|
1
|
Esser H, de Jong IEM, Roos FM, Bogensperger C, Brunner SM, Cardini B, Dutkowski P, Eker H, Ferreira-Gonzalez S, Forbes SJ, Friend PJ, Fundora Y, Junger H, Krendl FJ, Martins PN, de Meijer VE, Oberhuber R, Oniscu GC, Patrono D, Porte RJ, Resch T, Sadik H, Schlegel A, De Stefano N, Vidgren M, Watson CJE, Weißenbacher A, Schneeberger S. Consensus classification of biliary complications after liver transplantation: guidelines from the BileducTx meeting. Br J Surg 2025; 112:znae321. [PMID: 40313074 PMCID: PMC12046073 DOI: 10.1093/bjs/znae321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 05/03/2025]
Affiliation(s)
- Hannah Esser
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Iris E M de Jong
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Floris M Roos
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Christina Bogensperger
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan M Brunner
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Philipp Dutkowski
- Department of Surgery, Clarunis—University Centre for Gastrointestinal and Hepatopancreatobiliary Diseases, Basel, Switzerland and Department of Visceral Surgery, University Hospital Basel, Switzerland
| | - Hasan Eker
- Department for General and HPB Surgery and Liver Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Sofia Ferreira-Gonzalez
- Centre for Inflammation Research (CIR), University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, UK
| | - Yiliam Fundora
- Department of Surgery. HPB and Liver Transplant Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, UB, Barcelona, Spain
| | - Henrik Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Felix J Krendl
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Paulo N Martins
- Department of Surgery, Oklahoma University, Oklahoma City, USA
| | - Vincent E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands and UMCG Comprehensive Transplant Center, Groningen, The Netherlands
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Gabriel C Oniscu
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Damiano Patrono
- General Surgery 2U—Liver Transplant Centre, A.O.U. Città della Salute e della Scienza—Torino, Italy
| | - Robert J Porte
- Department of Surgery, Division of Hepato-Pancreato-Biliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Thomas Resch
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Hatem Sadik
- Nuffield Department of Surgical Sciences, University of Oxford, The Churchill Hospital, Oxford, UK
| | - Andrea Schlegel
- Transplantation Center and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nicola De Stefano
- General Surgery 2U—Liver Transplant Centre, A.O.U. Città della Salute e della Scienza—Torino, Italy
| | - Mathias Vidgren
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Christopher J E Watson
- The Roy Calne Transplant Unit and the University of Cambridge Department of Surgery, Addenbrooke's Hospital, Cambridge, UK
| | - Annemarie Weißenbacher
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, organLife Laboratory, Centre of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
2
|
Quelhas P, Morgado D, dos Santos J. Primary Cilia, Hypoxia, and Liver Dysfunction: A New Perspective on Biliary Atresia. Cells 2025; 14:596. [PMID: 40277920 PMCID: PMC12026149 DOI: 10.3390/cells14080596] [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: 03/10/2025] [Revised: 04/02/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and congenital defects. Biliary atresia (BA) is a progressive infantile cholangiopathy and the leading cause of pediatric liver transplantation. Although the exact etiology of BA remains unclear, evidence suggests a multifactorial pathogenesis influenced by both genetic and environmental factors. Patients with BA and laterality defects exhibit genetic variants associated with ciliopathies. Interestingly, even isolated BA without extrahepatic anomalies presents morphological and functional ciliary abnormalities, suggesting that environmental triggers may disrupt the ciliary function. Among these factors, hypoxia has emerged as a potential modulator of this dysfunction. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a central role in hepatic responses to oxygen deprivation, influencing bile duct remodeling and fibrosis, which are key processes in BA progression. This review explores the crosstalk between hypoxia and hepatic ciliopathies, with a focus on BA. It discusses the molecular mechanisms through which hypoxia may drive disease progression and examines the therapeutic potential of targeting hypoxia-related pathways. Understanding how oxygen deprivation influences ciliary function may open new avenues for treating biliary ciliopathies and improving patient outcomes.
Collapse
Affiliation(s)
| | | | - Jorge dos Santos
- RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; (P.Q.); (D.M.)
| |
Collapse
|
|
3
|
Ly M, Lau NS, Huang J, Ly H, Ewenson K, Mestrovic N, Yousif P, Liu K, Majumdar A, McCaughan G, Crawford M, Pulitano C. Ex vivo cholangioscopy in liver grafts: a novel technique to assess the biliary tree during organ preservation and machine perfusion: a experimental non-clinical study. Clin Endosc 2025; 58:303-310. [PMID: 40033491 PMCID: PMC11983137 DOI: 10.5946/ce.2024.099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/01/2024] [Accepted: 07/02/2024] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND/AIMS Biliary complications are a leading cause of morbidity after liver transplantation, but can be reduced using real-time assessment of the biliary tree. This study described a novel technique for performing ex vivo cholangioscopy during cold static storage and normothermic machine perfusion (NMP) to assess the biliary tree before liver transplantation. METHODS Human donor livers, which were considered unsuitable for transplantation, were perfused at 36ºC using a modified commercial ex vivo perfusion system. Ex vivo cholangioscopy was performed using a SpyGlass Discover system. Cholangioscopy was performed during cold static storage and after 12 hours in NMP. Bile duct biopsies and confocal microscopy were performed. RESULTS Ex vivo cholangioscopy was performed on eight grafts. During cold static storage, luminal debris was visualized throughout the biliary tree. After 12 hours of reperfusion, the bile ducts appeared hyperemic, heterogeneous, and mottled. Confocal microscopy confirmed perfusion of biliary microvasculature. CONCLUSIONS We describe the first use of ex vivo cholangioscopy to assess the biliary tree before liver transplantation. This real-time technique can be used to assess biliary trees during cold static storage and NMP. In addition, cholangioscopy-based interventions can be used to better assess intrahepatic bile ducts.
Collapse
Affiliation(s)
- Mark Ly
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
- Centenary Institute, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Ngee-Soon Lau
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Joanna Huang
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Hayden Ly
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
| | - Kasper Ewenson
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Nicole Mestrovic
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Paul Yousif
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
| | - Ken Liu
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
- Centenary Institute, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Avik Majumdar
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Geoffrey McCaughan
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
- Centenary Institute, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Michael Crawford
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Carlo Pulitano
- Centre for Organ Assessment Repair and Optimisation, Royal Prince Alfred Hospital, Sydney, Australia
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| |
Collapse
|
|
4
|
Shishido Y, Tracy KM, Petrovic M, Adesanya T, Fortier AK, Raietparvar K, Glomp GA, Simonds E, Harris TR, Simon V, Tucker WD, Petree B, Cortelli M, Cardwell NL, Crannell C, Liang J, Murphy AC, Fields BL, McReynolds M, Demarest CT, Ukita R, Rizzari M, Montenovo M, Magliocca JF, Karp SJ, Rauf MA, Shah AS, Bacchetta M. Novel Dynamic Organ Storage System Enhances Liver Graft Function in a Porcine Donation After Circulatory Death Model. ASAIO J 2024:00002480-990000000-00611. [PMID: 39693205 DOI: 10.1097/mat.0000000000002365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Donation after circulatory death (DCD) livers face increased risks of critical complications when preserved with static cold storage (SCS). Although machine perfusion (MP) may mitigate these risks, its cost and logistical complexity limit widespread application. We developed the Dynamic Organ Storage System (DOSS), which delivers oxygenated perfusate at 10°C with minimal electrical power requirement and allows real-time effluent sampling in a portable cooler. In a porcine DCD model, livers were preserved using DOSS or SCS for 10 hours and evaluated with 4 hours of normothermic MP, with n = 5 per group. After 4 hours of normothermic MP, the DOSS group demonstrated significantly lower perfusate lactate (p = 0.023), increased perfusate fibrinogen (p = 0.005), higher oxygen consumption (p = 0.018), greater bile production (p = 0.013), higher bile bicarbonate levels (p = 0.035) and bile/perfusate sodium ratio (p = 0.002), and lower hepatic arterial resistance after phenylephrine administration (p = 0.018). Histological analysis showed lower apoptotic markers in DOSS-preserved livers, with fewer cleaved caspase-3 (p = 0.039) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL; p = 0.009) positive cells. These findings suggest that DOSS can enhance DCD allograft function during transport, offering potential clinical benefits and contributing to the expansion of the donor pool.
Collapse
Affiliation(s)
- Yutaka Shishido
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kaitlyn M Tracy
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mark Petrovic
- Vanderbilt University Medical School , Nashville, Tennessee
| | | | | | | | | | | | - Timothy R Harris
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Victoria Simon
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - William D Tucker
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Brandon Petree
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Michael Cortelli
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Nancy L Cardwell
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Christian Crannell
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jiancong Liang
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Alexandria C Murphy
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Blanche L Fields
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Melanie McReynolds
- Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, State College, Pennsylvania
| | - Caitlin T Demarest
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rei Ukita
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Michael Rizzari
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Martin Montenovo
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Joseph F Magliocca
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Seth J Karp
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - M Ameen Rauf
- From the Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ashish S Shah
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew Bacchetta
- Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| |
Collapse
|
|
5
|
Esser H, Kilpatrick AM, Man TY, Aird R, Rodrigo-Torres D, Buch ML, Boulter L, Walmsley S, Oniscu GC, Schneeberger S, Ferreira-Gonzalez S, Forbes SJ. Primary cilia as a targetable node between biliary injury, senescence and regeneration in liver transplantation. J Hepatol 2024; 81:1005-1022. [PMID: 38879173 DOI: 10.1016/j.jhep.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/05/2024] [Accepted: 06/01/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND & AIMS Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly specialised sensory organelle, in biliary injury leading to post-transplant biliary complications. METHODS Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (n = 7) in comparison with recipients without biliary complications (n = 12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreERTKif3afl/fl mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers. RESULTS Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury. CONCLUSIONS Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation. IMPACT AND IMPLICATIONS Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications.
Collapse
Affiliation(s)
- Hannah Esser
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK; Department of Visceral, Transplant and Thoracic Surgery, OrganLife Laboratory, Centre of Operative Medicine, Innsbruck Medical University. Anichstrasse 35, 6020 Innsbruck, Austria
| | - Alastair Morris Kilpatrick
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Tak Yung Man
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Rhona Aird
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Daniel Rodrigo-Torres
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Madita Lina Buch
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK; Department of Visceral, Transplant and Thoracic Surgery, OrganLife Laboratory, Centre of Operative Medicine, Innsbruck Medical University. Anichstrasse 35, 6020 Innsbruck, Austria
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh; Edinburgh EH4 2XU, UK
| | - Sarah Walmsley
- Centre for Inflammation Research (CIR), University of Edinburgh. The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Gabriel Corneliu Oniscu
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh; 51 Little France Crescent, Edinburgh EH16 4SA, UK; Division of Transplantation, CLINTEC, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, OrganLife Laboratory, Centre of Operative Medicine, Innsbruck Medical University. Anichstrasse 35, 6020 Innsbruck, Austria
| | - Sofia Ferreira-Gonzalez
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK; Centre for Inflammation Research (CIR), University of Edinburgh. The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
| | - Stuart John Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
| |
Collapse
|
|
6
|
Rejas C, Junger H. Cholangiocyte Organoids in Liver Transplantation; a Comprehensive Review. Transpl Int 2024; 37:12708. [PMID: 39100755 PMCID: PMC11294148 DOI: 10.3389/ti.2024.12708] [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: 01/19/2024] [Accepted: 06/17/2024] [Indexed: 08/06/2024]
Abstract
Liver transplantation is the only curative option for many liver diseases that end up in liver failure, and cholangiopathy remains a challenging complication post-liver transplant, associated with significant morbidity and potential graft loss. The low availability of organs and high demand for transplantation motivate scientists to find novel interventions. Organoids, as three-dimensional cell cultures derived from adult cells or induced pluripotent cells, may help to address this problem. Different types of organoids have been described, from which cholangiocyte organoids offer a high level of versatility and plasticity for a deeper study of liver disease mechanisms. Cholangiocytes can be obtained from different segments of the biliary tree and have shown a remarkable capacity to adapt to new environments, presenting an effective system for studying cholangiopathies. Studies using cholangiocyte organoids show promising results for disease modeling, where organoids offer fundamental features to recapitulate the complexities of tissues in vitro and uncover fundamental pathological pathways to potentially reveal therapeutic strategies for personalized medicine. Organoids could hold the potential for regeneration of injured livers, representing tools of clinical impact in regenerative medicine when tissue damage is already present.
