaja
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
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Serifis N, Matheson R, Cloonan D, Rickert CG, Markmann JF, Coe TM. Machine Perfusion of the Liver: A Review of Clinical Trials. Front Surg 2021; 8:625394. [PMID: 33842530 PMCID: PMC8033162 DOI: 10.3389/fsurg.2021.625394] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/01/2021] [Indexed: 12/20/2022] Open
Abstract
Although efforts have been made by transplant centers to increase the pool of available livers by extending the criteria of liver acceptance, this practice creates risks for recipients that include primary non-function of the graft, early allograft dysfunction and post-operative complications. Donor liver machine perfusion (MP) is a promising novel strategy that not only decreases cold ischemia time, but also serves as a method of assessing the viability of the graft. In this review, we summarize the data from liver machine perfusion clinical trials and discuss the various techniques available to date as well as future applications of machine perfusion. A variety of approaches have been reported including hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP); the advantages and disadvantages of each are just now beginning to be resolved. Important in this effort is developing markers of viability with lactate being the most predictive of graft functionality. The advent of machine perfusion has also permitted completely ischemia free transplantation by utilization of in situ NMP showed promising results. Animal studies that focus on defatting steatotic livers via NMP as well as groups that work on regenerating liver tissue ex vivo via MP. The broad incorporation of machine perfusion into routine clinical practice seems incredible.
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Affiliation(s)
| | | | | | | | - James F. Markmann
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
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Zhang Y, Pan Q, Cheng Y, Liu Y. Effects of SP600125 and hypothermic machine perfusion on livers donated after cardiac death in a pig allograft transplantation model. Eur J Med Res 2021; 26:15. [PMID: 33546770 PMCID: PMC7863371 DOI: 10.1186/s40001-020-00472-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hypothermic machine perfusion (HMP) improves the quality of donor livers for transplantation, both in animal models and in clinical practice. Treatment with SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), can suppress the JNK signaling pathway to alleviate donor liver ischemia-reperfusion injury (IRI). We performed the present study with the objective of exploring the protective effects exerted by a combination of HMP and SP600125 on liver xenograft viability for donation after cardiac death (DCD) in a porcine model. METHODS 54 adult BAMA mini-pigs were randomly assigned to 5 groups, including sham, cold storage for 4 h (CS 4 h), CS 4 h + SP600125, CS 2 h + HMP 2 h, and CS 2 h + HMP 2 h + SP600125 groups. Donor livers in the CS 4 h and CS 4 h + SP600125 groups were conventionally cold preserved for 4 h, whereas donor livers in the CS 2 h + HMP 2 h and CS 2 h + HMP 2 h + SP600125 groups were cold preserved for 2 h and then treated with HMP for 2 h. The preservation and perfusion solutions contained SP600125 (20 µM). Follow-up was conducted for 5 days after liver transplantation to compare the surgical outcomes by means of serological examination, pathological results, and survival rate. RESULTS The most satisfactory outcome after liver transplantation was observed in the CS 2 h + HMP 2 h + SP600125 group, which presented with minimal damage of donor livers during 5 days' follow-up. Additionally, serological examination, pathological results, and survival rate concurred in showing better results in the CS 2 h + HMP 2 h ± SP600125 group than in the CS 4 h ± SP600125 group. CONCLUSION HMP in combination with SP600125 has hepatoprotective properties and improves the quality and viability of porcine livers collected after DCD, thus improving prognosis after liver transplantation.
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Affiliation(s)
- Yijie Zhang
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Ying Cheng
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Yongfeng Liu
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China. .,The Key Laboratory of Organ Transplantation of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.
