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Coilly A, Desterke C, Kaščáková S, Chiappini F, Samuel D, Vibert E, Guettier C, Le Naour F. Clinical Application of Infrared Spectroscopy in Liver Transplantation for Rapid Assessment of Lipid Content in Liver Graft. J Transl Med 2024; 104:102110. [PMID: 39004345 DOI: 10.1016/j.labinv.2024.102110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 07/02/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024] Open
Abstract
Liver transplantation (LT) is a major treatment for patients with end-stage liver diseases. Steatosis is a significant risk factor for primary graft nonfunction and associated with poor long-term graft outcomes. Traditionally, the evaluation of steatosis is based on frozen section examination to estimate the percentage of hepatocytes containing lipid vesicles. However, this visual evaluation correlates poorly with the true lipid content. This study aimed to address the potential of infrared (IR) microspectroscopy for rapidly estimating lipid content in the context of LT and assessing its impact on survival. Clinical data were collected for >20 months from 58 patients who underwent transplantation. For each liver graft, macrovacuolar steatosis and microvesicular steatosis were evaluated through histologic examination of frozen tissue section. Triglycerides (TG) were further quantified using gas phase chromatography coupled with a flame ionization detector (GC-FID) and estimated by IR microspectroscopy. A linear relationship and significant correlation were observed between the TG measured by GC-FID and those estimated using IR microspectroscopy (R2 = 0.86). In some cases, microvesicular steatosis was related to high lipid content despite low levels of macrovacuolar steatosis. Seven patients experienced posttransplantation liver failure, including 5 deceased patients. All patients underwent transplantation with grafts containing significantly high TG levels. A concentration of 250 nmol/mg was identified as the threshold above which the risk of failure after LT significantly increased, affecting 35% of patients. Our study established a strong correlation between LT outcomes and lipid content. IR microspectroscopy proved to be a rapid and reliable approach for assessing the lipid content in clinical settings.
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Affiliation(s)
- Audrey Coilly
- Inserm, Unité 1193, Villejuif, France; Université Paris Saclay, Institut André Lwoff, Villejuif, France; AP-HP Hôpital Paul Brousse, Centre Hépatobiliaire, Villejuif, France
| | - Christophe Desterke
- Université Paris Saclay, Institut André Lwoff, Villejuif, France; Inserm, US33, Villejuif, France
| | - Slávka Kaščáková
- Inserm, Unité 1193, Villejuif, France; Université Paris Saclay, Institut André Lwoff, Villejuif, France
| | - Franck Chiappini
- Inserm, Unité 1193, Villejuif, France; Université Paris Saclay, Institut André Lwoff, Villejuif, France
| | - Didier Samuel
- Inserm, Unité 1193, Villejuif, France; Université Paris Saclay, Institut André Lwoff, Villejuif, France; AP-HP Hôpital Paul Brousse, Centre Hépatobiliaire, Villejuif, France
| | - Eric Vibert
- Inserm, Unité 1193, Villejuif, France; Université Paris Saclay, Institut André Lwoff, Villejuif, France; AP-HP Hôpital Paul Brousse, Centre Hépatobiliaire, Villejuif, France
| | - Catherine Guettier
- Inserm, Unité 1193, Villejuif, France; Université Paris Saclay, Institut André Lwoff, Villejuif, France; AP-HP Hôpital Bicêtre, Service d'Anatomopathologie, Kremlin-Bicêtre, France.
| | - François Le Naour
- Inserm, Unité 1193, Villejuif, France; Université Paris Saclay, Institut André Lwoff, Villejuif, France; Inserm, US33, Villejuif, France.
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Abbas SH, Ceresa CDL, Hodson L, Nasralla D, Watson CJE, Mergental H, Coussios C, Kaloyirou F, Brusby K, Mora A, Thomas H, Kounali D, Keen K, Pollok JM, Gaurav R, Iype S, Jassem W, Perera MTP, Hakeem AR, Knight S, Friend PJ. Defatting of donor transplant livers during normothermic perfusion-a randomised clinical trial: study protocol for the DeFat study. Trials 2024; 25:386. [PMID: 38886851 PMCID: PMC11181618 DOI: 10.1186/s13063-024-08189-4] [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: 02/26/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes. METHODS In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months). DISCUSSION This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. TRIAL REGISTRATION ISRCTN ISRCTN14957538. Registered in October 2022.
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Affiliation(s)
- Syed Hussain Abbas
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK.
| | - Carlo D L Ceresa
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK
| | - David Nasralla
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Christopher J E Watson
- Department of Surgery, Addenbrooke's Hospital, Hills Road, University of Cambridge, Box 202, Cambridge, CB2 2QQ, UK
| | - Hynek Mergental
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK
- TransMedics Inc, 200 Minuteman Road, Andover, MA, 01810, USA
| | - Constantin Coussios
- Institute of Biomedical Engineering, Old Road Campus Research Building, University of Oxford, Oxford, OX3 7DQ, UK
| | | | | | - Ana Mora
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0BB, UK
| | - Helen Thomas
- NHS Blood and Transplant Clinical Trials Unit, Fox Den Road, Stoke Gifford, Bristol, BS34 8RR, UK
| | - Daphne Kounali
- Oxford Clinical Trials Research Unit (OCTRU), Centre for Statistics in Medicine (CSM), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Medical Sciences Division, The Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK
| | - Katie Keen
- NHSBT CTU, Long Road, Cambridge, CB2 0PT, UK
| | - Joerg-Matthias Pollok
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Rohit Gaurav
- Department of Surgery, Addenbrooke's Hospital, Hills Road, University of Cambridge, Box 202, Cambridge, CB2 2QQ, UK
| | - Satheesh Iype
- Royal Free London NHS Foundation Trust, The Royal Free Hospital, Pond St, Hampstead, London, NW3 2QG, UK
| | - Wayel Jassem
- Kings College Hospital, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK
| | - M Thamara Pr Perera
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TH, UK
| | - Abdul Rahman Hakeem
- Kings College Hospital, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK
- St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Beckett Street, Leeds, LS9 7TF, UK
| | - Simon Knight
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, OX3 7LJ, UK
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Watson CJ, Gaurav R, Butler AJ. Current Techniques and Indications for Machine Perfusion and Regional Perfusion in Deceased Donor Liver Transplantation. J Clin Exp Hepatol 2024; 14:101309. [PMID: 38274508 PMCID: PMC10806097 DOI: 10.1016/j.jceh.2023.101309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/27/2023] [Indexed: 01/27/2024] Open
Abstract
Since the advent of University of Wisconsin preservation solution in the 1980s, clinicians have learned to work within its confines. While affording improved outcomes, considerable limitations still exist and contribute to the large number of livers that go unused each year, often for fear they may never work. The last 10 years have seen the widespread availability of new perfusion modalities which provide an opportunity for assessing organ viability and prolonged organ storage. This review will discuss the role of in situ normothermic regional perfusion for livers donated after circulatory death. It will also describe the different modalities of ex situ perfusion, both normothermic and hypothermic, and discuss how they are thought to work and the opportunities afforded by them.
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Affiliation(s)
- Christopher J.E. Watson
- University of Cambridge Department of Surgery, Box 210, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
- The Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
| | - Rohit Gaurav
- The Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
| | - Andrew J. Butler
- University of Cambridge Department of Surgery, Box 210, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
- The Roy Calne Transplant Unit, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
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Xiang Z, Li J, Zeng H, Xiang X, Gao F, Wang K, Wei X, Zheng S, Xu X. Current Understanding of Marginal Grafts in Liver Transplantation. Aging Dis 2024; 16:1036-1058. [PMID: 38607739 PMCID: PMC11964436 DOI: 10.14336/ad.2024.0214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 02/14/2024] [Indexed: 04/14/2024] Open
Abstract
End-stage liver disease (ESLD), stemming from a spectrum of chronic liver pathologies including chronic liver failure, acute cirrhosis decompensation and hepatocellular carcinoma, imposes a significant global healthcare burden. Liver transplantation (LT) remains the only treatment for ESLD. However, the escalating mortality on transplant waitlists has prompted the utilization of marginal liver grafts in LT procedures. These grafts primarily encompass elderly livers, steatotic livers, livers from donation after circulatory death, split livers and those infected with the hepatitis virus. While the expansion of the donor pool offers promise, it also introduces concomitant risks. These encompass graft failure, biliary and cardiovascular complications, the recurrence of liver disease and reduced patient and graft survival. Consequently, various established strategies, ranging from improved donor-recipient matching to surgical interventions, have emerged to mitigate these risks. This article undertakes a comprehensive assessment of the current landscape, evaluating the viability of diverse marginal liver grafts. Additionally, it synthesizes approaches aimed at enhancing the quality of such marginal liver grafts. The overarching objective is to augment the donor pool and ameliorate the risk factors associated with the shortage of liver grafts.
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Affiliation(s)
- Ze Xiang
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Jiarui Li
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Huixuan Zeng
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Xiaonan Xiang
- Zhejiang University School of Medicine, Hangzhou 310058, China.
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, Cambridgeshire, UK.
| | - Fengqiang Gao
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Kai Wang
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
| | - Shusen Zheng
- Zhejiang University School of Medicine, Hangzhou 310058, China.
- Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China.
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China.
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
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Huang YL, Cheng J, Wang Y, Xu XL, Wang SW, Wei L, Dong Y. Hepatic steatosis using ultrasound-derived fat fraction: First technical and clinical evaluation. Clin Hemorheol Microcirc 2024; 86:51-61. [PMID: 37638422 DOI: 10.3233/ch-238102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
OBJECTIVES To explore the technical and clinical evaluation of ultrasound-derived fat fraction (UDFF) measurement in adult patients in whom fatty liver was suspected. MATERIALS AND METHODS In this prospective study, 41 participants were initially enrolled in our hospital between October 2022 and December 2022 and received UDFF assessment using Siemens ACUSON Sequoia system equipped with DAX transducer. UDFF measurement was performed three times to obtain UDFF values from each imaging location (V hepatic segment and VIII hepatic segment) per participant, and the depth (skin-to-capsule distance) was automatically measured. The echogenicity of liver tissue in B mode ultrasound (BMUS) was compared to the normal kidney tissue, and fatty liver was graded as mild (Grade 1), moderate (Grade 2), and severe (Grade 3). The median of the acquired overall median UDFF values was used for statistical analysis. All ultrasound examinations were performed by one of two radiologists (with 20 and 10 years of liver ultrasound imaging experience). RESULTS Finally, UDFF measurement was successfully performed on 38 participants to obtain valid values, including 21 men with a median age of 40.0 years (interquartile range [IQR]: 23.0 - 58.5) and 17 women with a median age of 60.0 years (IQR: 29.5 - 67.0). Fatty liver was diagnosed by BMUS features in 47.4% (18/38) participants. Among all participants, the median UDFF value was 7.0% (IQR: 4.0 - 15.6). A significant difference in UDFF values was found between participants with fatty liver and without fatty liver (U = 7.0, P < 0.001), and UDFF values elevated as the grade of the fatty liver increased (P < 0.001). The median UDFF values from the three UDFF measurements obtained during each ultrasound examination showed excellent agreement (ICC = 0.882 [95% confidence interval: 0.833 - 0.919]). The Spearman correlation of UDFF values in different depths was moderate, with a rs value of 0.546 (P < 0.001). No significant differences in UDFF values were found between V hepatic segment and VIII hepatic segment (U = 684.5, P = 0.697). CONCLUSIONS UDFF provides a novel non-invasive imaging tool for hepatic steatosis assessment with excellent feasibility.
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Affiliation(s)
- Yun-Lin Huang
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Juan Cheng
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Ying Wang
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xin-Liang Xu
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Shi-Wen Wang
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Li Wei
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yi Dong
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
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Kwong AJ, Kim WR, Lake J, Stock PG, Wang CJ, Wetmore JB, Melcher ML, Wey A, Salkowski N, Snyder JJ, Israni AK. Impact of Donor Liver Macrovesicular Steatosis on Deceased Donor Yield and Posttransplant Outcome. Transplantation 2023; 107:405-409. [PMID: 36042548 PMCID: PMC9877102 DOI: 10.1097/tp.0000000000004291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND The Scientific Registry of Transplant Recipients (SRTR) had not traditionally considered biopsy results in risk-adjustment models, yet biopsy results may influence outcomes and thus decisions regarding organ acceptance. METHODS Using SRTR data, which includes data on all donors, waitlisted candidates, and transplant recipients in the United States, we assessed (1) the impact of macrovesicular steatosis on deceased donor yield (defined as number of livers transplanted per donor) and 1-y posttransplant graft failure and (2) the effect of incorporating this variable into existing SRTR risk-adjustment models. RESULTS There were 21 559 donors with any recovered organ and 17 801 liver transplant recipients included for analysis. Increasing levels of macrovesicular steatosis on donor liver biopsy predicted lower organ yield: ≥31% macrovesicular steatosis on liver biopsy was associated with 87% to 95% lower odds of utilization, with 55% of these livers being discarded. The hazard ratio for graft failure with these livers was 1.53, compared with those with no pretransplant liver biopsy and 0% to 10% steatosis. There was minimal change on organ procurement organization-specific deceased donor yield or program-specific posttransplant outcome assessments when macrovesicular steatosis was added to the risk-adjustment models. CONCLUSIONS Donor livers with macrovesicular steatosis are disproportionately not transplanted relative to their risk for graft failure. To avoid undue risk aversion, SRTR now accounts for macrovesicular steatosis in the SRTR risk-adjustment models to help facilitate use of these higher-risk organs. Increased recognition of this variable may also encourage further efforts to standardize the reporting of liver biopsy results.
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Affiliation(s)
- Allison J. Kwong
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA
| | - W. Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA
- Scientific Registry of Transplant Recipients, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
| | - John Lake
- Scientific Registry of Transplant Recipients, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
| | - Peter G. Stock
- Scientific Registry of Transplant Recipients, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
- Division of Transplantation, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Connie J. Wang
- Division of Nephrology, Hennepin County Medical Center, and University of Minnesota, Minneapolis, MN, USA
| | - James B. Wetmore
- Division of Nephrology, Hennepin County Medical Center, and University of Minnesota, Minneapolis, MN, USA
| | - Marc L. Melcher
- Department of Surgery, Stanford University, Palo Alto, CA, USA
| | - Andrew Wey
- Scientific Registry of Transplant Recipients, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
| | - Nicholas Salkowski
- Scientific Registry of Transplant Recipients, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
| | - Jon J. Snyder
- Scientific Registry of Transplant Recipients, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
| | - Ajay K. Israni
- Scientific Registry of Transplant Recipients, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
- Division of Nephrology, Hennepin County Medical Center, and University of Minnesota, Minneapolis, MN, USA
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
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Li SX, Chen L, Li MQ, Lv GY. Pharmacological agents for defatting livers by normothermic machine perfusion. Artif Organs 2022. [PMID: 36514256 DOI: 10.1111/aor.14478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/28/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Ex-vivo normothermic machine perfusion (NMP) preserves the liver metabolism at 37°C and has rapidly developed as a promising approach for assessing the viability and improving the performance of organs from expanded criteria donors, including fatty liver grafts. NMP is an effective method for defatting fatty livers when combined with pharmaceutical therapies. Pharmacological agents have been shown to facilitate liver defatting by NMP. OBSERVATIONS This systematic review summarizes available pharmacological therapies for liver defatting, with a particular emphasis on defatting agents that can be employed clinically as defatting components during liver NMP as an ex vivo translational paradigm. CONCLUSION NMP provides an opportunity for organ treatment and can be used as a defatting platform in the future with defatting agents. Nagrath's cocktail is the most commonly used defatting cocktail in NMP; however, its carcinogenic components may limit its clinical application. Thus, the combination of a defatting cocktail with a new clinically applicable component, for example, a polyphenolic natural compound, may be a novel pharmacological option.
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Affiliation(s)
- Shu-Xuan Li
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
| | - Lanlan Chen
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
| | - Ming-Qian Li
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
| | - Guo-Yue Lv
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
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Scalera I, De Carlis R, Patrono D, Gringeri E, Olivieri T, Pagano D, Lai Q, Rossi M, Gruttadauria S, Di Benedetto F, Cillo U, Romagnoli R, Lupo LG, De Carlis L. How useful is the machine perfusion in liver transplantation? An answer from a national survey. Front Surg 2022; 9:975150. [PMID: 36211259 PMCID: PMC9535084 DOI: 10.3389/fsurg.2022.975150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Machine perfusion (MP) has been shown worldwide to offer many advantages in liver transplantation, but it still has some gray areas. The purpose of the study is to evaluate the donor risk factors of grafts, perfused with any MP, that might predict an ineffective MP setting and those would trigger post-transplant early allograft dysfunction (EAD). Data from donors of all MP-perfused grafts at six liver transplant centers have been analyzed, whether implanted or discarded after perfusion. The first endpoint was the negative events after perfusion (NegE), which is the number of grafts discarded plus those that were implanted but lost after the transplant. A risk factor analysis for NegE was performed and marginal grafts for MP were identified. Finally, the risk of EAD was analyzed, considering only implanted grafts. From 2015 to September 2019, 158 grafts were perfused with MP: 151 grafts were implanted and 7 were discarded after the MP phase because they did not reach viability criteria. Of 151, 15 grafts were lost after transplant, so the NegE group consisted of 22 donors. In univariate analysis, the donor risk index >1.7, the presence of hypertension in the medical history, static cold ischemia time, and the moderate or severe macrovesicular steatosis were the significant factors for NegE. Multivariate analysis confirmed that macrosteatosis >30% was an independent risk factor for NegE (odd ratio 5.643, p = 0.023, 95% confidence interval, 1.27-24.98). Of 151 transplanted patients, 34% experienced EAD and had worse 1- and 3-year-survival, compared with those who did not face EAD (NoEAD), 96% and 96% for EAD vs. 89% and 71% for NoEAD, respectively (p = 0.03). None of the donor/graft characteristics was associated with EAD even if the graft was moderately steatotic or fibrotic or from an aged donor. For the first time, this study shows that macrovesicular steatosis >30% might be a warning factor involved in the risk of graft loss or a cause of graft discard after the MP treatment. On the other hand, the MP seems to be useful in reducing the donor and graft weight in the development of EAD.