Collapse
Affiliation(s)
| | - H. Junger
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| |
Collapse
|
|
7
|
Mergental H, Laing RW, Kirkham AJ, Clarke G, Boteon YL, Barton D, Neil DAH, Isaac JR, Roberts KJ, Abradelo M, Schlegel A, Dasari BVM, Ferguson JW, Cilliers H, Morris C, Friend PJ, Yap C, Afford SC, Perera MTPR, Mirza DF. Discarded livers tested by normothermic machine perfusion in the VITTAL trial: Secondary end points and 5-year outcomes. Liver Transpl 2024; 30:30-45. [PMID: 38109282 DOI: 10.1097/lvt.0000000000000270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 08/27/2023] [Indexed: 12/20/2023]
Abstract
Normothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH >7.65 and bicarbonate levels >25 mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608).
Collapse
Affiliation(s)
- Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Richard W Laing
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- Hepato-pancreato Biliary Unit, Royal Stoke University Hospital, Stoke on Trent, UK
| | - Amanda J Kirkham
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - George Clarke
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Yuri L Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Darren Barton
- D3B team, Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Desley A H Neil
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK
- Department of Cellular Pathology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
| | - John R Isaac
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
| | - Keith J Roberts
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Manuel Abradelo
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- HPB and Abdominal Organ Transplantation Department, 12 de Octubre University Hospital, Madrid, Spain
| | - Andrea Schlegel
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, Milan, Italy
| | - Bobby V M Dasari
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
| | - James W Ferguson
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
| | - Hentie Cilliers
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
| | | | - Peter J Friend
- OrganOx Limited, Oxford, UK
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Christina Yap
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK
- Clinical Trials and Statistics Unit, The Institute for Cancer Research, London
| | - Simon C Afford
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - M Thamara P R Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham, UK
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK
| |
Collapse
|
|
8
|
Ly M, Lau NS, McKenzie C, Kench JG, Seyfi D, Majumdar A, Liu K, McCaughan G, Crawford M, Pulitano C. Histological Assessment of the Bile Duct before Liver Transplantation: Does the Bile Duct Injury Score Predict Biliary Strictures? J Clin Med 2023; 12:6793. [PMID: 37959258 PMCID: PMC10648970 DOI: 10.3390/jcm12216793] [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: 09/19/2023] [Revised: 10/03/2023] [Accepted: 10/17/2023] [Indexed: 11/15/2023] Open
Abstract
INTRODUCTION Histological injury to the biliary tree during organ preservation leads to biliary strictures after liver transplantation. The Bile Duct Injury (BDI) score was developed to assess histological injury and identify the grafts most likely to develop biliary strictures. The BDI score evaluates the bile duct mural stroma, peribiliary vascular plexus (PVP) and deep peribiliary glands (DPGs), which were correlated with post-transplant biliary strictures. However, the BDI score has not been externally validated. The aim of this study was to verify whether the BDI score could predict biliary strictures at our transplant centre. METHODS Brain-dead donor liver grafts transplanted at a single institution from March 2015 to June 2016 were included in this analysis. Bile duct biopsies were collected immediately before transplantation and assessed for bile duct injury by two blinded pathologists. The primary outcome was the development of clinically significant biliary strictures within 24 months post-transplant. RESULTS Fifty-seven grafts were included in the study which included 16 biliary strictures (28%). Using the BDI score, mural stromal, PVP and DPG injury did not correlate with biliary strictures including Non-Anastomotic Strictures. Severe inflammation (>50 leucocytes per HPF) was the only histological feature inversely correlated with the primary outcome (absent in the biliary stricture group vs. 41% in the no-stricture group, p = 0.001). CONCLUSIONS The current study highlights limitations of the histological assessment of bile duct injury. Although all grafts had bile duct injury, only inflammation was associated with biliary strictures. The BDI score was unable to predict post-transplant biliary strictures in our patient population.
Collapse
Affiliation(s)
- Mark Ly
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Ngee-Soon Lau
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Catriona McKenzie
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
| | - James G. Kench
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
| | - Doruk Seyfi
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Avik Majumdar
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Ken Liu
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Centenary Institute, Sydney, NSW 2050, Australia
| | - Geoffrey McCaughan
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Centenary Institute, Sydney, NSW 2050, Australia
| | - Michael Crawford
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Carlo Pulitano
- 9E Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, Sydney, NSW 2050, Australia; (M.L.)
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| |
Collapse
|
|
9
|
Gilbo N, Neil D, Brais R, Fieuws S, Lo Faro L, Friend P, Ploeg R, Monbaliu D. The Effect of Continuous Liver Normothermic Machine Perfusion on the Severity of Histological Bile Duct Injury. Transpl Int 2023; 36:11645. [PMID: 37727383 PMCID: PMC10505658 DOI: 10.3389/ti.2023.11645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 07/21/2023] [Indexed: 09/21/2023]
Abstract
Static Cold Storage (SCS) injures the bile duct, while the effect of Normothermic Machine Perfusion (NMP) is unknown. In a sub-study of the COPE trial on liver NMP, we investigated the impact of preservation type on histological bile duct injury score (BDIS). Transplants with at least one bile duct biopsy, either at end of preservation or 1 h post-reperfusion, were considered. BDIS was determined by assessing peribiliary glands injury, stromal and mural loss, haemorrhage, and thrombosis. A bivariate linear model compared BDIS (estimate, CI) between groups. Sixty-five transplants and 85 biopsies were analysed. Twenty-three grafts were preserved with SCS and 42 with NMP, with comparable baseline characteristics except for a shorter cold ischemic time in NMP. The BDIS increased over time regardless of preservation type (p = 0.04). The BDIS estimate was higher in NMP [8.02 (7.40-8.65)] than in SCS [5.39 (4.52-6.26), p < 0.0001] regardless of time. One patient in each group developed ischemic cholangiopathy, with a BDIS of 6 for the NMP-preserved liver. In six other NMP grafts, BDIS ranged 7-12 without development of ischemic cholangiopathy. In conclusion, BDIS increases over time, and the higher BDIS in NMP did not increase ischemic cholangiopathy. Thus, BDIS may overestimate this risk after liver NMP.
Collapse
Affiliation(s)
- Nicholas Gilbo
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, Faculty of Medicine, KU Leuven, Leuven, Belgium
- University Hospital of Liège, Liège, Belgium
| | - Desley Neil
- Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Rebecca Brais
- Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Steffen Fieuws
- Interuniversity Center for Biostatistics and Statistical Bioinformatics, UZ KU Leuven, Leuven, Belgium
| | - Letizia Lo Faro
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Peter Friend
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Rutger Ploeg
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Diethard Monbaliu
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, Faculty of Medicine, KU Leuven, Leuven, Belgium
- Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
10
|
Hughes CB, Nigmet Y, Villanueva FS, Chen X, Demetris AJ, Stolz DB, Pacella JJ, Humar A. Ultrasound-Targeted Microbubble Cavitation During Machine Perfusion Reduces Microvascular Thrombi and Graft Injury in a Rat Liver Model of Donation After Circulatory Death. Transplant Proc 2023; 55:485-495. [PMID: 36878745 DOI: 10.1016/j.transproceed.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/15/2023] [Accepted: 02/02/2023] [Indexed: 03/07/2023]
Abstract
BACKGROUND Ischemic cholangiopathy is a process of bile duct injury that might result from peribiliary vascular plexus (PBP) thrombosis and remains a dreaded complication in liver transplantation from donors after circulatory death (DCD). The aim of this study was to propose a mechanical method of clot destruction to clear microvascular thrombi in DCD livers before transplantation. METHODS Sonothrombolysis (STL) is a process by which inertial cavitation of circulating microbubbles entering an ultrasound field create a high-energy shockwave at a microbubble-thrombus interface, causing mechanical clot destruction. The effectiveness of STL in DCD liver treatment remains unclear. We carried out STL treatment during normothermic, oxygenated, ex vivo machine perfusion (NMP), introducing microbubbles into the perfusate with the liver enveloped in an ultrasound field. RESULTS The STL livers showed reduction in hepatic arterial and PBP thrombus and decreases in hepatic arterial and portal venous flow resistance, reduced parenchymal injury as measured by aspartate transaminase release and oxygen consumption, and improved cholangiocyte function. Light and electron microscopy showed reduction of hepatic arterial and PBP thrombus in STL livers compared with controls and preserved hepatocyte structure, sinusoid endothelial morphology, and biliary epithelial microvilli. CONCLUSION In this model, STL improved flow and functional measures in DCD livers undergoing NMP. These data suggest a novel therapeutic approach to treat PBP injury in DCD livers, which may ultimately increase the pool of grafts available to patients awaiting liver transplantation.
Collapse
Affiliation(s)
- Christopher B Hughes
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | - Yermek Nigmet
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Flordeliza S Villanueva
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh Medical, Pittsburgh, Pennsylvania
| | - Xucai Chen
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh Medical, Pittsburgh, Pennsylvania
| | - Anthony J Demetris
- Division of Transplant Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Donna B Stolz
- Center for Biological Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - John J Pacella
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh Medical, Pittsburgh, Pennsylvania
| | - Abhinav Humar
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| |
Collapse
|
|
11
|
Does an Additional Bile Duct Flush With Low-viscosity Preservation Solution Reduce Bile Duct Injury? A Single-blinded Randomized Clinical Trial. Transplant Direct 2023; 9:e1443. [PMID: 36875942 PMCID: PMC9977485 DOI: 10.1097/txd.0000000000001443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/12/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023] Open
Abstract
Biliary complications are a common cause of morbidity after liver transplantation and associated with bile duct injury. To reduce injury, a bile duct flush is performed with high-viscosity preservation solution. It has been suggested that an earlier additional bile duct flush with low-viscosity preservation solution may reduce bile duct injury and biliary complications. This study aimed to investigate whether an earlier additional bile duct flush would reduce bile duct injury or biliary complications. Methods A randomized trial was conducted using 64 liver grafts from brain dead donors. The control group received a bile duct flush with University of Wisconsin (UW) solution after donor hepatectomy. The intervention group received a bile duct flush using low-viscosity Marshall solution immediately after the onset of cold ischemia and a bile duct flush with University of Wisconsin solution after donor hepatectomy. The primary outcomes were the degree of histological bile duct injury, assessed using the bile duct injury score, and biliary complications within 24 mo of transplant. Results Bile duct injury scores were not different between the 2 groups. Similar rates of biliary complications occurred in the intervention group (31% [n = 9]) and controls (23% [n = 8]) (P = 0.573). No difference between groups was observed for anastomotic strictures (24% versus 20%, P = 0.766) or nonanastomotic strictures (7% versus 6%, P = 1.00). Conclusions This is the first randomized trial to investigate an additional bile duct flush using low-viscosity preservation solution during organ procurement. The findings from this study suggest that performing an earlier additional bile duct flush with Marshall solution does not prevent biliary complications and bile duct injury.
Collapse
|
|
12
|
Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents. EBioMedicine 2023; 88:104431. [PMID: 36608526 PMCID: PMC9826934 DOI: 10.1016/j.ebiom.2022.104431] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Ischemia of the bile duct is a common feature in liver disease and transplantation, which represents a major cause of morbidity and mortality, especially after liver transplantation. Detailed knowledge of its pathogenesis remains incomplete due to the lack of appropriate in vitro models. METHODS To recapitulate biliary damage induced by ischemia and reperfusion in vitro, human intrahepatic cholangiocyte organoids (ICOs) were grown at low oxygen levels of 1% up to 72 h, followed by re-oxygenation at normal levels. FINDINGS ICOs stressed by ischemia and subsequent re-oxygenation represented the dynamic change in biliary cell proliferation, upregulation of epithelial-mesenchymal transition (EMT)-associated markers, and the evocation of phase-dependent cell death programs similar to what is described in patients. Clinical-grade alpha-1 antitrypsin was identified as a potent inhibitor of both ischemia-induced apoptosis and necroptosis. INTERPRETATION These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies. FUNDING Dutch Digestive FoundationMLDS D16-26; TKI-LSH (Topconsortium Kennis en Innovatie-Life Sciences & Health) grant RELOAD, EMC-LSH19002; Medical Delta program "Regenerative Medicine 4D"; China Scholarship Council No. 201706230252.