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Navez J, Iesari S, Kourta D, Baami-Mariza K, Nadiri M, Goffette P, Baldin P, Ackenine K, Bonaccorsi-Riani E, Ciccarelli O, Coubeau L, Moreels T, Lerut J. The real incidence of biliary tract complications after adult liver transplantation: the role of the prospective routine use of cholangiography during post-transplant follow-up. Transpl Int 2021; 34:245-258. [PMID: 33188645 DOI: 10.1111/tri.13786] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/13/2020] [Accepted: 11/10/2020] [Indexed: 12/20/2022]
Abstract
Biliary tract complications (BTCs) still burden liver transplantation (LT). The wide reporting variability highlights the absence of systematic screening. From 2000 to 2009, simultaneous liver biopsy and direct biliary visualization were prospectively performed in 242 recipients at 3 and 6 months (n = 212, 87.6%) or earlier when indicated (n = 30, 12.4%). Median follow-up was 148 (107-182) months. Seven patients (2.9%) experienced postprocedural morbidity. BTCs were initially diagnosed in 76 (31.4%) patients; 32 (42.1%) had neither clinical nor biological abnormalities. Acute cellular rejection (ACR) was present in 27 (11.2%) patients and in 6 (22.2%) BTC patients. Nine (3.7%) patients with normal initial cholangiography developed BTCs after 60 (30-135) months post-LT. BTCs directly lead to 7 (2.9%) re-transplantations and 14 (5.8%) deaths resulting in 18 (7.4%) allograft losses. Bile duct proliferation at 12-month biopsy proved an independent risk factor for graft loss (P = 0.005). Systematic biliary tract and allograft evaluation allows the incidence and extent of biliary lesions to be documented more precisely and to avoid erroneous treatment of ACR. The combination 'abnormal biliary tract-canalicular proliferation' is an indicator of worse graft outcome. BTCs are responsible for important delayed allograft and patient losses. These results underline the importance of life-long follow-up and appropriate timing for re-transplantation.
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Affiliation(s)
- Julie Navez
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
- Medico-Surgical Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Samuele Iesari
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
- Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Dhoha Kourta
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Kente Baami-Mariza
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Marwan Nadiri
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Pierre Goffette
- Interventional Radiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Pamela Baldin
- Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Kevin Ackenine
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Eliano Bonaccorsi-Riani
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
- Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Olga Ciccarelli
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Laurent Coubeau
- Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Tom Moreels
- Hepato-gastroenterology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Jan Lerut
- Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Arnold M, Méndez-Carmona N, Wyss RK, Joachimbauer A, Casoni D, Carrel T, Longnus S. Comparison of Experimental Rat Models in Donation After Circulatory Death (DCD): in-situ vs. ex-situ Ischemia. Front Cardiovasc Med 2021; 7:596883. [PMID: 33521061 PMCID: PMC7838125 DOI: 10.3389/fcvm.2020.596883] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/14/2020] [Indexed: 12/16/2022] Open
Abstract
Introduction: Donation after circulatory death (DCD) could substantially improve donor heart availability. However, warm ischemia prior to procurement is of particular concern for cardiac graft quality. We describe a rat model of DCD with in-situ ischemia in order to characterize the physiologic changes during the withdrawal period before graft procurement, to determine effects of cardioplegic graft storage, and to evaluate the post-ischemic cardiac recovery in comparison with an established ex-situ ischemia model. Methods: Following general anesthesia in male, Wistar rats (404 ± 24 g, n = 25), withdrawal of life-sustaining therapy was simulated by diaphragm transection. Hearts underwent no ischemia or 27 min in-situ ischemia and were explanted. Ex situ, hearts were subjected to a cardioplegic flush and 15 min cold storage or not, and 60 min reperfusion. Cardiac recovery was determined and compared to published results of an entirely ex-situ ischemia model (n = 18). Results: In donors, hearts were subjected to hypoxia and hemodynamic changes, as well as increased levels of circulating catecholamines and free fatty acids prior to circulatory arrest. Post-ischemic contractile recovery was significantly lower in the in-situ ischemia model compared to the ex-situ model, and the addition of cardioplegic storage improved developed pressure-heart rate product, but not cardiac output. Conclusion: The in-situ model provides insight into conditions to which the heart is exposed before procurement. Compared to an entirely ex-situ ischemia model, hearts of the in-situ model demonstrated a lower post-ischemic functional recovery, potentially due to systemic changes prior to ischemia, which are partially abrogated by cardioplegic graft storage.