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Affiliation(s)
- Irene Scalera
- Hepatobiliary and Liver Transplant Unit, Department of Emergency and Organ Transplantation, University Hospital Policlinic of Bari, Bari, Italy
| | - R. De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - D. Patrono
- General Surgery 2U-Liver Transplant Centre, A.O.U. “Città della Salute e della Scienza”, Turin, Italy
| | - E. Gringeri
- Hepatobiliary Surgery and Liver Transplantation Unit, University Hospital of Padua, Padua, Italy
| | - T. Olivieri
- Hepato-Pancreato-Biliary Surgery and Liver Transplant Center, University of Modena and Reggio Emilia, Modena, Italy
| | - D. Pagano
- Department for the Treatment and the Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT, UPMC, Palermo, Italy
- Department of Surgery and Medical and Surgical Specialties, University of Catania, Catania, Italy
| | - Q. Lai
- Liver Transplant Unit, Sapienza University of Rome, Rome, Italy
| | - M. Rossi
- Liver Transplant Unit, Sapienza University of Rome, Rome, Italy
| | - S. Gruttadauria
- Department for the Treatment and the Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT, UPMC, Palermo, Italy
- Department of Surgery and Medical and Surgical Specialties, University of Catania, Catania, Italy
| | - F. Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplant Center, University of Modena and Reggio Emilia, Modena, Italy
| | - U. Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, University Hospital of Padua, Padua, Italy
| | - R. Romagnoli
- General Surgery 2U-Liver Transplant Centre, A.O.U. “Città della Salute e della Scienza”, Turin, Italy
| | - L. G. Lupo
- Hepatobiliary and Liver Transplant Unit, Department of Emergency and Organ Transplantation, University Hospital Policlinic of Bari, Bari, Italy
| | - L. De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
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Gedallovich SM, Ladner DP, VanWagner LB. Liver transplantation in the era of non-alcoholic fatty liver disease/metabolic (dysfunction) associated fatty liver disease: the dilemma of the steatotic liver graft on transplantation and recipient survival. Hepatobiliary Surg Nutr 2022; 11:425-429. [PMID: 35693416 PMCID: PMC9186195 DOI: 10.21037/hbsn-22-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/07/2022] [Indexed: 01/10/2025]
Affiliation(s)
- Seren M. Gedallovich
- Division of Palliative Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Daniela P. Ladner
- Division of Organ Transplantation, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Lisa B. VanWagner
- Division of Gastroenterology & Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Division of Epidemiology, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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10
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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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11
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Delacôte C, Favre M, El Amrani M, Ningarhari M, Lemaitre E, Ntandja‐Wandji LC, Bauvin P, Boleslawski E, Millet G, Truant S, Mathurin P, Louvet A, Canva V, Lebuffe G, Pruvot FR, Dharancy S, Lassailly G. Morbid obesity increases death and dropout from the liver transplantation waiting list: A prospective cohort study. United European Gastroenterol J 2022; 10:396-408. [PMID: 35470965 PMCID: PMC9103369 DOI: 10.1002/ueg2.12226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/18/2022] [Indexed: 12/17/2022] Open
Abstract
UNLABELLED Liver transplant (LT) candidates with a body mass index (BMI) over 40 kg/m2 have lower access to a liver graft without clear explanation. Thus, we studied the impact of obesity on the waiting list (WL) and aimed to explore graft proposals and refusal. METHOD Data between January 2007 and December 2017 were extracted from the French prospective national database: CRISTAL. Competing risk analyses were performed to evaluate predictors of receiving LT. Competitive events were (1) death/WL removal for disease aggravation or (2) improvement. The link between grade obesity, grafts propositions, and reason for refusal was studied. RESULTS 15,184 patients were analysed: 10,813 transplant, 2847 death/dropout for aggravation, 748 redirected for improvement, and 776 censored. Mortality/dropout were higher in BMI over 35 (18% vs. 14% 1 year after listing) than in other candidates. In multivariate analysis, BMI>35, age, hepatic encephalopathy, and ascites were independent predictors of death/dropout. Candidates with a BMI ≥ 35 kg/m2 had reduced access to LT, without differences in graft proposals. However, grafts refusal was more frequent especially for 'morphological incompatibility' (14.9% vs. 12.7% p < 0.01). CONCLUSION BMI over 35 kg/m2 reduces access to LT with increased risk of dropout and mortality. Increased mortality and dropout could be due to a lower access to liver graft secondary to increased graft refusal for morphological incompatibility.
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Affiliation(s)
- Claire Delacôte
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
| | - Mathilde Favre
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
| | - Medhi El Amrani
- Service de chirurgie digestive et transplantation hépatiqueCHRU de LilleLilleFrance
| | - Massih Ningarhari
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
| | - Elise Lemaitre
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
| | - Line Carolle Ntandja‐Wandji
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
| | - Pierre Bauvin
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
| | - Emmanuel Boleslawski
- Service de chirurgie digestive et transplantation hépatiqueCHRU de LilleLilleFrance
| | - Guillaume Millet
- Service de chirurgie digestive et transplantation hépatiqueCHRU de LilleLilleFrance
| | - Stephanie Truant
- Service de chirurgie digestive et transplantation hépatiqueCHRU de LilleLilleFrance
| | - Philippe Mathurin
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
| | - Alexandre Louvet
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
| | - Valérie Canva
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
| | - Gilles Lebuffe
- Service de chirurgie digestive et transplantation hépatiqueCHRU de LilleLilleFrance
- CHU de Lille, Anesthesiology and Intensive CareUniversity of LilleLilleFrance
| | - François René Pruvot
- Service de chirurgie digestive et transplantation hépatiqueCHRU de LilleLilleFrance
| | - Sébastien Dharancy
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
| | - Guillaume Lassailly
- INSERM U1286INFINTEInstitute for Translational Research in InflammationUniversity LilleLilleFrance
- Service des maladies de l'appareil, digestifUniversity Lille, CHU de LilleLilleFrance
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12
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Tien C, Remulla D, Kwon Y, Emamaullee J. Contemporary strategies to assess and manage liver donor steatosis: a review. Curr Opin Organ Transplant 2021; 26:474-481. [PMID: 34524179 PMCID: PMC8447219 DOI: 10.1097/mot.0000000000000893] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW Due to a persistent shortage of donor livers, attention has turned toward ways of utilizing marginal grafts, particularly those with steatosis, without incurring inferior outcomes. Here we review the evaluation and utilization of steatotic liver allografts, highlight recently published data, and discuss novel methods of graft rehabilitation. RECENT FINDINGS Although severe liver allograft (>60%) steatosis has been associated with inferior graft and recipient outcomes, mild (<30%) steatosis has not. There is ongoing debate regarding safe utilization of grafts with moderate (30-60%) steatosis. Presently, no established protocols for evaluating steatosis in donor candidates or utilizing such grafts exist. Liver biopsy is accepted as the gold standard technique, though noninvasive methods have shown promise in accurately predicting steatosis. More recently, machine perfusion has been shown to enhance ex situ liver function and reduce steatosis, emerging as a potential means of optimizing steatotic grafts prior to transplantation. SUMMARY Steatotic liver allografts constitute a large proportion of deceased donor organs. Further work is necessary to define safe upper limits for the acceptable degree of steatosis, develop standardized evaluation protocols, and establish utilization guidelines that prioritize safety. Machine perfusion has shown promise in rehabilitating steatotic grafts and offers the possibility of expanding the deceased donor pool.
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Affiliation(s)
- Christine Tien
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Daphne Remulla
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Yong Kwon
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Department of Surgery, University of Southern California, Los Angeles, CA
| | - Juliet Emamaullee
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Department of Surgery, University of Southern California, Los Angeles, CA
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13
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Asong-Fontem N, Panisello-Rosello A, Lopez A, Imai K, Zal F, Delpy E, Rosello-Catafau J, Adam R. A Novel Oxygen Carrier (M101) Attenuates Ischemia-Reperfusion Injuries during Static Cold Storage in Steatotic Livers. Int J Mol Sci 2021; 22:8542. [PMID: 34445250 PMCID: PMC8395216 DOI: 10.3390/ijms22168542] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/30/2021] [Accepted: 08/05/2021] [Indexed: 12/14/2022] Open
Abstract
The combined impact of an increasing demand for liver transplantation and a growing incidence of nonalcoholic liver disease has provided the impetus for the development of innovative strategies to preserve steatotic livers. A natural oxygen carrier, HEMO2life®, which contains M101 that is extracted from a marine invertebrate, has been used for static cold storage (SCS) and has shown superior results in organ preservation. A total of 36 livers were procured from obese Zucker rats and randomly divided into three groups, i.e., control, SCS-24H and SCS-24H + M101 (M101 at 1 g/L), mimicking the gold standard of organ preservation. Ex situ machine perfusion for 2 h was used to evaluate the quality of the livers. Perfusates were sampled for functional assessment, biochemical analysis and subsequent biopsies were performed for assessment of ischemia-reperfusion markers. Transaminases, GDH and lactate levels at the end of reperfusion were significantly lower in the group preserved with M101 (p < 0.05). Protection from reactive oxygen species (low MDA and higher production of NO2-NO3) and less inflammation (HMGB1) were also observed in this group (p < 0.05). Bcl-1 and caspase-3 were higher in the SCS-24H group (p < 0.05) and presented more histological damage than those preserved with HEMO2life®. These data demonstrate, for the first time, that the addition of HEMO2life® to the preservation solution significantly protects steatotic livers during SCS by decreasing reperfusion injury and improving graft function.