Collapse
|
|
13
|
Ferreira-Gonzalez S, Man TY, Esser H, Aird R, Kilpatrick AM, Rodrigo-Torres D, Younger N, Campana L, Gadd VL, Dwyer B, Aleksieva N, Boulter L, Macmillan MT, Wang Y, Mylonas KJ, Ferenbach DA, Kendall TJ, Lu WY, Acosta JC, Kurian D, O'Neill S, Oniscu GC, Banales JM, Krimpenfort PJ, Forbes SJ. Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage. Sci Transl Med 2022; 14:eabj4375. [PMID: 36475903 DOI: 10.1126/scitranslmed.abj4375] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)-dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.
Collapse
Affiliation(s)
- Sofia Ferreira-Gonzalez
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Tak Yung Man
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Hannah Esser
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
- Department of Visceral, Transplant and Thoracic Surgery, Centre of Operative Medicine, Innsbruck Medical University, Anichstrasse 35, Innsbruck 6020, Austria
| | - Rhona Aird
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Alastair M Kilpatrick
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Daniel Rodrigo-Torres
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Nicholas Younger
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Lara Campana
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Victoria L Gadd
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Benjamin Dwyer
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Niya Aleksieva
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Mark T Macmillan
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Yinmiao Wang
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Katie J Mylonas
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - David A Ferenbach
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Timothy J Kendall
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Wei-Yu Lu
- Centre for Inflammation Research (CIR), University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Juan Carlos Acosta
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh EH4 2XR, UK
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN, C/ Albert Einstein 22, Santander, 39011, Spain
| | - Dominic Kurian
- Proteomic and Metabolomics Unit, Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK
| | - Stephen O'Neill
- Department of Transplant Surgery, Belfast City Hospital, 51 Lisburn Road, Belfast BT9 7AB, UK
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Block A, Royal Victoria Hospital, Belfast BT12 6BA, UK
| | - Gabriel C Oniscu
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
- Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian 20014, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31009 Pamplona, Spain
| | | | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| |
Collapse
|
|
14
|
Beetz O, Cammann S, Weigle CA, Sieg L, Eismann H, Johanning K, Falk CS, Krech T, Oldhafer F, Vondran FWR. Interleukin-18 and High-Mobility-Group-Protein B1 are Early and Sensitive Indicators for Cell Damage During Normothermic Machine Perfusion after Prolonged Cold Ischemic Storage of Porcine Liver Grafts. Transpl Int 2022; 35:10712. [PMID: 36338535 PMCID: PMC9630326 DOI: 10.3389/ti.2022.10712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/04/2022] [Indexed: 11/22/2022]
Abstract
In the era of organ machine perfusion, experimental models to optimize reconditioning of (marginal) liver grafts are needed. Although the relevance of cytokine signatures in liver transplantation has been analyzed previously, the significance of molecular monitoring during normothermic machine perfusion (NMP) remains elusive. Therefore, we developed a porcine model of cold ischemic liver graft injury after prolonged static cold storage (SCS) and subsequent NMP: Livers obtained from ten minipigs underwent NMP for 6 h directly after procurement (control group) or after 20 h of SCS. Grafts after prolonged SCS showed significantly elevated AST, ALT, GLDH and GGT perfusate concentrations, and reduced lactate clearance. Bile analyses revealed reduced bile production, reduced bicarbonate and elevated glucose concentrations after prolonged SCS. Cytokine analyses of graft perfusate simultaneously demonstrated an increase of pro-inflammatory cytokines such as Interleukin-1α, Interleukin-2, and particularly Interleukin-18. The latter was the only significantly elevated cytokine compared to controls, peaking as early as 2 h after reperfusion (11,012 ng/ml vs. 1,493 ng/ml; p = 0.029). Also, concentrations of High-Mobility-Group-Protein B1 were significantly elevated after 2 h of reperfusion (706.00 ng/ml vs. 148.20 ng/ml; p < 0.001) and showed positive correlations with AST (r2 = 0.846) and GLDH (r2 = 0.918) levels. Molecular analyses during reconditioning of liver grafts provide insights into the degree of inflammation and cell damage and could thereby facilitate future interventions during NMP reducing acute and chronic graft injury.
Collapse
Affiliation(s)
- Oliver Beetz
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Sebastian Cammann
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Clara A. Weigle
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Lion Sieg
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Hendrik Eismann
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Kai Johanning
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research, DZIF, TTU-IICH Braunschweig Site, Hannover, Germany
- German Center for Lung Research DZL, BREATH, Hannover, Germany
| | - Till Krech
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Felix Oldhafer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Florian W. R. Vondran
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
- *Correspondence: Florian W. R. Vondran, , orcid.org/0000-0001-8355-5017
| |
Collapse
|
|
15
|
Dingfelder J, Rauter L, Berlakovich GA, Kollmann D. Biliary Viability Assessment and Treatment Options of Biliary Injury During Normothermic Liver Perfusion—A Systematic Review. Transpl Int 2022; 35:10398. [PMID: 35707635 PMCID: PMC9189281 DOI: 10.3389/ti.2022.10398] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/25/2022] [Indexed: 11/30/2022]
Abstract
In recent years, significant progress has been made in the field of liver machine perfusion. Many large transplant centers have implemented machine perfusion strategies in their clinical routine. Normothermic machine perfusion (NMP) is primarily used to determine the quality of extended criteria donor (ECD) organs and for logistical reasons. The vast majority of studies, which assessed the viability of perfused grafts, focused on hepatocellular injury. However, biliary complications are still a leading cause of post-transplant morbidity and the need for re-transplantation. To evaluate the extent of biliary injury during NMP, reliable criteria that consider cholangiocellular damage are needed. In this review, different approaches to assess damage to the biliary tree and the current literature on the possible effects of NMP on the biliary system and biliary injury have been summarized. Additionally, it provides an overview of novel biomarkers and therapeutic strategies that are currently being investigated. Although expectations of NMP to adequately assess biliary injury are high, scant literature is available. There are several biomarkers that can be measured in bile that have been associated with outcomes after transplantation, mainly including pH and electrolytes. However, proper validation of those and other novel markers and investigation of the pathophysiological effect of NMP on the biliary tree is still warranted.
Collapse
|
|
16
|
Hessheimer AJ, de la Rosa G, Gastaca M, Ruíz P, Otero A, Gómez M, Alconchel F, Ramírez P, Bosca A, López-Andújar R, Atutxa L, Royo-Villanova M, Sánchez B, Santoyo J, Marín LM, Gómez-Bravo MÁ, Mosteiro F, Villegas Herrera MT, Villar Del Moral J, González-Abos C, Vidal B, López-Domínguez J, Lladó L, Roldán J, Justo I, Jiménez C, López-Monclús J, Sánchez-Turrión V, Rodríguez-Laíz G, Velasco Sánchez E, López-Baena JÁ, Caralt M, Charco R, Tomé S, Varo E, Martí-Cruchaga P, Rotellar F, Varona MA, Barrera M, Rodríguez-Sanjuan JC, Briceño J, López D, Blanco G, Nuño J, Pacheco D, Coll E, Domínguez-Gil B, Fondevila C. Abdominal normothermic regional perfusion in controlled donation after circulatory determination of death liver transplantation: Outcomes and risk factors for graft loss. Am J Transplant 2022; 22:1169-1181. [PMID: 34856070 DOI: 10.1111/ajt.16899] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 01/25/2023]
Abstract
Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p < .001), ischemic type biliary lesions (OR 0.112, 95% CI 0.042-0.299, p < .001), graft loss (HR 0.371, 95% CI 0.267-0.516, p < .001), and patient death (HR 0.540, 95% CI 0.373-0.781, p = .001). Cold ischemia time (HR 1.004, 95% CI 1.001-1.007, p = .021) and re-transplantation indication (HR 9.552, 95% CI 3.519-25.930, p < .001) were significant independent predictors for graft loss among cDCD livers with A-NRP. While use of A-NRP helps overcome traditional limitations in cDCD liver transplantation, opportunity for improvement remains for cases with prolonged cold ischemia and/or technically complex recipients, indicating a potential role for complimentary ex situ perfusion preservation techniques.
Collapse
Affiliation(s)
- Amelia J Hessheimer
- General & Digestive Surgery, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain.,General & Digestive Surgery Service, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Spain.,IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | | | | | | | - Alejandra Otero
- Complejo Hospitalario Universitario La Coruña, A Coruna, Spain
| | - Manuel Gómez
- Complejo Hospitalario Universitario La Coruña, A Coruna, Spain
| | - Felipe Alconchel
- Hospital Clínico Universitario Virgen de la Arrixaca, IMIB, El Palmar, Spain
| | - Pablo Ramírez
- Hospital Clínico Universitario Virgen de la Arrixaca, IMIB, El Palmar, Spain
| | - Andrea Bosca
- Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Rafael López-Andújar
- Hospital Universitario y Politécnico La Fe, Valencia, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Lánder Atutxa
- Hospital Universitario Donostia, San Sebastián, Spain
| | | | | | | | - Luís M Marín
- Hospital Universitario Virgen del Rocío, Seville, Spain
| | | | | | | | | | - Carolina González-Abos
- General & Digestive Surgery Service, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Spain
| | - Bárbara Vidal
- Hospital General Universitario de Castellón, Castellón, Spain
| | | | - Laura Lladó
- Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Spain
| | - José Roldán
- Hospital Universitario de Navarra, Pamplona, Spain
| | - Iago Justo
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | | | | | - Gonzalo Rodríguez-Laíz
- Department of General & Digestive Surgery, ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | | | | | - Mireia Caralt
- Hospital Universitario Vall d'Hebrón, Barcelona, Spain
| | - Ramón Charco
- Hospital Universitario Vall d'Hebrón, Barcelona, Spain
| | - Santiago Tomé
- Complejo Hospitalario Universitario Santiago, Santiago de Compostela, Spain
| | - Evaristo Varo
- Complejo Hospitalario Universitario Santiago, Santiago de Compostela, Spain
| | - Pablo Martí-Cruchaga
- HPB and Liver Transplant Unit, General & Digestive Surgery, Clínica Universitaria de Navarra, Pamplona, Spain
| | - Fernando Rotellar
- HPB and Liver Transplant Unit, General & Digestive Surgery, Clínica Universitaria de Navarra, Pamplona, Spain
| | - María A Varona
- Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Manuel Barrera
- Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | | | | | - Diego López
- Hospital Universitario Infanta Cristina, Badajoz, Spain
| | | | - Javier Nuño
- Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - David Pacheco
- Hospital Universitario Río Hortega, Valladolid, Spain
| | | | | | - Constantino Fondevila
- General & Digestive Surgery, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain.,General & Digestive Surgery Service, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Spain.,IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
17
|
Crannell WC, Sally M, McConnell K, Connelly C, Maynard E, Dewey E, Abt P, Enestvedt CK. Thromboelastography profiles for controlled circulatory death donors: Validating the role of heparin. Clin Transplant 2021; 36:e14518. [PMID: 34668240 DOI: 10.1111/ctr.14518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 11/29/2022]
Abstract
Controlled donation after circulatory death (cDCD) liver transplants are associated with increased ischemic-type biliary complications. Microvascular thrombosis secondary to decreased donor fibrinolysis may contribute to bile duct injury. We hypothesized that cDCD donors are hypercoagulable with impaired fibrinolysis and aim to use thromboelastography to characterize cDCD coagulation profiles.