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Affiliation(s)
- Maria Arnold
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Natalia Méndez-Carmona
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Rahel K Wyss
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Anna Joachimbauer
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Daniela Casoni
- Experimental Surgery Facility (ESF), Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Thierry Carrel
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sarah Longnus
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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Justo I, Nutu A, García-Conde M, Marcacuzco A, Manrique A, Calvo J, García-Sesma Á, Caso Ó, Martín-Arriscado C, Andrés A, Paz E, Jiménez-Romero C. Incidence and risk factors of primary non-function after liver transplantation using grafts from uncontrolled donors after circulatory death. Clin Transplant 2020; 35:e14134. [PMID: 33128296 DOI: 10.1111/ctr.14134] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 10/12/2020] [Accepted: 10/24/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Graft primary non-function (PNF) is the most severe complication after orthotopic liver transplantation (OLT) and is frequently associated with livers from uncontrolled circulatory death (uDCD). METHODS We reviewed retrospectively the incidence, risk factors, and outcome of patients showing PNF after receiving uDCD liver grafts. The series comprises 75 OLT performed during 11 years. RESULTS The incidence of PNF using uDCD livers was 8%. We compared patients who developed PNF (n = 6) vs. patients without PNF (n = 69). Mean pump flow of donors during normothermic regional perfusion (NRP) was significantly lower in PNF (p = .032). Day 1 post-OLT levels of transaminases and the incidence of renal complications and postoperative mortality were also significantly higher in the PNF group, but 5-year patient survival was similar in both groups (66.7% in PNF and 68.5% in non-PNF). All PNF patients underwent re-OLT, and 2 died. PNF incidence has decreased in the last 5-years. Binary logistic regression analysis confirmed final ALT value >4 times the normal value as risk factor for PNF, and median donor pump flow >3700 ml/min as protective effect. CONCLUSIONS Adequate donor pump flow during NRP was a protective.
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Affiliation(s)
- Iago Justo
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - Anisa Nutu
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - María García-Conde
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - Alberto Marcacuzco
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - Alejandro Manrique
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - Jorge Calvo
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - Álvaro García-Sesma
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - Óscar Caso
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
| | - Carmen Martín-Arriscado
- Unit of Statistical Analysis, "Doce de Octubre" Hospital, Complutense University, Madrid, Spain
| | - Amado Andrés
- Service of Nephrology and Kidney Transplantation, "Doce de Octubre" Hospital, Complutense University, Madrid, Spain
| | - Estela Paz
- Service of Immunology, "Doce de Octubre" Hospital, Complutense University, Madrid, Spain
| | - Carlos Jiménez-Romero
- Unit of HPB Surgery and Abdominal Organ Transplantation, Department of Surgery, Faculty of Medicine, Doce de Octubre" Hospital, Instituto de Investigación (imas12), Complutense University, Madrid, Spain
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Panayotova GG, Lunsford KE, Guarrera JV. Bile formation in long-term (1 week), ex situ perfused livers: Analysis and commentary. Surgery 2020; 169:1551-1552. [PMID: 33218702 DOI: 10.1016/j.surg.2020.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Guergana G Panayotova
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, Newark, NJ
| | - Keri E Lunsford
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, Newark, NJ; Center for Immunity and Inflammation, Institute for Infectious and Inflammatory Disease, Rutgers New Jersey Medical School, Newark, NJ
| | - James V Guarrera
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, Newark, NJ.
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Perfusate Analysis During Dual Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Correlations With Donor Factors and Early Outcomes. Transplantation 2020; 104:1929-1942. [PMID: 32769628 DOI: 10.1097/tp.0000000000003398] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver graft viability assessment has long been considered a limit of hypothermic oxygenated machine perfusion (HOPE). Aim of this study was assessing correlations of easily available perfusate parameters (PP) (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glucose, lactate, and pH) with graft features and outcome. METHODS In the period October 2018-February 2020, perfusate samples were obtained every 30 minutes during 50 dual-HOPE (D-HOPE) procedures. Correlations of PP with graft factors, 90-day graft loss, early allograft dysfunction (EAD), L-GrAFT score, acute kidney injury, and comprehensive complication index were analyzed using Pearson coefficient, receiver-operating characteristics analysis and by univariable and multivariable regression. RESULTS Median D-HOPE time was 122 minutes. All parameters were normalized to liver weight. Only macrovesicular steatosis (MaS) significantly impacted PP levels and slope. Grafts with ≥30% MaS exhibited significantly different PP values and slope. Graft loss and EAD rate were 2% (n = 1) and 26% (n = 13). All PP except lactate correlated with EAD, 90-minute alanine aminotransferase showing the highest area under the receiver-operating characteristics curve (0.84). However, at multivariable analysis, the only factor independently associated with EAD was MaS (odds ratio, 5.44; confidence interval, 1.05-28.21; P = 0.04). Ninety minutes lactate dehydrogenase had the strongest correlation with L-GrAFT (R = 0.70; P < 0.001). PP correlated poorly with comprehensive complication index and grades 2-3 acute kidney injury rate. CONCLUSIONS PP were predictive of graft function after transplant, but their association with graft survival and clinical outcomes requires further evaluation. MaS influenced levels of PP and was the only independent predictor of EAD.