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Affiliation(s)
- Njikem Asong-Fontem
- Unité Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, 94800 Villejuif, France; (A.L.); (R.A.)
| | - Arnau Panisello-Rosello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Catalonia, Spain; (A.P.-R.); (J.R.-C.)
| | - Alexandre Lopez
- Unité Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, 94800 Villejuif, France; (A.L.); (R.A.)
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8555, Japan;
| | - Franck Zal
- Hémarina SA, Aéropôle Centre, 29600 Morlaix, France; (F.Z.); (E.D.)
| | - Eric Delpy
- Hémarina SA, Aéropôle Centre, 29600 Morlaix, France; (F.Z.); (E.D.)
| | - Joan Rosello-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Catalonia, Spain; (A.P.-R.); (J.R.-C.)
| | - René Adam
- Unité Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, 94800 Villejuif, France; (A.L.); (R.A.)
- Centre Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Université Paris-Saclay, Villejuif, 94800 Paris, France
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14
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Goumard C, Turco C, Sakka M, Aoudjehane L, Lesnik P, Savier E, Conti F, Scatton O. Ex-Vivo Pharmacological Defatting of the Liver: A Review. J Clin Med 2021; 10:jcm10061253. [PMID: 33803539 PMCID: PMC8002874 DOI: 10.3390/jcm10061253] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 12/16/2022] Open
Abstract
The ongoing organ shortage has forced transplant teams to develop alternate sources of liver grafts. In this setting, ex-situ machine perfusion has rapidly developed as a promising tool to assess viability and improve the function of organs from extended criteria donors, including fatty liver grafts. In particular, normothermic machine perfusion represents a powerful tool to test a liver in full 37 °C metabolism and add pharmacological corrections whenever needed. In this context, many pharmacological agents and therapeutics have been tested to induce liver defatting on normothermic machine perfusion with promising results even on human organs. This systematic review makes a comprehensive synthesis on existing pharmacological therapies for liver defatting, with special focus on normothermic liver machine perfusion as an experimental ex-vivo translational model.
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Affiliation(s)
- Claire Goumard
- Department of Hepatobiliary Surgery and Liver Transplantation, Sorbonne Université, Hôpital Pitié-Salpêtrière, Assistance Publique-Hopitaux de Paris, 75013 Paris, France; (C.T.); (E.S.); (O.S.)
- Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS-938, Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France; (L.A.); (F.C.)
- Correspondence:
| | - Célia Turco
- Department of Hepatobiliary Surgery and Liver Transplantation, Sorbonne Université, Hôpital Pitié-Salpêtrière, Assistance Publique-Hopitaux de Paris, 75013 Paris, France; (C.T.); (E.S.); (O.S.)
- Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS-938, Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France; (L.A.); (F.C.)
| | - Mehdi Sakka
- Department of Metabolic Biochemistry, Sorbonne Université, Hôpital Pitié-Salpêtrière, Assistance Publique- Hopitaux de Paris, 75013 Paris, France;
| | - Lynda Aoudjehane
- Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS-938, Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France; (L.A.); (F.C.)
| | - Philippe Lesnik
- Sorbonne Université, INSERM UMRS-1166, Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France;
| | - Eric Savier
- Department of Hepatobiliary Surgery and Liver Transplantation, Sorbonne Université, Hôpital Pitié-Salpêtrière, Assistance Publique-Hopitaux de Paris, 75013 Paris, France; (C.T.); (E.S.); (O.S.)
- Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS-938, Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France; (L.A.); (F.C.)
| | - Filomena Conti
- Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS-938, Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France; (L.A.); (F.C.)
| | - Olivier Scatton
- Department of Hepatobiliary Surgery and Liver Transplantation, Sorbonne Université, Hôpital Pitié-Salpêtrière, Assistance Publique-Hopitaux de Paris, 75013 Paris, France; (C.T.); (E.S.); (O.S.)
- Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS-938, Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France; (L.A.); (F.C.)
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15
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Mazilescu LI, Selzner M, Selzner N. Defatting strategies in the current era of liver steatosis. JHEP Rep 2021; 3:100265. [PMID: 34027337 PMCID: PMC8121960 DOI: 10.1016/j.jhepr.2021.100265] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 02/14/2021] [Accepted: 02/19/2021] [Indexed: 12/25/2022] Open
Abstract
Liver steatosis is emerging as a major cause of chronic liver disease worldwide, mainly due to the increasing rate of obesity, type 2 diabetes, and metabolic syndrome. Because of the increased incidence of liver steatosis, many organs are currently declined for transplantation despite high demand and waiting list mortality. Defatting strategies have recently emerged as a means of rapidly reducing liver steatosis to expand the pool of available organs. This review summarises advances in defatting strategies in experimental and human models of liver steatosis over the last 20 years.
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Key Words
- GDNF, glial cell-line derived neurotrophic factor
- HFD, high-fat diet
- HIEC, hepatic endothelial cells
- HOPE, hypothermic machine perfusion
- LDs, lipid droplets
- Macrosteatosis
- NAFL, non-alcoholic fatty liver
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NEsLP, normothermic ex situ machine perfusion
- PHHs, primary human hepatocytes
- PPAR, peroxisome proliferator-activated receptor
- PXR, pregnane X receptor
- SCS, static cold storage
- SRS, steatosis reduction supplements
- TG, triglyceride
- ischemia-reperfusion injury
- liver transplantation
- machine perfusion
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Affiliation(s)
- Laura Ioana Mazilescu
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Markus Selzner
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
| | - Nazia Selzner
- Ajmera Transplant Program, Toronto General Hospital, Ontario, Canada
- Corresponding author. Address: Multi-Organ Transplant Program, Toronto General Hospital, 585 University Avenue, 11 PMB-178 Toronto, ON, Canada M5G 2N2.
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16
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Magro B, Tacelli M, Mazzola A, Conti F, Celsa C. Biliary complications after liver transplantation: current perspectives and future strategies. Hepatobiliary Surg Nutr 2021; 10:76-92. [PMID: 33575291 DOI: 10.21037/hbsn.2019.09.01] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 08/29/2019] [Indexed: 12/29/2022]
Abstract
Importance Liver transplantation (LT) is a life-saving therapy for patients with end-stage liver disease and with acute liver failure, and it is associated with excellent outcomes and survival rates at 1 and 5 years. The incidence of biliary complications (BCs) after LT is reported to range from 5% to 20%, most of them occurring in the first three months, although they can occur also several years after transplantation. Objective The aim of this review is to summarize the available evidences on pathophysiology, risk factors, diagnosis and therapeutic management of BCs after LT. Evidence Review a literature review was performed of papers on this topic focusing on risk factors, classifications, diagnosis and treatment. Findings Principal risk factors include surgical techniques and donor's characteristics for biliary leakage and anastomotic biliary strictures and vascular alterations for non- anastomotic biliary strictures. MRCP is the gold standard both for intra- and extrahepatic BCs, while invasive cholangiography should be restricted for therapeutic uses or when MRCP is equivocal. About treatment, endoscopic techniques are the first line of treatment with success rates of 70-100%. The combined success rate of ERCP and PTBD overcome 90% of cases. Biliary leaks often resolve spontaneously, or with the positioning of a stent in ERCP for major bile leaks. Conclusions and Relevance BCs influence morbidity and mortality after LT, therefore further evidences are needed to identify novel possible risk factors, to understand if an immunological status that could lead to their development exists and to compare the effectiveness of innovative surgical and machine perfusion techniques.
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Affiliation(s)
- Bianca Magro
- Section of Gastroenterology and Hepatology, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy.,Service d'Hépatologie et Transplantation Hépatique, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France
| | - Matteo Tacelli
- Section of Gastroenterology and Hepatology, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
| | - Alessandra Mazzola
- Service d'Hépatologie et Transplantation Hépatique, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France
| | - Filomena Conti
- Service d'Hépatologie et Transplantation Hépatique, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France
| | - Ciro Celsa
- Section of Gastroenterology and Hepatology, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
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17
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Boteon YL, Boteon AP. Impact of Graded Donor Liver Steatosis on Ischemia-Reperfusion Injury After Liver Transplantation: Where are We now? J Clin Exp Hepatol 2021; 11:157-158. [PMID: 33679054 PMCID: PMC7897850 DOI: 10.1016/j.jceh.2020.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 06/14/2020] [Indexed: 12/12/2022] Open
Affiliation(s)
- Yuri L. Boteon
- Department of Liver Transplant, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
| | - Amanda P.C.S. Boteon
- Department of Liver Transplant, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
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18
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Gao J, He K, Xia Q, Zhang J. Research progress on hepatic machine perfusion. Int J Med Sci 2021; 18:1953-1959. [PMID: 33850464 PMCID: PMC8040389 DOI: 10.7150/ijms.56139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/12/2021] [Indexed: 01/08/2023] Open
Abstract
Nowadays, liver transplantation is the most effective treatment for end-stage liver disease. However, the increasing imbalance between growing demand for liver transplantation and the shortage of donor pool restricts the development of liver transplantation. How to expand the donor pool is a significant problem to be solved clinically. Many doctors have devoted themselves to marginal grafting, which introduces livers with barely passable quality but a high risk of transplant failure into the donor pool. However, existing common methods of preserving marginal grafts lead to both high risk of postoperative complications and high mortality. The application of machine perfusion allows surgeons to make marginal livers meet the standard criteria for transplant, which shows promising prospect in preserving and repairing donor livers and improving ischemia reperfusion injury. This review summarizes the progress of recent researches on hepatic machine perfusion.