Collapse
Affiliation(s)
- W Christian Crannell
- Department of Surgery, Division of Abdominal Organ Transplantation, Oregon Health & Science University, Portland, Oregon, USA
| | - Mitch Sally
- Department of Surgery, Division of Trauma, Critical Care, and Acute Care Surgery, Oregon Health & Science University, Portland, Oregon, USA
| | - Keeley McConnell
- Department of Surgery, Division of Trauma, Critical Care, and Acute Care Surgery, Oregon Health & Science University, Portland, Oregon, USA
| | - Chris Connelly
- Department of Surgery, Division of Abdominal Organ Transplantation, Oregon Health & Science University, Portland, Oregon, USA
| | - Erin Maynard
- Department of Surgery, Division of Abdominal Organ Transplantation, Oregon Health & Science University, Portland, Oregon, USA
| | - Elizabeth Dewey
- Department of Surgery, Division of Abdominal Organ Transplantation, Oregon Health & Science University, Portland, Oregon, USA
| | - Peter Abt
- Department of Surgery, Division of Transplantation, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - C Kristian Enestvedt
- Department of Surgery, Division of Abdominal Organ Transplantation, Oregon Health & Science University, Portland, Oregon, USA
| |
Collapse
|
|
18
|
Bütikofer S, Lenggenhager D, Wendel Garcia PD, Maggio EM, Haberecker M, Reiner CS, Brüllmann G, Buehler PK, Gubler C, Müllhaupt B, Jüngst C, Morell B. Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19. Liver Int 2021; 41:2404-2417. [PMID: 34018314 PMCID: PMC8242687 DOI: 10.1111/liv.14971] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 05/16/2021] [Accepted: 05/18/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS Little is known about cholestasis, including its most severe variant secondary sclerosing cholangitis (SSC), in critically ill patients with coronavirus disease 19 (COVID-19). In this study, we analysed the occurrence of cholestatic liver injury and SSC, including clinical, serological, radiological and histopathological findings. METHODS We conducted a retrospective single-centre analysis of all consecutive patients admitted to the intensive care unit (ICU) as a result of severe COVID-19 at the University Hospital Zurich to describe cholestatic injury in these patients. The findings were compared to a retrospective cohort of patients with severe influenza A. RESULTS A total of 34 patients with severe COVID-19 admitted to the ICU were included. Of these, 14 patients (41%) had no cholestasis (group 0), 11 patients (32%, group 1) developed mild and 9 patients (27%, group 2) severe cholestasis. Patients in group 2 had a more complicated disease course indicated by significantly longer ICU stay (median 51 days, IQR 25-86.5) than the other groups (group 0: median 9.5 days, IQR 3.8-18.3, P = .001; and group 1: median 16 days, IQR 8-30, P < .05 respectively). Four patients in group 2 developed SSC compared to none in the influenza A cohort. The available histopathological findings suggest an ischaemic damage to the perihilar bile ducts. CONCLUSIONS The development of SSC represents an important complication of critically ill COVID-19 patients and needs to be considered in the diagnostic work up in prolonged cholestasis. The occurrence of SSC is of interest in the ongoing pandemic since it is associated with considerable morbidity and mortality.
Collapse
Affiliation(s)
- Simon Bütikofer
- Department of Gastroenterology and HepatologyUniversity Hospital ZurichZurichSwitzerland
| | - Daniela Lenggenhager
- Department of Pathology and Molecular PathologyUniversity Hospital ZurichZurichSwitzerland
| | | | - Ewerton M. Maggio
- Department of Pathology and Molecular PathologyUniversity Hospital ZurichZurichSwitzerland
| | - Martina Haberecker
- Department of Pathology and Molecular PathologyUniversity Hospital ZurichZurichSwitzerland
| | - Cäcilia S. Reiner
- Institute of Diagnostic and Interventional RadiologyUniversity Hospital ZurichZurichSwitzerland
| | - Gregor Brüllmann
- Institute of Intensive CareUniversity Hospital ZurichZurichSwitzerland
| | | | - Christoph Gubler
- Department of Gastroenterology and HepatologyUniversity Hospital ZurichZurichSwitzerland
| | - Beat Müllhaupt
- Department of Gastroenterology and HepatologyUniversity Hospital ZurichZurichSwitzerland
| | - Christoph Jüngst
- Department of Gastroenterology and HepatologyUniversity Hospital ZurichZurichSwitzerland
| | - Bernhard Morell
- Department of Gastroenterology and HepatologyUniversity Hospital ZurichZurichSwitzerland
| |
Collapse
|
|
19
|
Regulations and Procurement Surgery in DCD Liver Transplantation: Expert Consensus Guidance From the International Liver Transplantation Society. Transplantation 2021; 105:945-951. [PMID: 33675315 DOI: 10.1097/tp.0000000000003729] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Donation after circulatory death (DCD) donors are an increasingly more common source of livers for transplantation in many parts of the world. Events that occur during DCD liver recovery have a significant impact on the success of subsequent transplantation. This working group of the International Liver Transplantation Society evaluated current evidence as well as combined experience and created this guidance on DCD liver procurement. Best practices for the recovery and transplantation of livers arising through DCD after euthanasia and organ procurement with super-rapid cold preservation and recovery as well as postmortem normothermic regional perfusion are described, as are the use of adjuncts during DCD liver procurement.
Collapse
|
|
20
|
Ghinolfi D, Melandro F, Torri F, Martinelli C, Cappello V, Babboni S, Silvestrini B, De Simone P, Basta G, Del Turco S. Extended criteria grafts and emerging therapeutics strategy in liver transplantation. The unstable balance between damage and repair. Transplant Rev (Orlando) 2021; 35:100639. [PMID: 34303259 DOI: 10.1016/j.trre.2021.100639] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/10/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
Due to increasing demand for donor organs, "extended criteria" donors are increasingly considered for liver transplantation, including elderly donors and donors after cardiac death. The grafts of this subgroup of donors share a major risk to develop significant features of ischemia reperfusion injury, that may eventually lead to graft failure. Ex-situ machine perfusion technology has gained much interest in liver transplantation, because represents both a useful tool for improving graft quality before transplantation and a platform for the delivery of therapeutics directly to the organ. In this review, we survey ongoing clinical evidences supporting the use of elderly and DCD donors in liver transplantation, and the underlying mechanistic aspects of liver aging and ischemia reperfusion injury that influence graft quality and transplant outcome. Finally, we highlight evidences in the field of new therapeutics to test in MP in the context of recent findings of basic and translational research.
Collapse
Affiliation(s)
- Davide Ghinolfi
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy.
| | - Fabio Melandro
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Francesco Torri
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Caterina Martinelli
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Valentina Cappello
- Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia, Piazza S. Silvestro 12, 56127 Pisa, Italy
| | - Serena Babboni
- Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi 1, 56124 Pisa, Italy
| | - Beatrice Silvestrini
- Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, 56122 Pisa, Italy.
| | - Paolo De Simone
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Giuseppina Basta
- Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi 1, 56124 Pisa, Italy
| | - Serena Del Turco
- Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi 1, 56124 Pisa, Italy.
| |
Collapse
|
|
21
|
Haque O, Raigani S, Rosales I, Carroll C, Coe TM, Baptista S, Yeh H, Uygun K, Delmonico FL, Markmann JF. Thrombolytic Therapy During ex-vivo Normothermic Machine Perfusion of Human Livers Reduces Peribiliary Vascular Plexus Injury. Front Surg 2021; 8:644859. [PMID: 34222314 PMCID: PMC8245781 DOI: 10.3389/fsurg.2021.644859] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 05/24/2021] [Indexed: 12/29/2022] Open
Abstract
Background: A major limitation in expanding the use of donation after circulatory death (DCD) livers in transplantation is the increased risk of graft failure secondary to ischemic cholangiopathy. Warm ischemia causes thrombosis and injury to the peribiliary vascular plexus (PVP), which is supplied by branches of the hepatic artery, causing higher rates of biliary complications in DCD allografts. Aims/Objectives: We aimed to recondition discarded DCD livers with tissue plasminogen activator (tPA) while on normothermic machine perfusion (NMP) to improve PVP blood flow and reduce biliary injury. Methods: Five discarded DCD human livers underwent 12 h of NMP. Plasminogen was circulated in the base perfusate prior to initiation of perfusion and 1 mg/kg of tPA was administered through the hepatic artery at T = 0.5 h. Two livers were split prior to perfusion (S1, S2), with tPA administered in one lobe, while the other served as a control. The remaining three whole livers (W1-W3) were compared to seven DCD control liver perfusions (C1-C7) with similar hepatocellular and biliary viability criteria. D-dimer levels were measured at T = 1 h to verify efficacy of tPA. Lactate, total bile production, bile pH, and difference in biliary injury scores before and after perfusion were compared between tPA and non-tPA groups using unpaired, Mann-Whitney tests. Results: Average weight-adjusted D-dimer levels were higher in tPA livers in the split and whole-liver model, verifying drug function. There were no differences in perfusion hepatic artery resistance, portal vein resistance, and arterial lactate between tPA livers and non-tPA livers in both the split and whole-liver model. However, when comparing biliary injury between hepatocellular and biliary non-viable whole livers, tPA livers had significantly lower PVP injury scores (0.67 vs. 2.0) and mural stroma (MS) injury scores (1.3 vs. 2.7). Conclusion: This study demonstrates that administration of tPA into DCD livers during NMP can reduce PVP and MS injury. Further studies are necessary to assess the effect of tPA administration on long term biliary complications.
Collapse
Affiliation(s)
- Omar Haque
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Siavash Raigani
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Ivy Rosales
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Cailah Carroll
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States
| | - Taylor M Coe
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Sofia Baptista
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States
| | - Heidi Yeh
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Korkut Uygun
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Shriners Hospitals for Children, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Francis L Delmonico
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States.,New England Donor Services (NEDS), Waltham, MA, United States
| | - James F Markmann
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States.,Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| |
Collapse
|
|
22
|
Boeva I, Karagyozov PI, Tishkov I. Post-liver transplant biliary complications: Current knowledge and therapeutic advances. World J Hepatol 2021; 13:66-79. [PMID: 33584987 PMCID: PMC7856868 DOI: 10.4254/wjh.v13.i1.66] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 11/01/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is the current standard of care for end-stage liver disease and an accepted therapeutic option for acute liver failure and primary liver tumors. Despite the remarkable advances in the surgical techniques and immunosuppressive therapy, the postoperative morbidity and mortality still remain high and the leading causes are biliary complications, which affect up to one quarter of recipients. The most common biliary complications are anastomotic and non-anastomotic biliary strictures, leaks, bile duct stones, sludge and casts. Despite the absence of a recommended treatment algorithm many options are available, such as surgery, percutaneous techniques and interventional endoscopy. In the last few years, endoscopic techniques have widely replaced the more aggressive percutaneous and surgical approaches. Endoscopic retrograde cholangiography is the preferred technique when duct-to-duct anastomosis has been performed. Recently, new devices and techniques have been developed and this has led to a remarkable increase in the success rate of minimally invasive procedures. Understanding the mechanisms of biliary complications helps in their early recognition which is the prerequisite for successful treatment. Aggressive endoscopic therapy is essential for the reduction of morbidity and mortality in these cases. This article focuses on the common post-transplant biliary complications and the available interventional treatment modalities.