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Karangwa S, Panayotova G, Dutkowski P, Porte RJ, Guarrera JV, Schlegel A. Hypothermic machine perfusion in liver transplantation. Int J Surg 2020; 82S:44-51. [PMID: 32353556 DOI: 10.1016/j.ijsu.2020.04.057] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/14/2020] [Accepted: 04/22/2020] [Indexed: 12/24/2022]
Abstract
Dynamic preservation strategies are a promising option to improve graft quality before transplantation, and to extend preservation time for either logistic or treatment reasons. In contrast to normothermic oxygenated perfusion, which intends to mimic physiological conditions in the human body, with subsequent clinical application for up to 24 hrs, hypothermic perfusion is mainly used for a relatively short period with protection of mitochondria and subsequent reduction of oxidative injury upon implantation. The results from two randomized controlled trials, where recruitment has finished are expected this year. Both ex situ perfusion techniques are increasingly applied in clinical transplantation including recent reports on viability assessment, which could open the door for an increased liver utilization in the future.
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Affiliation(s)
- S Karangwa
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - G Panayotova
- Department of Surgery, Division of Transplant and HPB Surgery, Rutgers NJMS/ University Hospital, Newark, NJ, USA
| | - P Dutkowski
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - R J Porte
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - J V Guarrera
- Department of Surgery, Division of Transplant and HPB Surgery, Rutgers NJMS/ University Hospital, Newark, NJ, USA
| | - A Schlegel
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, United Kingdom.
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Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation. EBioMedicine 2020; 60:103014. [PMID: 32979838 PMCID: PMC7519249 DOI: 10.1016/j.ebiom.2020.103014] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models. METHODS We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation. FINDINGS Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function. INTERPRETATION Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation. FUNDING detailed information can be found in Acknowledgments.
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Czigany Z, Craigie EC, Lurje G, Song S, Yonezawa K, Yamamoto Y, Minor T, Tolba RH. Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation. Int J Mol Sci 2020; 21:E6747. [PMID: 32938013 PMCID: PMC7555737 DOI: 10.3390/ijms21186747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 12/14/2022] Open
Abstract
Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20-25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany;
- Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, 52074 Aachen, Germany;
| | - Eve Christiana Craigie
- Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, 52074 Aachen, Germany;
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum–Charité-Universitätsmedizin, 13353 Berlin, Germany;
| | - Shaowei Song
- Department of Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110122, China;
| | - Kei Yonezawa
- Department of Surgery, Shizuoka City Hospital, Shizuoka 420-8527, Japan;
| | - Yuzo Yamamoto
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita 010-0825, Japan;
| | - Thomas Minor
- Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, 45147 Essen, Germany;
| | - René Hany Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, 52074 Aachen, Germany;
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Panayotova GG, Rosado J, Paterno F, Deo D, Dikdan G, McCarty MA, Arrington B, Giudice A, Fano A, Dhaduk N, Lunsford KE, Rao P, Guarrera JV. Novel oxygenation technique for hypothermic machine perfusion of liver grafts: Validation in porcine Donation after Cardiac Death (DCD) liver model. Am J Surg 2020; 220:1270-1277. [PMID: 32892979 DOI: 10.1016/j.amjsurg.2020.06.072] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/29/2020] [Accepted: 06/26/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Hypothermic oxygenated machine perfusion improves outcomes in Liver Transplantation, but application is limited as O2 is supplied by a stationary circuit. A novel technique of O2 "pre-charge" in a portable pump would broaden use and further mitigate ischemia damage from organ transport. METHODS Porcine DCD livers were randomized to static cold storage (SCS, n = 8) or hypothermic machine perfusion (HMP). HMP was stratified into HMP-O2 (n = 5), non-O2 open to air HMP-RA (n = 5), and non-O2 with sealed lids or no air HMP-NA (n = 5). HMP-O2 was "pre-charged" using 100% O2 delivered at 10 L/min over 15 min. Perfusate and tissue O2 tension (pO2), liver biopsies, and fluid chemistries were analyzed. RESULTS "Pre-charge" achieves sustained tissue and perfusate pO2 vs others. HMP-O2 results in decreased markers of hepatocyte injury: ALT (p < 0.05) and LDH (p < 0.05), lower expression of CRP and higher expression of SOD1 vs SCS. This suggests decreased inflammation and improved ROS scavenging. CONCLUSIONS "Pre-charge" is an effective technique, which allows portability and transport without an O2 source and improves graft parameters.