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Affiliation(s)
- Junda Gao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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19
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Oxygen Transport during Ex Situ Machine Perfusion of Donor Livers Using Red Blood Cells or Artificial Oxygen Carriers. Int J Mol Sci 2020; 22:ijms22010235. [PMID: 33379394 PMCID: PMC7795786 DOI: 10.3390/ijms22010235] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/14/2020] [Accepted: 12/24/2020] [Indexed: 12/21/2022] Open
Abstract
Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use.
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20
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Gill MG, Majumdar A. Metabolic associated fatty liver disease: Addressing a new era in liver transplantation. World J Hepatol 2020; 12:1168-1181. [PMID: 33442446 PMCID: PMC7772736 DOI: 10.4254/wjh.v12.i12.1168] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/08/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD), previously termed non-alcoholic fatty liver disease, is the leading global cause of liver disease and is fast becoming the most common indication for liver transplantation. The recent change in nomenclature to MAFLD refocuses the conceptualisation of this disease entity to its metabolic underpinnings and may help to spur a paradigm shift in the approach to its management, including in the setting of liver transplantation. Patients with MAFLD present significant challenges in the pre-, peri- and post-transplant settings, largely due to the presence of medical comorbidities that include obesity, metabolic syndrome and cardiovascular risk factors. As the community prevalence of MAFLD increases concurrently with the obesity epidemic, donor liver steatosis is also a current and future concern. This review outlines current epidemiology, nomenclature, management issues and outcomes of liver transplantation in patients with MAFLD.
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Affiliation(s)
- Madeleine G Gill
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, New South Wales, Australia
| | - Avik Majumdar
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, New South Wales, Australia
- Central Clinical School, The University of Sydney, Sydney 2050, New South Wales, Australia
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21
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Liu Z, Wang W, Zhuang L, Liu J, Que S, Zhu D, Dong L, Yu J, Zhou L, Zheng S. Clear mortality gap caused by graft macrosteatosis in Chinese patients after cadaveric liver transplantation. Hepatobiliary Surg Nutr 2020; 9:739-758. [PMID: 33299829 PMCID: PMC7720047 DOI: 10.21037/hbsn.2019.12.02] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/21/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Liver transplantation (LT) is one of the most effective surgical treatment for patients with end-stage liver disease. Steatosis is a contributor for inferior graft quality. But its impact and safety on transplantation was less assessed in Chinese patients. METHODS Graft steatosis and related information involved in recipients, donors and surgical procedures were retrospectively collected from 239 patients. RESULTS Donor macrosteatosis (MaS) caused about 2.14 and 2.80 folds of increment on patient and graft mortality. Dose-response analysis revealed prominent risk of grafts on overall patient/organ mortality when MaS content exceeded 10% (P<0.05). Noteworthy, deaths were only observed in MaS group when concurrent with extremely higher post-transplant alanine aminotransferase (ALT, 64%). However, microsteatosis (MiS) grafts didn't affect outcomes after LT. In a cohort of Chinese patients, MaS had comprehensive effects on post-transplant outcomes with relatively lower safety threshold at 10%. Mortality gap caused by MaS grafts was observed in patients with severer ischemia reperfusion injury. CONCLUSIONS Our study revealled the graft MaS affected the post-transplant outcomes in lower risk cutoff in Chinese patients. Further study is worthy to validate these results and investigate inner mechanism under the phenomenon.
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Affiliation(s)
- Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenchao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Zhuang
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Jingfeng Liu
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Shuping Que
- Science for Life Laboratory, KTH - Royal Institute of Technology, SE-171 21, Stockholm, Sweden
- Dingxiang Clinics, Hangzhou, China
| | - Dan Zhu
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Linfang Dong
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Jian Yu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
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22
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Chen G, Jiang J, Wang X, Yang M, Xie Y, Guo H, Tang H, Zhou L, Hu D, Kamel IR, Chen Z, Li Z. Evaluation of hepatic steatosis before liver transplantation in ex vivo by volumetric quantitative PDFF-MRI. Magn Reson Med 2020; 85:2805-2814. [PMID: 33197060 DOI: 10.1002/mrm.28592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/20/2020] [Accepted: 10/20/2020] [Indexed: 01/06/2023]
Abstract
PURPOSE Over the last two decades, extended criteria have promoted an increased number of donor livers available for liver transplantation. But posttransplant graft loss is still a major concern. Macrovesicular hepatic steatosis (MHS) is recognized as the most significant prognostic histologic parameter in predicting posttransplant graft loss. We aimed to evaluate the utility of ex vivo volumetric quantitative MRI for quantifying MHS before liver transplantation using proton density fat-fraction (PDFF-MRI) histogram analysis. METHODS PDFF-MRI was performed at 3.0T in 40 livers. We obtained histogram parameters of whole-liver volume of interest, including the mean, median, 5th, 10th, 25th, 75th, 90th, and 95th percentile PDFF; skewness; kurtosis; entropy; and volume. RESULTS Livers from 40 cadaveric donors were included, and histologic ex vivo fat quantification was available for 33 livers. Ten livers had MHS and 23 had normal fat content. The MHS group had higher mean, median, 5th, 10th, 25th, 75th, 90th, and 95th percentile PDFF, and entropy than the group with normal fat content (P < .05). Median PDFF had greater area under the curve value than other parameters. Mean PDFF showed an excellent correlation with entropy and a moderate correlation with MHS quantification on histology. CONCLUSIONS Ex vivo volumetric quantitative PDFF-MRI histogram analysis is a very useful and noninvasive method to detect MHS before liver transplantation. Median PDFF was the best predictor of the presence of MHS. Entropy is a very promising parameter.
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Affiliation(s)
- Gen Chen
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jipin Jiang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xinqiang Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Min Yang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yalong Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hui Guo
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hao Tang
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lifen Zhou
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Daoyu Hu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ihab R Kamel
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Zhishui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhen Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Miyachi Y, Yagi S, Hirata M, Iwamura S, Yao S, Shirai H, Okumura S, Iida T, Ito T, Uozumi R, Kaido T, Uemoto S. Etiology of Liver Steatosis Influences the Severity of Ischemia/Reperfusion Injury and Survival After Liver Transplantation in Rats. Liver Transpl 2020; 26:1504-1515. [PMID: 32511857 DOI: 10.1002/lt.25814] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/27/2020] [Accepted: 05/21/2020] [Indexed: 01/13/2023]
Abstract
Liver steatosis is a leading cause of graft disposal in liver transplantation, though the degree of steatosis is often the single factor determining acceptability of the graft. We investigated how the cause of liver steatosis affects graft function in rat orthotopic liver transplantation (OLT). OLT was performed using 2 types of steatotic liver grafts: the fasting and hyperalimentation (FHA) model and the methionine- and choline-deficient diet models. The FHA and 4-week feeding of a methionine- and choline-deficient diet (MCDD4wk) groups showed similar liver triglyceride levels without signs of steatohepatitis. Therefore, the 2 groups were compared in the following experiment. With 6-hour cold storage, the 7-day survival rate after OLT was far worse in the FHA than in the MCDD4wk group (0% versus 100%, P = 0.002). With 1-hour cold storage, the FHA group showed higher aspartate aminotransferase and alanine aminotransferase levels and histological injury scores in zones 1 and 2 at 24 hours after reperfusion than the normal liver and MCDD4wk groups. Intrahepatic microcirculation and tissue adenosine triphosphate levels were significantly lower in the FHA group after reperfusion. Hepatocyte necrosis, sinusoidal endothelial cell injury, and abnormal swelling of the mitochondria were also found in the FHA group after reperfusion. Tissue malondialdehyde levels were higher in the MCDD4wk group before and after reperfusion. However, the grafts up-regulated several antioxidant enzymes soon after reperfusion. Even though the degree of steatosis was equivalent, the 2 liver steatosis models possessed quite unique basal characteristics and showed completely different responses against ischemia/reperfusion injury and survival after transplantation. Our results demonstrate that the degree of fat accumulation is not a single determinant for the usability of steatotic liver grafts.