Collapse
Affiliation(s)
- Irina Boeva
- Department of Interventional Gastroenterology, Acibadem City Clinic Tokuda Hospital, Sofia 1407, Bulgaria
| | - Petko Ivanov Karagyozov
- Department of Interventional Gastroenterology, Clinic of Gastroenterology, Acibadem City Clinic Tokuda Hospital, Sofia 1407, Bulgaria.
| | - Ivan Tishkov
- Department of Interventional Gastroenterology, Acibadem City Clinic Tokuda Hospital, Sofia 1407, Bulgaria
| |
Collapse
|
|
23
|
Zheng BW, Yi SH, Wu T, Liao M, Zhang YC, Yuan LX, Zheng RQ, Yang Y, Ren J. CEUS detection of biliary ischaemia during the first 4 weeks after liver transplantation predicts non-anastomotic biliary stricture. Clin Hemorheol Microcirc 2021; 79:519-530. [PMID: 34366329 DOI: 10.3233/ch-211097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Biliary ischaemia is an important factor in the pathogenesis of non-anastomotic biliary stricture (NAS) after liver transplantation (LT). Contrast-enhanced ultrasound (CEUS) can be used to detect biliary ischaemia, but no study has examined the utility of CEUS in predicting NAS. OBJECTIVE To evaluate whether repeated CEUS as a non-invasive method of biliary ischaemia can identify NAS. METHODS Consecutive LT patients who underwent CEUS examinations at 1-4 weeks after LT from September 2012 to December 2015 at our institution were included. The CEUS images and clinical data were analysed. RESULTS Among 116 eligible LT patients, 39 (33.6%) were diagnosed with NAS within 1 year after LT. The patients with NAS had a significantly higher CEUS score at weeks 2-4 (all P < 0.05) and a higher slope of CEUS score progression (0.480 vs -0.044, P < 0.001). The accuracy of CEUS in identifying NAS improved over time after LT, reaching its maximum at week 4, with a sensitivity of 66.7%, a specificity of 87.9%, a positive predictive value (PPV) of 75.9%, a negative predictive value (NPV) of 82.3%, and an accuracy of 80.2%in the full cohort when a CEUS score≥3 was used as the cut-off. Multivariate analysis identified gamma-glutamyl transpeptidase (GGT), alanine transaminase (ALT) and the CEUS score at week 4 as independent predictors of NAS. In the task of identifying NAS, an NAS score combining the above 3 variables at week 4 showed areas under the receiver operating characteristic curve of 0.88 (95%CI, 0.78-0.99) in the estimation group (n = 60) and 0.82 (95%CI, 0.69-0.96) in the validation group (n = 56). An NAS score cut-off of 0.396 identified 87.2%of NAS cases in the estimation group, with a PPV of 93.3%; and 75.0%of NAS cases in the validation group, with a PPV of 58.8%. CONCLUSIONS CEUS examination during the first 4 weeks is useful in assessing the risk of NAS within 1 year after LT. In particular, an NAS score combining the CEUS score, GGT level, and ALT level at week 4 can be used to accurately predict the risk of NAS in LT patients.
Collapse
Affiliation(s)
- Bo-Wen Zheng
- Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Shu-Hong Yi
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Tao Wu
- Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Mei Liao
- Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Ying-Cai Zhang
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Lian-Xiong Yuan
- Department of Scientific Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Rong-Qin Zheng
- Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Yang Yang
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| | - Jie Ren
- Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou, Guangdong, People's Republic of China
| |
Collapse
|
|
24
|
Panayotova GG, Lunsford KE, Guarrera JV. Bile formation in long-term (1 week), ex situ perfused livers: Analysis and commentary. Surgery 2020; 169:1551-1552. [PMID: 33218702 DOI: 10.1016/j.surg.2020.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Guergana G Panayotova
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, Newark, NJ
| | - Keri E Lunsford
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, Newark, NJ; Center for Immunity and Inflammation, Institute for Infectious and Inflammatory Disease, Rutgers New Jersey Medical School, Newark, NJ
| | - James V Guarrera
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, Newark, NJ.
| |
Collapse
|
|
25
|
Ly M, Crawford M, Verran D. Biliary complications in donation after circulatory death liver transplantation: the Australian National Liver Transplantation Unit's experience. ANZ J Surg 2020; 91:445-450. [PMID: 32985774 DOI: 10.1111/ans.16304] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND Biliary complications are the most common complications of donation after circulatory death (DCD) liver transplantation and the international experience with DCD transplants suggests increased rates of biliary complications compared to donation after brain death transplants. Therefore, it is important to understand factors that are associated with the development of biliary complications within the Australian DCD context in order to inform future practice. The aim of this study is to determine the incidence of biliary complications after DCD liver transplantation at the Australian National Liver Transplantation Unit and identify factors associated with this outcome. METHODS A retrospective analysis of all adult DCD liver transplants at the Australian National Liver Transplantation Unit from 2007 to 2015 was undertaken. The primary outcome measure was the incidence of biliary complications and was censored on 31 December 2016. Recipients were then stratified into groups based on the development of biliary complications and risk factor analysis was performed. RESULTS Biliary complications occurred in 35% of DCD transplants, including seven anastomotic strictures and 10 non-anastomotic strictures. Higher donor risk index scores (P = 0.03), post-transplant portal vein complications (P = 0.042) and peak gamma-glutamyl transferase levels within 7 days post-transplant (P = 0.047) were associated with biliary complications. CONCLUSION Findings from this study demonstrate that biliary complications remain common in DCD liver recipients. Recipients who developed a biliary complication tended to have higher donor risk index, elevated peak gamma-glutamyl transferase levels within 7 days post-transplant or a portal vein complication. The presence of any of these factors should prompt close monitoring for post-transplant biliary complications.
Collapse
Affiliation(s)
- Mark Ly
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Michael Crawford
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.,Department of Upper Gastrointestinal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Deborah Verran
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| |
Collapse
|
|
26
|
Hessheimer AJ, Gastaca M, Miñambres E, Colmenero J, Fondevila C. Donation after circulatory death liver transplantation: consensus statements from the Spanish Liver Transplantation Society. Transpl Int 2020; 33:902-916. [PMID: 32311806 PMCID: PMC7496958 DOI: 10.1111/tri.13619] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 02/06/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
Livers from donation after circulatory death (DCD) donors are an increasingly more common source of organs for transplantation. While there are few high-level studies in the field of DCD liver transplantation, clinical practice has undergone progressive changes during the past decade, in particular due to mounting use of postmortem normothermic regional perfusion (NRP). In Spain, uncontrolled DCD has been performed since the late 1980s/early 1990s, while controlled DCD was implemented nationally in 2012. Since 2012, the rise in DCD liver transplant activity in Spain has been considerable, and the great majority of DCD livers transplanted in Spain today are recovered with NRP. A panel of the Spanish Liver Transplantation Society was convened in 2018 to evaluate current evidence and accumulated experience in DCD liver transplantation, in particular addressing issues related to DCD liver evaluation, acceptance criteria, and recovery as well as recipient selection and postoperative management. This panel has created a series of consensus statements for the standard of practice in Spain and has published these statements with the hope they might help guide other groups interested in implementing new forms of DCD liver transplantation and/or introducing NRP into their clinical practices.
Collapse
Affiliation(s)
- Amelia J. Hessheimer
- Liver Transplant UnitCIBERehdIDIBAPSHospital ClínicUniversity of BarcelonaBarcelonaSpain
| | - Mikel Gastaca
- Hospital Universitario CrucesBilbaoSpain
- SETH Board of DirectorsSpain
| | - Eduardo Miñambres
- Transplant Coordination Unit & Intensive Care ServiceIDIVALHospital Universitario Marqués de ValdecillaUniversity of CantabriaSantanderSpain
| | - Jordi Colmenero
- Liver Transplant UnitCIBERehdIDIBAPSHospital ClínicUniversity of BarcelonaBarcelonaSpain
- SETH Board of DirectorsSpain
| | - Constantino Fondevila
- Liver Transplant UnitCIBERehdIDIBAPSHospital ClínicUniversity of BarcelonaBarcelonaSpain
| |
Collapse
|
|
27
|
Biliary Bicarbonate, pH, and Glucose Are Suitable Biomarkers of Biliary Viability During Ex Situ Normothermic Machine Perfusion of Human Donor Livers. Transplantation 2020; 103:1405-1413. [PMID: 30395120 PMCID: PMC6613725 DOI: 10.1097/tp.0000000000002500] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ex situ normothermic machine perfusion (NMP) can be used to assess viability of suboptimal donor livers before implantation. Our aim was to assess the diagnostic accuracy of bile biochemistry for the assessment of bile duct injury (BDI). METHODS In a preclinical study, 23 human donor livers underwent 6 hours of end-ischemic NMP to determine biomarkers of BDI. Livers were divided into groups with low or high BDI, based on a clinically relevant histological grading system. During NMP, bile was analyzed biochemically and potential biomarkers were correlated with the degree of BDI. Receiver operating characteristics curves were generated to determine optimal cutoff values. For clinical validation, identified biomarkers were subsequently included as viability criteria in a clinical trial (n = 6) to identify transplantable liver grafts with low BDI. RESULTS Biliary bicarbonate and pH were significantly higher and biliary glucose was significantly lower in livers with low BDI, compared with high BDI. The following cutoff values were associated with low BDI: biliary bicarbonate greater than 18 mmol/L (P = 0.002), biliary pH greater than 7.48 (P = 0.019), biliary glucose less than 16 mmol/L (P = 0.013), and bile/perfusate glucose ratio less than 0.67 (P = 0.013). In the clinical trial, 4 of 6 livers met these criteria and were transplanted, and none developed clinical evidence of posttransplant cholangiopathy. CONCLUSIONS Biliary bicarbonate, pH, and glucose during ex situ NMP of liver grafts are accurate biomarkers of BDI and can be easily determined point of care, making them suitable for the pretransplant assessment of bile duct viability. This may improve graft selection and decrease the risk of posttransplant cholangiopathy.
Collapse
|
|
28
|
Huang C, Huang S, Tang Y, Zhao Q, Wang D, Ju W, Yang L, Zhang J, Wu L, Chen M, Zhang Z, Zhu Z, Wang L, Zhu C, Zhang Y, Sun C, Xiong W, Shen Y, Chen X, Ma Y, Hu A, Zhu X, Rong J, Cai C, Guo Z, He X. Prospective, single-centre, randomised controlled trial to evaluate the efficacy and safety of ischaemia-free liver transplantation (IFLT) in the treatment of end-stage liver disease. BMJ Open 2020; 10:e035374. [PMID: 32376754 PMCID: PMC7223152 DOI: 10.1136/bmjopen-2019-035374] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION During conventional liver transplantation (CLT), ischaemia-reperfusion injury (IRI) is inevitable and is associated with complications such as early allograft dysfunction (EAD), primary non-function and ischaemic-type biliary lesions. We have established a novel procedure called ischaemia-free liver transplantation (IFLT). The results from a pilot study suggest that IFLT might prevent IRI and yield better transplant outcomes than CLT. The purpose of this study was to further assess the efficacy and safety of IFLT versus CLT in patients with end-stage liver disease. METHODS AND ANALYSIS This is an investigator-initiated, open-label, phase III, prospective, single-centre randomised controlled trial on the effects of IFLT in patients with end-stage liver disease. Adult patients (aged 18-75 years) eligible for liver transplantation will be screened for participation in this trial and will be randomised between the IFLT group (n=34) and the CLT group (n=34). In the IFLT group, the donor liver will be procured, preserved and implanted with continuous normothermic machine perfusion (NMP). In the CLT group, the donor liver will be procured after a fast cold flush, preserved in 0°C-4°C solution and implanted under hypothermic and hypoxic conditions. Patients in both groups will be managed according to the standard protocol of our centre. The primary end point is the incidence of EAD after liver transplantation. Intraoperative and postoperative parameters of donor livers and recipients will be observed and recorded, and postoperative liver graft function, complications and recipient and graft survival will be evaluated. After a 12-month follow-up of the last enrolled recipient, the outcomes will be analysed to evaluate the safety and efficacy of IFLT versus CLT in patients with end-stage liver disease. ETHICS AND DISSEMINATION The protocol was reviewed and approved by the Ethics Committee of The First Affiliated Hospital of Sun Yat-sen University. The findings will be disseminated to the public through conference presentations and peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER ChiCTR1900021158.