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Affiliation(s)
- Guergana G Panayotova
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA.
| | - Jesus Rosado
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA
| | - Flavio Paterno
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA
| | - Dayanand Deo
- New Jersey Sharing Network, 691 Central Avenue, New Providence, NJ, 07974, USA
| | - George Dikdan
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA
| | - Matthew A McCarty
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA
| | - Ben Arrington
- Organ Recovery Systems, One Pierce Place, Suite 475W, Itasca, IL, 60143, USA
| | - Anthony Giudice
- Organ Recovery Systems, One Pierce Place, Suite 475W, Itasca, IL, 60143, USA
| | - Adam Fano
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA
| | - Nehal Dhaduk
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA
| | - Keri E Lunsford
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA
| | - Prakash Rao
- New Jersey Sharing Network, 691 Central Avenue, New Providence, NJ, 07974, USA
| | - James V Guarrera
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, 185 South Orange Ave MSB G586, Newark, NJ, 07103, USA.
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Li T, Hu Z, Wang L, Lv GY. Details determining the success in establishing a mouse orthotopic liver transplantation model. World J Gastroenterol 2020; 26:3889-3898. [PMID: 32774064 PMCID: PMC7385559 DOI: 10.3748/wjg.v26.i27.3889] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/03/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is currently the only effective treatment option for end-stage liver disease. The importance of animal models in transplantation is widely recognized among researchers. Because of the well-characterized mouse genome and the greater diversity and availability of both genetically modified animals and research reagents, mouse orthotopic LT (MOLT) has become an ideal model for the investigation of liver biology, tissue injury, regulation of alloimmunity and tolerance induction, and the pathogenesis of specific liver diseases. However, due to its complicated and technically demanding procedure, the model has merely been used by only a few research groups in the world for years. For a new learner, training lasting at least a couple of months or even years is required. Most of the investigators have emphasized the importance of elaborate techniques and dedicated instruments in establishing a MOLT model, but some details are often neglected. The nontechnical details are also significant, especially for researchers who have little experience in mouse microsurgery. Here, we review and summarize the crucial technical and nontechnical details in establishing the model of MOLT based on scientific articles and our experience in six aspects: animal selection, anesthesia, perioperative management, organ procurement, back-table preparation, and implantation surgery. We aim to enable research groups to shorten the learning curve and implement the mouse LT procedure with high technical success.
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Affiliation(s)
- Ting Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun 130061, Jilin Province, China
| | - Lei Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guo-Yue Lv
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Ishihara Y, Bochimoto H, Kondoh D, Obara H, Matsuno N. The ultrastructural characteristics of bile canaliculus in porcine liver donated after cardiac death and machine perfusion preservation. PLoS One 2020; 15:e0233917. [PMID: 32470051 PMCID: PMC7259665 DOI: 10.1371/journal.pone.0233917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 05/14/2020] [Indexed: 12/16/2022] Open
Abstract
The effects of each type of machine perfusion preservation (MP) of liver grafts donated after cardiac death on the bile canaliculi of hepatocytes remain unclear. We analyzed the intracellular three-dimensional ultrastructure of the bile canaliculi and hepatocyte endomembrane systems in porcine liver grafts after warm ischemia followed by successive MP with modified University of Wisconsin gluconate solution. Transmission and osmium-maceration scanning electron microscopy revealed that lumen volume of the bile canaliculi decreased after warm ischemia. In liver grafts preserved by hypothermic MP condition, bile canaliculi tended to recover in terms of lumen volume, while their microvilli regressed. In contrast, midthermic MP condition preserved the functional form of the microvilli of the bile canaliculi. Machine perfusion preservation potentially restored the bile canaliculus lumen and alleviated the cessation of cellular endocrine processes due to warm ischemia. In addition, midthermic MP condition prevented the retraction of the microvilli of bile canaliculi, suggesting further mitigation of the damage of the bile canaliculi.