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Affiliation(s)
- Yosuke Miyachi
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shintaro Yagi
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Masaaki Hirata
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Sena Iwamura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Siyuan Yao
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Hisaya Shirai
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shinya Okumura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Taku Iida
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Ryuji Uozumi
- Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
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AI finally provides augmented intelligence to liver surgeons. EBioMedicine 2020; 61:103064. [PMID: 33096474 PMCID: PMC7578663 DOI: 10.1016/j.ebiom.2020.103064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 09/25/2020] [Indexed: 11/29/2022] Open
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25
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Parente A, Osei-Bordom DC, Ronca V, Perera MTPR, Mirza D. Organ Restoration With Normothermic Machine Perfusion and Immune Reaction. Front Immunol 2020; 11:565616. [PMID: 33193335 PMCID: PMC7641637 DOI: 10.3389/fimmu.2020.565616] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation is the only recognized effective treatment for end-stage liver disease. However, organ shortages have become the main challenge for patients and physicians within the transplant community. Waiting list mortality remains an issue with around 10% of patients dying whilst waiting for an available organ. The post-transplantation period is also associated with an adverse complication rate for these specific cohorts of high-risk patients, particularly regarding patient and graft survival. Ischaemia reperfusion injury (IRI) has been highlighted as the mechanism of injury that increases parenchymal damage, which eventually lead to significant graft dysfunction and other poor outcome indicators. The consequences of IRI in clinical practice such as reperfusion syndrome, primary non-function of graft, allograft dysfunction, ischaemic biliary damage and early biliary complications can be life-threatening. IRI dictates the development of a significant inflammatory response that drives the pathway to eventual cell death. The main mechanisms of IRI are mitochondrial damage due to low oxygen tension within the hepatic micro-environment and severe adenosine triphosphate (ATP) depletion during the ischaemic period. After the restoration of normal blood flow, this damage is further enhanced by reoxygenation as the mitochondria respond to reperfusion by releasing reactive oxygen species (ROS), which in turn activate Kupffer cells within the hepatic micro-environment, leading to a pro-inflammatory response and eventual parenchymal cell apoptosis and associated tissue degradation. Machine perfusion (MP) is one emergent strategy considered to be one of the most important advances in organ preservation, restoration and transplantation. Indeed, MP has the potential to rescue frequently discarded organs and has been shown to limit the extent of IRI, leading to suppression of the deleterious pro-inflammatory response. This immunomodulation reduces the prevalence of allograft rejection, the use of immunosuppression therapy and minimizes post-transplant complications. This review aims to update the current knowledge of MP with a focus on normothermic machine liver perfusion (NMLP) and its potential role in immune response pathways.
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Affiliation(s)
- Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Daniel-Clement Osei-Bordom
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- National Institute for Health Research Birmingham Liver Biomedical Research Centre, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - M. Thamara P. R. Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Darius Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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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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27
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Majumdar A, Tsochatzis EA. Changing trends of liver transplantation and mortality from non-alcoholic fatty liver disease. Metabolism 2020; 111S:154291. [PMID: 32531295 DOI: 10.1016/j.metabol.2020.154291] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 05/18/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023]
Abstract
The rising tide of non-alcoholic fatty liver disease (NAFLD) associated with the obesity epidemic is a major international health concern. NAFLD is the leading global cause of liver disease with an estimated prevalence of 25% and is the fastest growing indication for liver transplantation (LT). The presence and severity of liver fibrosis is the only histologic predictor of clinical outcomes in this group. NAFLD poses several challenges in the peri-transplant setting including the management of multiple metabolic co-morbidities, post-transplant obesity and cardiovascular risk. However, post-LT outcomes in well-selected NAFLD patients appear similar to non-NAFLD indications, including in the setting of hepatocellular carcinoma (HCC). The rising prevalence of NAFLD may impact potential liver graft donors, which may in-turn adversely affect post-LT outcomes. This review outlines the current epidemiology, natural history and outcomes of NAFLD with a focus on pre- and post-liver transplant settings.
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Affiliation(s)
- Avik Majumdar
- AW Morrow Gastroenterology and Liver Centre, Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, Australia; Central Clinical School, The University of Sydney, Australia
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK; Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK.
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28
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Lai Q, Ruberto F, Pawlik TM, Pugliese F, Rossi M. Use of machine perfusion in livers showing steatosis prior to transplantation: a systematic review. Updates Surg 2020; 72:595-604. [PMID: 32449031 DOI: 10.1007/s13304-020-00797-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 05/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The role of machine perfusion (MP) in the evaluation of liver grafts with macrovesicular steatosis (MaS) remains ill-defined as only a limited number of studies has been reported. The objective of the current study was to provide a systematic review to evaluate the role of MP in the setting of MaS livers. METHODS A systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed. Eligible articles published up to April 2019 were included using the MEDLINE, Scopus, and Google Scholar databases. RESULTS Among the 422 articles screened, only 16 papers met the inclusion criteria. A total of 54 cases of MP use before liver transplantation were included. Sixteen (29.6%) grafts were from donors after circulatory death. In 22 (40.7%) cases, hypothermic machine perfusion was performed. Normothermic machine perfusion was done in the remaining 32 (59.3%) cases. According to the histological results of the donor core biopsy, a MaS value < 30% was observed in 41 (75.9%) cases, whereas 13 (24.1%) patients had moderate-to-severe (≥ 30%) MaS. Following categorization of the pooled population according to the presence of moderate-to-severe (≥ 30%) MaS in the donor graft, no differences were noted in terms of post-transplant death or severe complications following MP. There was no correlation between the proportion of MaS in the donor graft relative to post-transplant peak ALT among patients treated with MP. Among the entire pooled cohort, there was also no correlation between MaS values and ALT peak (R = 0.13; P = 0.42). CONCLUSIONS MP appears to be feasible and safe in MaS livers. Experience to date has been very limited, and the benefit of MP remains not determined. Prospective studies will need to define better the potential effect of "defatting" drugs used during the perfusion process on MaS.
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Affiliation(s)
- Quirino Lai
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
| | - Franco Ruberto
- Department of Anaesthesiology, Critical Care Medicine and Pain Therapy, Sapienza University of Rome, Rome, Italy
| | - Timothy M Pawlik
- The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Francesco Pugliese
- Department of Anaesthesiology, Critical Care Medicine and Pain Therapy, Sapienza University of Rome, Rome, Italy
| | - Massimo Rossi
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
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29
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Raigani S, Carroll C, Griffith S, Pendexter C, Rosales I, Deirawan H, Beydoun R, Yarmush M, Uygun K, Yeh H. Improvement of steatotic rat liver function with a defatting cocktail during ex situ normothermic machine perfusion is not directly related to liver fat content. PLoS One 2020; 15:e0232886. [PMID: 32396553 PMCID: PMC7217452 DOI: 10.1371/journal.pone.0232886] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 04/23/2020] [Indexed: 12/12/2022] Open
Abstract
There is a significant organ shortage in the field of liver transplantation, partly due to a high discard rate of steatotic livers from donors. These organs are known to function poorly if transplanted but make up a significant portion of the available pool of donated livers. This study demonstrates the ability to improve the function of steatotic rat livers using a combination of ex situ machine perfusion and a "defatting" drug cocktail. After 6 hours of perfusion, defatted livers demonstrated lower perfusate lactate levels and improved bile quality as demonstrated by higher bile bicarbonate and lower bile lactate. Furthermore, defatting was associated with decreased gene expression of pro-inflammatory cytokines and increased expression of enzymes involved in mitochondrial fatty acid oxidation. Rehabilitation of marginal or discarded steatotic livers using machine perfusion and tailored drug therapy can significantly increase the supply of donor livers for transplantation.
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Affiliation(s)
- Siavash Raigani
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Shriners Hospital for Children, Boston, Massachusetts, United States of America
| | - Cailah Carroll
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Shriners Hospital for Children, Boston, Massachusetts, United States of America
| | - Stephanie Griffith
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Shriners Hospital for Children, Boston, Massachusetts, United States of America
| | - Casie Pendexter
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Shriners Hospital for Children, Boston, Massachusetts, United States of America
| | - Ivy Rosales
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Hany Deirawan
- Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, United States of America
| | - Rafic Beydoun
- Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, United States of America
| | - Martin Yarmush
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Shriners Hospital for Children, Boston, Massachusetts, United States of America
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - Korkut Uygun
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Shriners Hospital for Children, Boston, Massachusetts, United States of America
| | - Heidi Yeh
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
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30
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Nostedt JJ, Shapiro J, Freed DH, Bigam DL. Addressing organ shortages: progress in donation after circulatory death for liver transplantation. Can J Surg 2020; 63:E135-E141. [PMID: 32195556 DOI: 10.1503/cjs.005519] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Reducing wait list mortality among patients awaiting liver transplantation remains a substantial challenge because of organ shortage. In efforts to expand the donor pool there has been a trend toward increased use of donation after circulatory death (DCD) liver grafts. However, these marginal grafts are prone to higher complication rates, particularly biliary complications. In addition, many procured DCD livers are then deemed unsuitable for transplant. Despite these limitations, DCD grafts represent an important resource to address the current organ shortage, and as such there are research efforts directed toward improving the use of and outcomes for transplantation of these grafts. We review the current progress in DCD liver transplantation.