Collapse
Affiliation(s)
- Changjun Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Shanzhou Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Dongping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Lu Yang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Linwei Wu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiheng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zebin Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Linhe Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Caihui Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yixi Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Chengjun Sun
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Wei Xiong
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuekun Shen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoxiang Chen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yi Ma
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Anbin Hu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jian Rong
- Department of Cardiopulmonary Bypass, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Changjie Cai
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| |
Collapse
|
|
29
|
van Leeuwen OB, van Reeven M, van der Helm D, IJzermans JNM, de Meijer VE, van den Berg AP, Darwish Murad S, van Hoek B, Alwayn IPJ, Porte RJ, Polak WG. Donor hepatectomy time influences ischemia-reperfusion injury of the biliary tree in donation after circulatory death liver transplantation. Surgery 2020; 168:160-166. [PMID: 32223984 DOI: 10.1016/j.surg.2020.02.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/26/2020] [Accepted: 02/10/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Donor hepatectomy time is associated with graft survival after liver transplantation. The aim of this study was to identify the impact of donor hepatectomy time on biliary injury during donation after circulatory death liver transplantation. METHODS First, bile duct biopsies of livers included in (pre)clinical machine perfusion research were analyzed. Secondly, of the same livers, bile samples were collected during normothermic machine perfusion. Lastly, a nationwide retrospective cohort study was performed including 273 adult patients undergoing donation after circulatory death liver transplantation between January 1, 2002 and January 1, 2017. Primary endpoint was development of non-anastomotic biliary strictures within 2 years of donation after circulatory death liver transplantation. Cox proportional-hazards regression analyses were used to assess the influence of hepatectomy time on the development of non-anastomotic biliary strictures. RESULTS Livers with severe histological bile duct injury had a higher median hepatectomy time (P = .03). During normothermic machine perfusion, livers with a hepatectomy time >50 minutes had lower biliary bicarbonate and bile pH levels. In the nationwide retrospective study, donor hepatectomy time was an independent risk factor for non-anastomotic biliary strictures after donation after circulatory death liver transplantation (Hazard Ratio 1.18 per 10 minutes increase, 95% Confidence Interval 1.06-1.30, P value = .002). CONCLUSION Donor hepatectomy time negatively influences histological bile duct injury before normothermic machine perfusion and bile composition during normothermic machine perfusion. Additionally, hepatectomy time is a significant independent risk factor for the development of non-anastomotic biliary strictures after donation after circulatory death liver transplantation.
Collapse
Affiliation(s)
- Otto B van Leeuwen
- Division of HPB Surgery & Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Marjolein van Reeven
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC University Medical Center Rotterdam, the Netherlands
| | - Danny van der Helm
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, the Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC University Medical Center Rotterdam, the Netherlands
| | - Vincent E de Meijer
- Division of HPB Surgery & Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Aad P van den Berg
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Sarwa Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, the Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, the Netherlands
| | - Ian P J Alwayn
- Department of Surgery, Division of Transplant Surgery, Leiden University Medical Center, the Netherlands
| | - Robert J Porte
- Division of HPB Surgery & Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands
| | - Wojciech G Polak
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC University Medical Center Rotterdam, the Netherlands.
| |
Collapse
|
|
30
|
Cascales-Campos PA, Ferreras D, Alconchel F, Febrero B, Royo-Villanova M, Martínez M, Rodríguez JM, Fernández-Hernández JÁ, Ríos A, Pons JA, Sánchez-Bueno F, Robles R, Martínez-Barba E, Martínez-Alarcón L, Parrilla P, Ramírez P. Controlled donation after circulatory death up to 80 years for liver transplantation: Pushing the limit again. Am J Transplant 2020; 20:204-212. [PMID: 31329359 DOI: 10.1111/ajt.15537] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/20/2019] [Accepted: 07/09/2019] [Indexed: 01/25/2023]
Abstract
Our main objective was to compare liver transplant (LT) results between donation after circulatory death (DCD) and donation after brainstem death (DBD) in our hospital and to analyze, within the DCD group, the influence of age on the results obtained with DCD donors aged >70 years and up to 80 years. All DCD-LTs performed were analyzed prospectively. The results of the DCD group were compared with those of a control group who received a DBD-LT immediately after each DCD-LT. Later, the results obtained within the DCD group were analyzed according to the age of the donors, considering 2 subgroups with a cut-off point at 70 years. Survival results for LT with DCD and super rapid recovery were not inferior to those obtained in a similar group of patients transplanted with DBD livers. However, the cost of DCD was a higher rate of biliary complications, including ischemic cholangiopathy. Donor age was not a negative factor.
Collapse
Affiliation(s)
- Pedro A Cascales-Campos
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - David Ferreras
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Felipe Alconchel
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Beatriz Febrero
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Mario Royo-Villanova
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
- Intensive Care Unit, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - María Martínez
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
- Intensive Care Unit, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - José M Rodríguez
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Juan Á Fernández-Hernández
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Antonio Ríos
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - José A Pons
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
- Department of Hepatology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Francisco Sánchez-Bueno
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Ricardo Robles
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Enrique Martínez-Barba
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
- Department of Patholoy, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Laura Martínez-Alarcón
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Pascual Parrilla
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Pablo Ramírez
- Department of Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| |
Collapse
|
|
31
|
Meurisse N, Monbaliu D, Berlakovich G, Muiesan P, Oliverius M, Adam R, Pirenne J. Heterogeneity of Bile Duct Management in the Development of Ischemic Cholangiopathy After Liver Transplantation: Results of a European Liver and Intestine Transplant Association Survey. Transplant Proc 2019; 51:1926-1933. [PMID: 31301856 DOI: 10.1016/j.transproceed.2019.04.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 04/22/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Surgical factors and direct cytotoxicity of bile salts on cholangiocytes may play a role in the development of ischemic cholangiopathy (IC) after liver transplantation (LTx). There is no validated consensus on how to protect the bile ducts during procurement, static preservation, and LTx. Meanwhile, IC remains the most troublesome complication after LTx. AIM To characterize bile duct management techniques during the LTx process among European transplant centers in cases of donation after brain death (DBD) and circulatory death (DCD). METHOD An European Liver and Intestine Transplant Association-European Liver Transplant Registry web survey designed to conceal respondents' personal information was sent to surgeons procuring and/or transplanting livers in Europe. RESULTS Sixty-five percent of responses came from large transplant centers (>50 procurements/y). In 8% of DBDs and 14% of DCDs the bile duct is not rinsed. In 46% of DBDs and 52% of DCDs surgeons prefer to remove the gallbladder after graft reperfusion. Protocols concerning preservation solutions (nature, pressure, volume) are extremely heterogeneous. In 54% of DBDs and 61% of DCDs an arterial back table pressure perfusion is performed. Steroids (20%-10%), heparin (72%-60%), prostacyclin (3%-7%), and fibrinolytics (4%-11%) are used as donor-protective interventions in DBD and DCD cases, respectively. In 2% of DBD and 6% of DCD cases a hepatic artery reperfusion is performed first. In 4% of DBD and 6% of DCD cases, fibrinolytics are administered through the hepatic artery during the bench and/or implantation. CONCLUSION This European web survey shows for the first time the heterogeneity in the management of bile ducts during procurement, preservation, and transplantation in Europe. In the context of sharing more marginal liver grafts, an expert meeting must be organized to formulate guidelines to be applied to protect liver grafts against IC.
Collapse
Affiliation(s)
- Nicolas Meurisse
- Department of Abdominal Transplant Surgery, University of Liege Academic Hospital, ULg CHU, Liege, Belgium; Department of Abdominal Transplant Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Department of Abdominal Transplant Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Gabriela Berlakovich
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Paolo Muiesan
- Liver Unit, University of Birmingham, Birmingham, United Kingdom
| | - Martin Oliverius
- Department of Surgery of the 3rd Faculty of Medicine Charles University and Kralovske Vinohrady Hospital, Prague, Czech Republic
| | - René Adam
- APHP Hospital Paul Brousse, Inserm U985, University Paris Sud, Paris, France
| | - Jacques Pirenne
- Department of Abdominal Transplant Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
| |
Collapse
|
|
32
|
Diogo D, Pacheco C, Oliveira R, Martins R, Oliveira P, Cipriano MA, Tralhão JG, Furtado E. Influence of Ischemia Time in Injury of Deep Peribiliary Glands of the Bile Ducts Graft: A Prospective Study. Transplant Proc 2019; 51:1545-1548. [PMID: 31155189 DOI: 10.1016/j.transproceed.2019.01.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The deep peribiliary glands (DPBG) are a niche of progenitor cells in the wall of the biliary duct (BD) and are the second line of multiplication when severe lesion of the epithelium occurs. Previous studies have identified DPBG injury as a cause of post-liver transplant (LT) biliary stenosis; this complication is a major cause of post-LT morbidity. The incidence of biliary stenosis in our center is high (38.1%). This study evaluates the lesion of DPBG in response to ischemia. Graft BD was collected in adult LT between August 2016-July 2017, from donation after brain death. Samples of 45 grafts were collected at 2 moments: BD1-during graft preparation and BD2-before biliary anastomosis. Histological analysis of the samples was performed and then classified according to degree of lesion (0, ≤50%, and >50%). A comparison was made between the degree of lesion and graft ischemia, graft histology, donor, and procurement variables. The DPBG lesion was more frequent in BD2 (20.9% vs 7%, P = .079). BD2 lesions with DPBG lesions had higher medians and means at all times of ischemia. The difference was greater in the warm ischemia time (0: 43.3 ± 12.53 minutes vs ≤50%: 52.4 ± 14.38 minutes, P = .068). The group of BD1 with DPBG lesion presented superior median cold ischemia time (CIT). In the analysis of the remaining variables there were also no statistically significant differences. We concluded that during the period of CIT there is already lesion of the DPBG, which increases after reperfusion of the graft, in greater association with longer warm ischemia time.
Collapse
Affiliation(s)
- D Diogo
- Adult and Paediatric Liver Transplantation Unit, Coimbra Hospital and University Centre, Coimbra, Portugal.
| | - C Pacheco
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - R Oliveira
- Department of Pathologic Anatomy, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - R Martins
- Adult and Paediatric Liver Transplantation Unit, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - P Oliveira
- Adult and Paediatric Liver Transplantation Unit, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - M A Cipriano
- Department of Pathologic Anatomy, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - J G Tralhão
- Department of Surgery, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - E Furtado
- Adult and Paediatric Liver Transplantation Unit, Coimbra Hospital and University Centre, Coimbra, Portugal
| |
Collapse
|
|
33
|
Franchitto A, Overi D, Mancinelli R, Mitterhofer AP, Muiesan P, Tinti F, Umbro I, Hubscher SG, Onori P, Gaudio E, Carpino G. Peribiliary gland damage due to liver transplantation involves peribiliary vascular plexus and vascular endothelial growth factor. Eur J Histochem 2019; 63:3022. [PMID: 31113191 PMCID: PMC6517787 DOI: 10.4081/ejh.2019.3022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Extrahepatic bile ducts are characterized by the presence of peribiliary glands (PBGs), which represent stem cell niches implicated in biliary regeneration. Orthotopic liver transplantation may be complicated by non-anastomotic strictures (NAS) of the bile ducts, which have been associated with ischemic injury of PBGs and occur more frequently in livers obtained from donors after circulatory death than in those from brain-dead donors. The aims of the present study were to investigate the PBG phenotype in bile ducts after transplantation, the integrity of the peribiliary vascular plexus (PVP) around PBGs, and the expression of vascular endothelial growth factor-A (VEGF-A) by PBGs. Transplanted ducts obtained from patients who underwent liver transplantation were studied (N=62). Controls included explanted bile duct samples not used for transplantation (N=10) with normal histology. Samples were processed for histology, immunohistochemistry and immunofluorescence. Surface epithelium is severely injured in transplanted ducts; PBGs are diffusely damaged, particularly in ducts obtained from circulatory-dead compared to brain-dead donors. PVP is reduced in transplanted compared to controls. PBGs in transplanted ducts contain more numerous progenitor and proliferating cells compared to controls, show higher positivity for VEGF-A compared to controls, and express VEGF receptor-2. In conclusion, PBGs and associated PVP are damaged in transplanted extrahepatic bile ducts; however, an activation of the PBG niche takes place and is characterized by proliferation and VEGF-A expression. This response could have a relevant role in reconstituting biliary epithelium and vascular plexus and could be implicated in the genesis of non-anastomotic strictures.