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Affiliation(s)
- Yo Ishihara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Bochimoto
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Japan
- Division of Aerospace Medicine, Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku, Japan
- * E-mail:
| | - Daisuke Kondoh
- Laboratory of Veterinary Anatomy, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Hiromichi Obara
- Department of Mechanical Engineering, Tokyo Metropolitan University, Hachioji, Japan
| | - Naoto Matsuno
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Japan
- Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
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Kvietkauskas M, Leber B, Strupas K, Stiegler P, Schemmer P. Machine Perfusion of Extended Criteria Donor Organs: Immunological Aspects. Front Immunol 2020; 11:192. [PMID: 32180769 PMCID: PMC7057848 DOI: 10.3389/fimmu.2020.00192] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 01/24/2020] [Indexed: 12/20/2022] Open
Abstract
Due to higher vulnerability and immunogenicity of extended criteria donor (ECD) organs used for organ transplantation (Tx), the discovery of new treatment strategies, involving tissue allorecognition pathways, is important. The implementation of machine perfusion (MP) led to improved estimation of the organ quality and introduced the possibility to achieve graft reconditioning prior to Tx. A significant number of experimental and clinical trials demonstrated increasing support for MP as a promising method of ECD organ preservation compared to classical static cold storage. MP reduced ischemia-reperfusion injury resulting in the protection from inadequate activation of innate immunity. However, there are no general agreements on MP protocols, and clinical application is limited. The objective of this comprehensive review is to summarize literature on immunological effects of MP of ECD organs based on experimental studies and clinical trials.
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Affiliation(s)
- Mindaugas Kvietkauskas
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Bettina Leber
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
| | | | - Philipp Stiegler
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
| | - Peter Schemmer
- Department of General, Visceral and Transplant Surgery, Medical University of Graz, Graz, Austria
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Oldani G, Peloso A, Slits F, Gex Q, Delaune V, Orci LA, van de Looij Y, Colin DJ, Germain S, de Vito C, Rubbia-Brandt L, Lacotte S, Toso C. The impact of short-term machine perfusion on the risk of cancer recurrence after rat liver transplantation with donors after circulatory death. PLoS One 2019; 14:e0224890. [PMID: 31765399 PMCID: PMC6876876 DOI: 10.1371/journal.pone.0224890] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 10/23/2019] [Indexed: 12/27/2022] Open
Abstract
Hypothermic and normothermic ex vivo liver perfusions promote organ recovery after donation after circulatory death (DCD). We tested whether these perfusions can reduce the risk of hepatocellular carcinoma (HCC) recurrence in a 1h-DCD syngeneic transplantation model, using Fischer F344 rats. DCD grafts were machine perfused for 2h with hypothermic perfusion (HOPE) or normothermic perfusion (NORMO), and transplanted. After reperfusion, we injected HCC cells into the vena porta. On day 28 after transplantation, we assessed tumour volumes by MRI. Control rats included transplantations with Fresh and non-perfused DCD livers. We observed apoptotic-necrotic hepatocyte foci in all DCD grafts, which were more visible than in the Fresh liver grafts. Normothermic perfusion allowed a faster post-transplant recovery, with lower day 1 levels of transaminases compared with the other DCD. Overall, survival was similar in all four groups and all animals developed HCCs. Total tumor volume was lower in the Fresh liver recipients compared to the DCD and DCD+HOPE recipients. Volumes in DCD+NORMO recipients were not significantly different from those in the Fresh group. This experiment confirms that ischemia/reperfusion injury promotes HCC cell engraftment/growth after DCD liver transplantation. Using the present extreme 1h ischemia model, both hypothermic and normothermic perfusions were not effective in reducing this risk.
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Affiliation(s)
- Graziano Oldani
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
- * E-mail:
| | - Andrea Peloso
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Florence Slits
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Quentin Gex
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Vaihere Delaune
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Lorenzo A. Orci
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Yohan van de Looij
- Division of Child Development & Growth, University Children's Hospital Geneva, Geneva, Switzerland
- Institute of Translational Molecular Imaging, University of Geneva, Geneva, Switzerland
| | - Didier J. Colin
- MicroPET/SPECT/CT Imaging Laboratory, Centre for BioMedical Imaging, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Stéphane Germain
- MicroPET/SPECT/CT Imaging Laboratory, Centre for BioMedical Imaging, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Claudio de Vito
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
- Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
- Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Stéphanie Lacotte
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
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