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Affiliation(s)
- Jordan J. Nostedt
- From the Department of Surgery, Division of General Surgery, University of Alberta Hospital, Edmonton, Alta. (Nostedt, Shapiro, Bigam); the Department of Physiology, University of Alberta, Edmonton, Alta. (Freed); and the Department of Surgery, Division of Cardiac Surgery, University of Alberta, Alberta Heart Institute, Edmonton, Alta. (Freed)
| | - James Shapiro
- From the Department of Surgery, Division of General Surgery, University of Alberta Hospital, Edmonton, Alta. (Nostedt, Shapiro, Bigam); the Department of Physiology, University of Alberta, Edmonton, Alta. (Freed); and the Department of Surgery, Division of Cardiac Surgery, University of Alberta, Alberta Heart Institute, Edmonton, Alta. (Freed)
| | - Darren H. Freed
- From the Department of Surgery, Division of General Surgery, University of Alberta Hospital, Edmonton, Alta. (Nostedt, Shapiro, Bigam); the Department of Physiology, University of Alberta, Edmonton, Alta. (Freed); and the Department of Surgery, Division of Cardiac Surgery, University of Alberta, Alberta Heart Institute, Edmonton, Alta. (Freed)
| | - David L. Bigam
- From the Department of Surgery, Division of General Surgery, University of Alberta Hospital, Edmonton, Alta. (Nostedt, Shapiro, Bigam); the Department of Physiology, University of Alberta, Edmonton, Alta. (Freed); and the Department of Surgery, Division of Cardiac Surgery, University of Alberta, Alberta Heart Institute, Edmonton, Alta. (Freed)
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Czigany Z, Lurje I, Schmelzle M, Schöning W, Öllinger R, Raschzok N, Sauer IM, Tacke F, Strnad P, Trautwein C, Neumann UP, Fronek J, Mehrabi A, Pratschke J, Schlegel A, Lurje G. Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications. J Clin Med 2020; 9:E846. [PMID: 32244972 PMCID: PMC7141496 DOI: 10.3390/jcm9030846] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP-which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion-will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Isabella Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Pavel Strnad
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Christian Trautwein
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Jiri Fronek
- Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic;
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Andrea Schlegel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK;
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
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32
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Matton APM, Selten JW, Roest HP, de Jonge J, IJzermans JNM, de Meijer VE, Porte RJ, van der Laan LJW. Cell-free microRNAs as early predictors of graft viability during ex vivo normothermic machine perfusion of human donor livers. Clin Transplant 2020; 34:e13790. [PMID: 31984571 PMCID: PMC7154637 DOI: 10.1111/ctr.13790] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 12/20/2019] [Accepted: 01/19/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cell-free microRNAs (miRs) have emerged as early and sensitive biomarkers for tissue injury and function. This study aimed to investigate whether the release of hepatocyte-derived microRNAs (HDmiRs) and cholangiocyte-derived miRs (CDmiRs) correlates with hepato-cholangiocellular injury and function during oxygenated, normothermic machine perfusion (NMP) of human liver grafts. METHODS Donor livers (n = 12), declined for transplantation, were subjected to oxygenated NMP (6 hours) after a period of static cold storage (median 544 minutes (IQR 421-674)). Perfusate and bile samples were analyzed by qRT-PCR for HDmiR-122 and CDmiR-222. Spearman correlations were performed between miR levels and currently available indicators and classic markers. RESULTS Both HDmiR-122 and CDmiR-222 levels in perfusate at 30 minutes of NMP strongly correlated with hepatocyte injury (peak perfusate AST) and cholangiocyte injury (peak biliary LDH). In bile, only CDmiR-222 correlated with these injury markers. For hepato-cholangiocellular function, both miRs in perfusate correlated with total bilirubin, while HDmiR-122 (in perfusate) and CDmiR-222 (in bile) correlated with bicarbonate secretion. Both the relative ratio of HDmiR-122/CDmiR-222 and AST in perfusate at 30 minutes significantly correlated with cumulative bile production, but only the relative ratio was predictive of histopathological injury after 6 hours NMP. CONCLUSION Early levels of HDmiR-122 and CDmiR-222, in perfusate and/or bile, are predictive of excretory functions and hepato-cholangiocellular injury after 6 hours NMP. These miRs may represent new biomarkers for graft viability and function during machine perfusion.
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Affiliation(s)
- Alix P. M. Matton
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Surgical Research LaboratoryDepartment of SurgeryUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Jasmijn W. Selten
- Department of SurgeryErasmus MC – University Medical Center RotterdamRotterdamThe Netherlands
| | - Henk P. Roest
- Department of SurgeryErasmus MC – University Medical Center RotterdamRotterdamThe Netherlands
| | - Jeroen de Jonge
- Department of SurgeryErasmus MC – University Medical Center RotterdamRotterdamThe Netherlands
| | - Jan N. M. IJzermans
- Department of SurgeryErasmus MC – University Medical Center RotterdamRotterdamThe Netherlands
| | - Vincent E. de Meijer
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Robert J. Porte
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Luc J. W. van der Laan
- Department of SurgeryErasmus MC – University Medical Center RotterdamRotterdamThe Netherlands
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33
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Affiliation(s)
- Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Yu Nie
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
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34
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Croome KP, Lee DD, Croome S, Chadha R, Livingston D, Abader P, Keaveny AP, Taner CB. The impact of postreperfusion syndrome during liver transplantation using livers with significant macrosteatosis. Am J Transplant 2019; 19:2550-2559. [PMID: 30821923 DOI: 10.1111/ajt.15330] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/24/2019] [Accepted: 02/19/2019] [Indexed: 01/25/2023]
Abstract
The impact of postreperfusion syndrome (PRS) during liver transplantation (LT) using donor livers with significant macrosteatosis is largely unknown. Clinical outcomes of all patients undergoing LT with donor livers with moderate macrosteatosis (30%-60%) (N = 96) between 2000 and 2017 were compared to propensity score matched cohorts of patients undergoing LT with donor livers with mild macrosteatosis (10%-29%) (N = 96) and no steatosis (N = 96). Cardiac arrest at the time of reperfusion was seen in eight (8.3%) of the patients in the moderate macrosteatosis group compared to one (1.0%) of the patients in the mild macrosteatosis group (P = .02) and zero (0%) of the patients in the no steatosis group (P = .004). Patients in the moderate macrosteatosis group had a higher rate of PRS (37.5% vs 18.8%; P = .004), early allograft dysfunction (EAD) (76.4% vs 25.8%; P < .001), renal dysfunction requiring continuous renal replacement therapy following transplant (18.8% vs 8.3%; P = .03) and return to the OR within 30 days (24.0% vs 7.3%; P = .002), than the no steatosis group. Both long-term patient (P = .30 and P = .08) and graft survival (P = .15 and P = .12) were not statistically when comparing the moderate macrosteatosis group to the mild macrosteatosis and no steatosis groups. Recipients of LT using livers with moderate macrosteatosis are at a significant increased risk of PRS. If patients are able to overcome the initial increased perioperative risk of using these donor livers, long-term graft survival does not appear to be different than matched recipients receiving grafts with no steatosis.
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Affiliation(s)
| | - David D Lee
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida
| | - Sarah Croome
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida
| | - Ryan Chadha
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida
| | - David Livingston
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida
| | - Peter Abader
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida
| | | | - C Burcin Taner
- Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida
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35
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Boteon YL, Attard J, Boteon APCS, Wallace L, Reynolds G, Hubscher S, Mirza DF, Mergental H, Bhogal RH, Afford SC. Manipulation of Lipid Metabolism During Normothermic Machine Perfusion: Effect of Defatting Therapies on Donor Liver Functional Recovery. Liver Transpl 2019; 25:1007-1022. [PMID: 30821045 PMCID: PMC6618030 DOI: 10.1002/lt.25439] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 02/12/2019] [Indexed: 12/20/2022]
Abstract
Strategies to increase the use of steatotic donor livers are required to tackle the mortality on the transplant waiting list. We aimed to test the efficacy of pharmacological enhancement of the lipid metabolism of human livers during ex situ normothermic machine perfusion to promote defatting and improve the functional recovery of the organs. Because of steatosis, 10 livers were discarded and were allocated either to a defatting group that had the perfusate supplemented with a combination of drugs to enhance lipid metabolism or to a control group that received perfusion fluid with vehicle only. Steatosis was assessed using tissue homogenate and histological analyses. Markers for lipid oxidation and solubilization, oxidative injury, inflammation, and biliary function were evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and in-gel protein detection. Treatment reduced tissue triglycerides by 38% and macrovesicular steatosis by 40% over 6 hours. This effect was driven by increased solubility of the triglycerides (P = 0.04), and mitochondrial oxidation as assessed by increased ketogenesis (P = 0.008) and adenosine triphosphate synthesis (P = 0.01) were associated with increased levels of the enzymes acyl-coenzyme A oxidase 1, carnitine palmitoyltransferase 1A, and acetyl-coenzyme A synthetase. Concomitantly, defatted livers exhibited enhanced metabolic functional parameters such as urea production (P = 0.03), lower vascular resistance, lower release of alanine aminotransferase (P = 0.049), and higher bile production (P = 0.008) with a higher bile pH (P = 0.03). The treatment down-regulated the expression of markers for oxidative injury as well as activation of immune cells (CD14; CD11b) and reduced the release of inflammatory cytokines in the perfusate (tumor necrosis factor α; interleukin 1β). In conclusion, pharmacological enhancement of intracellular lipid metabolism during normothermic machine perfusion decreased the lipid content of human livers within 6 hours. It also improved the intracellular metabolic support to the organs, leading to successful functional recovery and decreased expression of markers of reperfusion injury.