Collapse
Affiliation(s)
- Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Moy BT, Birk JW. A Review on the Management of Biliary Complications after Orthotopic Liver Transplantation. J Clin Transl Hepatol 2019; 7:61-71. [PMID: 30944822 PMCID: PMC6441650 DOI: 10.14218/jcth.2018.00028] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 09/23/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Orthotopic liver transplantation is the definitive treatment for end-stage liver disease and hepatocellular carcinomas. Biliary complications are the most common complications seen after transplantation, with an incidence of 10-25%. These complications are seen both in deceased donor liver transplant and living donor liver transplant. Endoscopic treatment of biliary complications with endoscopic retrograde cholangiopancreatography (commonly known as ERCP) has become a mainstay in the management post-transplantation. The success rate has reached 80% in an experienced endoscopist's hands. If unsuccessful with ERCP, percutaneous transhepatic cholangiography can be an alternative therapy. Early recognition and treatment has been shown to improve morbidity and mortality in post-liver transplant patients. The focus of this review will be a learned discussion on the types, diagnosis, and treatment of biliary complications post-orthotopic liver transplantation.
Collapse
Affiliation(s)
- Brian T. Moy
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - John W. Birk
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- *Correspondence to: John W. Birk, Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT 06030, USA. E-mail:
| |
Collapse
|
|
35
|
van Rijn R, van den Berg AP, Erdmann JI, Heaton N, van Hoek B, de Jonge J, Leuvenink HGD, Mahesh SVK, Mertens S, Monbaliu D, Muiesan P, Perera MTPR, Polak WG, Rogiers X, Troisi RI, de Vries Y, Porte RJ. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol 2019; 19:40. [PMID: 30866837 PMCID: PMC6416838 DOI: 10.1186/s12876-019-0956-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 02/22/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The major concern in liver transplantation of grafts from donation after circulatory death (DCD) donors remains the high incidence of non-anastomotic biliary strictures (NAS). Machine perfusion has been proposed as an alternative strategy for organ preservation which reduces ischemia-reperfusion injury (IRI). Experimental studies have shown that dual hypothermic oxygenated machine perfusion (DHOPE) is associated with less IRI, improved hepatocellular function, and better preserved mitochondrial and endothelial function compared to conventional static cold storage (SCS). Moreover, DHOPE was safely applied with promising results in a recently performed phase-1 study. The aim of the current study is to determine the efficacy of DHOPE in reducing the incidence of NAS after DCD liver transplantation. METHODS This is an international multicenter randomized controlled trial. Adult patients (≥18 yrs. old) undergoing transplantation of a DCD donor liver (Maastricht category III) will be randomized between the intervention and control group. In the intervention group, livers will be subjected to two hours of end-ischemic DHOPE after SCS and before implantation. In the control group, livers will be subjected to care as usual with conventional SCS only. Primary outcome is the incidence of symptomatic NAS diagnosed by a blinded adjudication committee. In all patients, magnetic resonance cholangiography will be obtained at six months after transplantation. DISCUSSION DHOPE is associated with reduced IRI of the bile ducts. Whether reduced IRI of the bile ducts leads to lower incidence of NAS after DCD liver transplantation can only be examined in a randomized controlled trial. TRIAL REGISTRATION The trial was registered in Clinicaltrials.gov in September 2015 with the identifier NCT02584283 .
Collapse
Affiliation(s)
- Rianne van Rijn
- Section Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Aad P. van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Joris I. Erdmann
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Nigel Heaton
- Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London, UK
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeroen de Jonge
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Henri G. D. Leuvenink
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Shekar V. K. Mahesh
- Department of Radiology, University Medical Center Groningen, Groningen, The Netherlands
| | - Sarah Mertens
- Department of Abdominal Transplantation Surgery, University Hospitals of Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Department of Abdominal Transplantation Surgery, University Hospitals of Leuven, Leuven, Belgium
| | - Paolo Muiesan
- Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - M. Thamara P. R. Perera
- Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Wojciech G. Polak
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Xavier Rogiers
- Department of Transplant Surgery, Ghent University Hospital, Ghent, Belgium
| | - Roberto I. Troisi
- Department of Transplant Surgery, Ghent University Hospital, Ghent, Belgium
| | - Yvonne de Vries
- Section Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J. Porte
- Section Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
36
|
Porcine Isolated Liver Perfusion for the Study of Ischemia Reperfusion Injury: A Systematic Review. Transplantation 2019; 102:1039-1049. [PMID: 29509572 DOI: 10.1097/tp.0000000000002156] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Understanding ischemia reperfusion injury (IRI) is essential to further improve outcomes after liver transplantation (LT). Porcine isolated liver perfusion (ILP) is increasingly used to reproduce LT-associated IRI in a strictly controlled environment. However, whether ILP is a reliable substitute of LT was never validated. METHODS We systematically reviewed the current experimental setups for ILP and parameters of interest reflecting IRI. RESULTS Isolated liver perfusion was never compared with transplantation in animals. Considerable variability exists between setups, and comparative data are unavailable. Experience so far suggests that centrifugal pump(s) with continuous flow are preferred to reduce the risk of embolism. Hepatic outflow can be established by cannulation of the inferior vena cava or freely drained in an open bath. Whole blood at approximately 38°C, hematocrit of 20% or greater, and the presence of leukocytes to trigger inflammation is considered the optimal perfusate. A number of parameters related to the 4 liver compartments (hepatocyte, cholangiocyte, endothelium, immune cells) are available; however, their significance and relation to clinical outcomes is not well described. CONCLUSIONS Porcine ILP provides a reproducible model to study early IRI events. As all models, it has its limitations. A standardization of the setup would allow comparison of data and progress in the field.
Collapse
|
|
37
|
Schlegel A, Dutkowski P. Impact of Machine Perfusion on Biliary Complications after Liver Transplantation. Int J Mol Sci 2018; 19:3567. [PMID: 30424553 PMCID: PMC6274934 DOI: 10.3390/ijms19113567] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 11/01/2018] [Accepted: 11/05/2018] [Indexed: 12/13/2022] Open
Abstract
We describe in this review the different types of injuries caused to the biliary tree after liver transplantation. Furthermore, we explain underlying mechanisms and why oxygenated perfusion concepts could not only protect livers, but also repair high-risk grafts to prevent severe biliary complications and graft loss. Accordingly, we summarize experimental studies and clinical applications of machine liver perfusion with a focus on biliary complications after liver transplantation. Key points: (1) Acute inflammation with subsequent chronic ongoing liver inflammation and injury are the main triggers for cholangiocyte injury and biliary tree transformation, including non-anastomotic strictures; (2) Hypothermic oxygenated perfusion (HOPE) protects livers from initial oxidative injury at normothermic reperfusion after liver transplantation. This is a unique feature of a cold oxygenation approach, which is effective also end-ischemically, e.g., after cold storage, due to mitochondrial repair mechanisms. In contrast, normothermic oxygenated perfusion concepts protect by reducing cold ischemia, and are therefore most beneficial when applied instead of cold storage; (3) Due to less downstream activation of cholangiocytes, hypothermic oxygenated perfusion also significantly reduces the development of biliary strictures after liver transplantation.
Collapse
Affiliation(s)
- Andrea Schlegel
- Department of Surgery & Transplantation, University Hospital Zurich, 8091 Zurich, Switzerland.
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham B15 2TH, UK.
- NIHR Liver Biomedical Research Unit, University Hospitals Birmingham, Birmingham B15 2TH, UK.
| | - Philipp Dutkowski
- Department of Surgery & Transplantation, University Hospital Zurich, 8091 Zurich, Switzerland.
| |
Collapse
|
|
38
|
Ciria R, Navarro E, Sánchez-Frías M, Gallardo AB, Medina J, Ayllón MD, Gomez-Luque I, Ruiz-Rabelo J, Luque A, de la Mata M, Rufián S, López-Cillero P, Briceño J. Preliminary results from the use of intraoperative real-time biliary oxygen monitoring in liver transplantation. Clin Transplant 2018; 32:e13433. [PMID: 30365182 DOI: 10.1111/ctr.13433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 10/16/2018] [Accepted: 10/19/2018] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND AIMS Biliary anastomosis is a frequent area of complications after liver transplantation (LT) and a potential area of "microangiopathy". The concept of a "marginal bile duct" is unexplored. The main aim was to make a preliminary evaluation of the utility of an innovative real-time oxygen microtension (pO2mt) testing device for the assessment of bile duct viability during LT and to correlate these pO2mt values with microvascular tissue quality by histopathology and outcomes. PATIENTS AND METHODS Observational prospective cohort study with 23 patients. Oxygen microtension measurements were made placing a micropO2 probe in different areas of recipient and donor's bile duct intraoperative. RESULTS Mean pO2mt in the graft bile duct at the level of the anastomosis 103.82 (31-157) mm Hg, being 121.52 (55-174) mm Hg 1.5 cm proximal to the hilar plate (P < 0.001). Mean pO2mt in the recipient's bile duct was 117.87 (62-185) mm Hg, while a value of 137.30 (81-198) mm Hg was observed 1.5 cm distal to the anastomosis (P < 0.001). Cystic duct resection (12 cases) was also related with higher pO2mt values at anastomosis [117.8 (93-157) vs 88.54 (31-124) mm Hg] and distal to anastomosis [135.6 (111-174) vs 106.2 (55-133) mm Hg; P < 0.001]. Patients with 1-, 3-, and 12-month biliary complications had significantly lower pO2mt in the intraoperative measurements. CONCLUSION Our preliminary results show that distal borders of donor and recipient bile ducts may be low-vascularized areas. Tissue pO2mt is significantly higher in areas close to the hilar plate and to the duodenum in donor and recipient's sides, respectively. Bile duct injury and biliary complications are associated with worse tissue pO2mt.
Collapse
Affiliation(s)
- Ruben Ciria
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Elena Navarro
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | | | - Ana-Belen Gallardo
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Javier Medina
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - María-Dolores Ayllón
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Irene Gomez-Luque
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Juan Ruiz-Rabelo
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Antonio Luque
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Manuel de la Mata
- Liver Research Unit, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, Cordoba, Spain
| | - Sebastián Rufián
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Pedro López-Cillero
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| | - Javier Briceño
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofía, IMIBIC, Ciber-EHD, University of Cordoba, Cordoba, Spain
| |
Collapse
|
|
39
|
A Comparative Study of Single and Dual Perfusion During End-ischemic Subnormothermic Liver Machine Preservation. Transplant Direct 2018; 4:e400. [PMID: 30534591 PMCID: PMC6233661 DOI: 10.1097/txd.0000000000000840] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 09/11/2018] [Indexed: 12/19/2022] Open
Abstract
Background It remains controversial if arterial perfusion in addition to portal vein perfusion during machine preservation improves liver graft quality. Comparative studies using both techniques are lacking. We studied the impact of using single or dual machine perfusion of donation after circulatory death rat livers. In addition, we analyzed the effect of pulsatile versus continuous arterial flow. Methods Donation after circulatory death rat livers (n = 18) were preserved by 6 hours cold storage, followed by 1 hour subnormothermic machine perfusion (20°C, pressure of 40/5 mm Hg) and 2 hours ex vivo warm reperfusion (37°C, pressure of 80/11 mm Hg, 9% whole blood). Machine preservation was either through single portal vein perfusion (SP), dual pulsatile (DPP), or dual continuous perfusion (DCP) of the portal vein and hepatic artery. Hydrodynamics, liver function tests, histopathology, and expression of endothelial specific genes were assessed during 2 hours warm reperfusion. Results At the end of reperfusion, arterial flow in DPP livers tended to be higher compared to DCP and SP grafts. However, this difference was not significant nor was better flow associated with better outcome. No differences in bile production or alanine aminotransferase levels were observed. SP livers had significantly lower lactate compared to DCP, but not DPP livers. Levels of Caspase-3 and tumor necrosis factor-α were similar between the groups. Expression of endothelial genes Krüppel-like-factor 2 and endothelial nitric oxide synthase tended to be higher in dual perfused livers, but no histological evidence of better preservation of the biliary endothelium or vasculature of the hepatic artery was observed. Conclusions This study shows comparable outcomes after using a dual or single perfusion approach during end-ischemic subnormothermic liver machine preservation.
Collapse
|
|
40
|
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.