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Affiliation(s)
- Yuri L. Boteon
- Liver UnitQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- National Institute for Health Research Birmingham Biomedical Research CentreUniversity Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Centre for Liver and Gastrointestinal ResearchInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Joseph Attard
- Liver UnitQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- National Institute for Health Research Birmingham Biomedical Research CentreUniversity Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Centre for Liver and Gastrointestinal ResearchInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Amanda P. C. S. Boteon
- Liver UnitQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
| | - Lorraine Wallace
- National Institute for Health Research Birmingham Biomedical Research CentreUniversity Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Centre for Liver and Gastrointestinal ResearchInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Gary Reynolds
- National Institute for Health Research Birmingham Biomedical Research CentreUniversity Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Centre for Liver and Gastrointestinal ResearchInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Stefan Hubscher
- Liver UnitQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Department of Cellular PathologyQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
| | - Darius F. Mirza
- Liver UnitQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- National Institute for Health Research Birmingham Biomedical Research CentreUniversity Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Centre for Liver and Gastrointestinal ResearchInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Hynek Mergental
- Liver UnitQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- National Institute for Health Research Birmingham Biomedical Research CentreUniversity Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Centre for Liver and Gastrointestinal ResearchInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Ricky H. Bhogal
- The Royal Marsden, Department of Academic SurgeryFulham RoadChelseaLondon
| | - Simon C. Afford
- National Institute for Health Research Birmingham Biomedical Research CentreUniversity Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
- Centre for Liver and Gastrointestinal ResearchInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
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Liu Z, Jia J, Ning H, Que S, Zhou L, Zheng S. Systematic Evaluation of the Safety Threshold for Allograft Macrovesicular Steatosis in Cadaveric Liver Transplantation. Front Physiol 2019; 10:429. [PMID: 31105577 PMCID: PMC6494939 DOI: 10.3389/fphys.2019.00429] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/28/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Currently, 30% macrovesicular steatosis (MaS) content is usually assigned empirically as the boundary between “use” and “refuse” a donor liver for liver transplantation (LT); however, this cut-off is questionable due to the lack of systemic evidence of the efficiency relative to prognosis prediction. Clinicians have tried to identify the threshold for optimized utilization of marginal steatotic allografts, but controversy exists among different studies. Aim: Our study aimed to systematically determine an acceptable donor MaS content cut-off without incurring extra risk in liver transplantation, using meta-analysis. Methods: The relevant literature reporting the relationship between MaS content and post-transplant mortality/morbidity was searched and retrieved in Pubmed, Embase, and ISI Web of Science. Results: Nine studies were enrolled into the final analysis. A categorical comparison revealed that patients who received allografts with moderate steatosis (MaS content >30%) had significantly higher risks of graft failure/dysfunction, but not of mortality. Dose-response analysis showed that donor MaS content affected the graft failure/dysfunction in a non-linear relationship. Risks associated with MaS content in terms of poorer outcomes were independent of other risk covariates for liver transplantation. A non-significant increase in risk of inferior post-transplant outcomes was observed in patients who received allografts with a MaS content <35%. The risks of post-transplant graft failure and dysfunction increased with severe donor MaS content infiltration, without a consistent relationship. Conclusions: The threshold of allograft MaS content can be safely extended to 35% without additional risk burden on post-transplant inferior outcomes. Clarification on “the effects of stratification” for MaS content can provide theoretical evidence for further optimal utilization of marginal steatotic allografts in liver transplantation.
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Affiliation(s)
- Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Huaijun Ning
- Department of Pediatrics, Women and Children's Hospital of Guangxi, Nanning, China
| | - Shuping Que
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lin Zhou
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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Croome KP, Lee DD, Taner CB. The "Skinny" on Assessment and Utilization of Steatotic Liver Grafts: A Systematic Review. Liver Transpl 2019; 25:488-499. [PMID: 30817859 DOI: 10.1002/lt.25408] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 12/25/2018] [Indexed: 02/07/2023]
Abstract
The frequency at which steatotic deceased donor liver grafts are encountered will likely continue to increase. Utilization of liver grafts with moderate-to-severe steatosis for liver transplantation (LT) has been previously shown to be associated with increased rates of primary nonfunction and decreased recipient survival. In order to better inform clinical decision making and guide future research, critical evaluation of the literature on donor liver steatosis and posttransplantation outcome is needed. This literature review aims to provide the "skinny" on using deceased donor steatotic livers for LT.
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Affiliation(s)
| | - David D Lee
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
| | - C Burcin Taner
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
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38
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Boteon YL, Afford SC. Machine perfusion of the liver: Which is the best technique to mitigate ischaemia-reperfusion injury? World J Transplant 2019; 9:14-20. [PMID: 30697517 PMCID: PMC6347667 DOI: 10.5500/wjt.v9.i1.14] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 12/11/2018] [Accepted: 01/05/2019] [Indexed: 02/05/2023] Open
Abstract
Longstanding research describes the mechanisms whereby the restoration of blood flow and reoxygenation (reperfusion) aggravates the ischaemic injury caused by a period of anoxia to a donor liver. This phenomenon, called ischaemia-reperfusion injury (IRI), leads to parenchymal cell death, microcirculatory failure, and inflammatory immune response. Clinically, IRI is the main factor responsible for the occurrence of posttransplant graft dysfunction and ischaemic-type biliary lesions. While extended criteria donor livers are more vulnerable to IRI, their utilisation is required to address the shortfall in donor organs. Thus, the mitigation of IRI should drive the setting of a new benchmark for marginal organ preservation. Herein, strategies incorporating different modalities of machine perfusion of the liver to alleviate IRI are discussed in conjunction with advantages and disadvantages of individual protocols. Techniques leading to reperfusion of the liver during machine perfusion (in situ normothermic regional perfusion and ex situ normothermic machine perfusion) may mitigate IRI by shortening the ischaemic period of the organs. This benefit potentially escalates from the minimum level, obtained following just partial alleviation of the ischaemic period, to the maximum level, which can be potentially achieved with ischaemia-free organ transplantation. Techniques that do not lead to reperfusion of the liver during machine perfusion (hypothermic, subnormothermic, and controlled-oxygenated rewarming) optimise mitochondrial oxidative function and replenish cellular energy stores, thereby lowering reactive oxygen species production as well as the activation of downstream inflammatory pathways during reperfusion. Further mechanistic insights into IRI may guide the development of donor-specific protocols of machine perfusion on the basis of the limitations of individual categories of extended criteria donor organs.
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Affiliation(s)
- Yuri L Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2WB, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, United Kingdom
| | - Simon C Afford
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, United Kingdom
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Boteon YL, Boteon APCS, Attard J, Wallace L, Bhogal RH, Afford SC. Impact of machine perfusion of the liver on post-transplant biliary complications: A systematic review. World J Transplant 2018; 8:220-231. [PMID: 30370232 PMCID: PMC6201326 DOI: 10.5500/wjt.v8.i6.220] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/09/2018] [Accepted: 10/10/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To review the clinical impact of machine perfusion (MP) of the liver on biliary complications post-transplantation, particularly ischaemic-type biliary lesions (ITBL).
METHODS This systematic review was performed in accordance with the Preferred Reporting Systematic Reviews and Meta-Analysis (PRISMA) protocol. The following databases were searched: PubMed, MEDLINE and Scopus. The keyword “liver transplantation” was used in combination with the free term “machine perfusion”. Clinical studies reporting results of transplantation of donor human livers following ex situ or in situ MP were analysed. Details relating to donor characteristics, recipients, technique of MP performed and post-operative biliary complications (ITBL, bile leak and anastomotic strictures) were critically analysed.
RESULTS Fifteen articles were considered to fit the criteria for this review. Ex situ normothermic MP was used in 6 studies, ex situ hypothermic MP in 5 studies and the other 4 studies investigated in situ normothermic regional perfusion (NRP) and controlled oxygenated rewarming. MP techniques which have per se the potential to alleviate ischaemia-reperfusion injury: Such as hypothermic MP and NRP, have also reported lower rates of ITBL. Other biliary complications, such as biliary leak and anastomotic biliary strictures, are reported with similar incidences with all MP techniques. There is currently less clinical evidence available to support normothermic MP as a mitigator of biliary complications following liver transplantation. On the other hand, restoration of organ to full metabolism during normothermic MP allows assessment of hepatobiliary function before transplantation, although universally accepted criteria have yet to be validated.
CONCLUSION MP of the liver has the potential to have a positive impact on post-transplant biliary complications, specifically ITBL, and expand extended criteria donor livers utilisation.
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Affiliation(s)
- Yuri L Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2WB, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2 TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, United Kingdom
| | - Amanda PCS Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2WB, United Kingdom
| | - Joseph Attard
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2WB, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2 TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, United Kingdom
| | - Lorraine Wallace
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2 TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, United Kingdom
| | - Ricky H Bhogal
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2 TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, United Kingdom
| | - Simon C Afford
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2 TT, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, United Kingdom
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