Collapse
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
| |
Collapse
|
|
41
|
Watson CJE, Kosmoliaptsis V, Pley C, Randle L, Fear C, Crick K, Gimson AE, Allison M, Upponi S, Brais R, Jochmans I, Butler AJ. Observations on the ex situ perfusion of livers for transplantation. Am J Transplant 2018; 18:2005-2020. [PMID: 29419931 PMCID: PMC6099221 DOI: 10.1111/ajt.14687] [Citation(s) in RCA: 269] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 01/26/2018] [Accepted: 01/31/2018] [Indexed: 01/25/2023]
Abstract
Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH < 7.4) from those that did not (pH > 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25-50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid-base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.
Collapse
Affiliation(s)
- Christopher J. E. Watson
- Department of SurgeryUniversity of CambridgeAddenbrooke's HospitalCambridgeUK,NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of CambridgeCambridgeUK,NIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Vasilis Kosmoliaptsis
- Department of SurgeryUniversity of CambridgeAddenbrooke's HospitalCambridgeUK,NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of CambridgeCambridgeUK,NIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Caitlin Pley
- Department of SurgeryUniversity of CambridgeAddenbrooke's HospitalCambridgeUK,NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of CambridgeCambridgeUK,NIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Lucy Randle
- Department of SurgeryUniversity of CambridgeAddenbrooke's HospitalCambridgeUK,NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of CambridgeCambridgeUK,NIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Corinna Fear
- Department of SurgeryUniversity of CambridgeAddenbrooke's HospitalCambridgeUK,NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of CambridgeCambridgeUK,NIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Keziah Crick
- Department of SurgeryUniversity of CambridgeAddenbrooke's HospitalCambridgeUK,NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of CambridgeCambridgeUK,NIHR Cambridge Biomedical Research CentreCambridgeUK
| | - Alexander E. Gimson
- NIHR Cambridge Biomedical Research CentreCambridgeUK,Department of MedicineCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Michael Allison
- NIHR Cambridge Biomedical Research CentreCambridgeUK,Department of MedicineCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Sara Upponi
- NIHR Cambridge Biomedical Research CentreCambridgeUK,Department of RadiologyCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Rebecca Brais
- NIHR Cambridge Biomedical Research CentreCambridgeUK,Department of PathologyCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Ina Jochmans
- Department of Microbiology and ImmunologyLaboratory of Abdominal TransplantationKatholieke Universiteit LeuvenLeuvenBelgium,Department of Abdominal Transplant SurgeryUniversity Hospitals LeuvenLeuvenBelgium
| | - Andrew J. Butler
- Department of SurgeryUniversity of CambridgeAddenbrooke's HospitalCambridgeUK,NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of CambridgeCambridgeUK,NIHR Cambridge Biomedical Research CentreCambridgeUK
| |
Collapse
|
|
42
|
van Rijn R, van Leeuwen OB, Matton APM, Burlage LC, Wiersema‐Buist J, van den Heuvel MC, de Kleine RHJ, de Boer MT, Gouw ASH, Porte RJ. Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers. Liver Transpl 2018; 24:655-664. [PMID: 29369470 PMCID: PMC5947530 DOI: 10.1002/lt.25023] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/18/2017] [Accepted: 01/07/2018] [Indexed: 12/27/2022]
Abstract
Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE-preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655-664 2018 AASLD.
Collapse
Affiliation(s)
- Rianne van Rijn
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Otto B. van Leeuwen
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Alix P. M. Matton
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Laura C. Burlage
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Janneke Wiersema‐Buist
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of Groningenthe Netherlands
| | - Marius C. van den Heuvel
- Department of Pathology, University Medical Center GroningenUniversity of Groningenthe Netherlands
| | - Ruben H. J. de Kleine
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
| | - Marieke T. de Boer
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
| | - Annette S. H. Gouw
- Department of Pathology, University Medical Center GroningenUniversity of Groningenthe Netherlands
| | - Robert J. Porte
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, University Medical Center Groningen, University of Groningenthe Netherlands
| |
Collapse
|
|
43
|
Hessheimer AJ, Vendrell M, Muñoz J, Ruíz Á, Díaz A, Sigüenza LF, Lanzilotta JR, Delgado Oliver E, Fuster J, Navasa M, García-Valdecasas JC, Taurá P, Fondevila C. Heparin but not tissue plasminogen activator improves outcomes in donation after circulatory death liver transplantation in a porcine model. Liver Transpl 2018; 24:665-676. [PMID: 29351369 DOI: 10.1002/lt.25013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 12/07/2017] [Accepted: 01/06/2018] [Indexed: 02/07/2023]
Abstract
Ischemic-type biliary lesions (ITBLs) arise most frequently after donation after circulatory death (DCD) liver transplantation and result in high morbidity and graft loss. Many DCD grafts are discarded out of fear for this complication. In theory, microvascular thrombi deposited during donor warm ischemia might be implicated in ITBL pathogenesis. Herein, we aim to evaluate the effects of the administration of either heparin or the fibrinolytic drug tissue plasminogen activator (TPA) as means to improve DCD liver graft quality and potentially avoid ITBL. Donor pigs were subjected to 1 hour of cardiac arrest (CA) and divided among 3 groups: no pre-arrest heparinization nor TPA during postmortem regional perfusion; no pre-arrest heparinization but TPA given during regional perfusion; and pre-arrest heparinization but no TPA during regional perfusion. In liver tissue sampled 1 hour after CA, fibrin deposition was not detected, even when heparin was not given prior to arrest. Although it was not useful to prevent microvascular clot formation, pre-arrest heparin did offer cytoprotective effects during CA and beyond, reflected in improved flows during regional perfusion and better biochemical, functional, and histological parameters during posttransplantation follow-up. In conclusion, this study demonstrates the lack of impact of TPA use in porcine DCD liver transplantation and adds to the controversy over whether the use of TPA in human DCD liver transplantation really offers any protective effect. On the other hand, when it is administered prior to CA, heparin does offer anti-inflammatory and other cytoprotective effects that help improve DCD liver graft quality. Liver Transplantation 24 665-676 2018 AASLD.
Collapse
Affiliation(s)
- Amelia J Hessheimer
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Marina Vendrell
- Departments of Anesthesia, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Javier Muñoz
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Ángel Ruíz
- Department of Hepatobiliary and Liver Transplant Surgery, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Alba Díaz
- Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Luís Flores Sigüenza
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Jorge Rodríguez Lanzilotta
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Eduardo Delgado Oliver
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Jose Fuster
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Miquel Navasa
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Juan Carlos García-Valdecasas
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Pilar Taurá
- Departments of Anesthesia, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Constantino Fondevila
- Department of Surgery, Institut de Malalties Digestives I Metabòliques, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain.,Department of Hepatobiliary and Liver Transplant Surgery, Hospital Clínic, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
44
|
Shi R, Liu T, Liu Z, Zhang Y, Shen Z. Clinical Analysis of Classification and Prognosis of Ischemia-Type Biliary Lesions After Liver Transplantation. Ann Transplant 2018. [PMID: 29555897 PMCID: PMC6248068 DOI: 10.12659/aot.907240] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The aim of this study was to classify ischemia-type biliary lesions after liver transplantation according to their imaging findings and severity of clinical manifestations and to analyze the relationship between such classification and prognosis. MATERIAL AND METHODS We collected clinical data of patients with ischemia-type biliary lesions (ITBL) after liver transplantation in the Organ Transplantation Center, the First Central Hospital of Tianjin, from August 2012 to July 2013; all patients were classified according to their imaging findings and relevant clinical data to analyze the relationship between their classification and prognosis. RESULTS The mean postoperative survival time, as well as the 1-, 3-, and 5-year survival rate, in Group ITBL showed statistical significance when compared with those in Group NITBL (log rank=12.13, P<0.001), but the mean postoperative survival times among the mild, moderate, and severe ITBL cases showed no statistical significance. The incidence rates of 1-, 3-, and 5-year adverse prognosis in Group ITBL showed statistical significance when compared with Group NITBL with <2% patients who had anastomotic biliary obstruction (log rank=277.06, P<0.001), among which the difference in the incidence rate of adverse prognosis between severe and moderate ITBL cases showed no statistical significance. The difference in the incidence rate of adverse prognosis between mild and moderate ITBL cases showed statistical significance (log rank=6.01, P=0.014), and the difference in the incidence rate of adverse prognosis between mild and severe ITBL cases showed statistical significance (log rank=10.98, P=0.001). CONCLUSIONS ITBL classification based on the severity of biliary imaging and bilirubin level can predict the prognosis of ITBL.
Collapse
Affiliation(s)
- Rui Shi
- Organ Transplantation Center, The First Central Hospital of Tianjin, Tianjin, China (mainland)
| | - Tong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China (mainland)
| | - Zirong Liu
- Organ Transplantation Center, The First Central Hospital of Tianjin, Tianjin, China (mainland)
| | - Yamin Zhang
- Organ Transplantation Center, The First Central Hospital of Tianjin, Tianjin, China (mainland)
| | - Zhongyang Shen
- Organ Transplantation Center, The First Central Hospital of Tianjin, Tianjin, China (mainland)
| |
Collapse
|
|
45
|
He X, Ji F, Zhang Z, Tang Y, Yang L, Huang S, Li W, Su Q, Xiong W, Zhu Z, Wang L, Lv L, Yao J, Zhang L, Zhang L, Guo Z. Combined liver-kidney perfusion enhances protective effects of normothermic perfusion on liver grafts from donation after cardiac death. Liver Transpl 2018; 24:67-79. [PMID: 29024427 DOI: 10.1002/lt.24954] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 09/18/2017] [Accepted: 09/26/2017] [Indexed: 12/31/2022]
Abstract
It has been shown that combined liver-kidney normothermic machine perfusion (NMP) is able to better maintain the circuit's biochemical milieu. Nevertheless, whether the combined perfusion is superior to liver perfusion alone in protecting livers from donation after circulatory death (DCD) is unclear. We aimed to test the hypothesis and explored the mechanisms. Livers from 15 DCD pig donors were subjected to either static cold storage (group A), liver-alone NMP (group B), or combined liver-kidney NMP (group C). Livers were preserved for 6 hours and reperfused ex vivo for 2 hours to simulate transplantation or were transplanted in situ. During perfusion, group C showed an improved acid-base and biochemical environment in the circuit over group B. After reperfusion, the architecture of the liver grafts was best preserved in group C, followed by group B, then group A, as shown by the histology and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining of both hepatocytes and biliary epithelium. Ki-67 staining showed substantial hepatocyte proliferation and biliary epithelial regeneration after perfusion in group B and group C. Group C produced more bile in the reperfusion phase than those in group A and group B, with more physiological bile composition and less severe biliary epithelium injury. Von Willebrand factor-positive endothelial cells and E-selectin expression decreased in both group B and group C. Combined liver-kidney NMP not only produced more adenosine triphosphate, protected the nitric oxide signaling pathway, but also diminished oxidative stress (high mobility group box-1 protein and 8-hydroxy-2-deoxy guanosine levels) and inflammatory cytokine (IL6 and IL8) release when compared with liver-alone NMP and CS. In addition, the 7-day survival rate of liver transplant recipients was higher in group C than that in groups A and B. In conclusion, combined liver-kidney NMP can better protect DCD livers from warm ischemia and reperfusion injury probably by maintaining the stability of the internal environment and by abolishing oxidative stress injury. Liver Transplantation 24 67-79 2018 AASLD.
Collapse
Affiliation(s)
- Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Fei Ji
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiheng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Lu Yang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shanzhou Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Wenwen Li
- Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiao Su
- Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Xiong
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zebin Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Linhe Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Lei Lv
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jiyou Yao
- Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Linan Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Longjuan Zhang
- Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| |
Collapse
|
|
46
|
Reducing Non-Anastomotic Biliary Strictures in Donation After Circulatory Death Liver Transplantation. Ann Surg 2017; 266:e118-e119. [DOI: 10.1097/sla.0000000000001949] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|
|
47
|
Ghinolfi D, Rreka E, Pezzati D, Filipponi F, De Simone P. Perfusion machines and hepatocellular carcinoma: a good match between a marginal organ and an advanced disease? Transl Gastroenterol Hepatol 2017; 2:87. [PMID: 29264425 DOI: 10.21037/tgh.2017.10.01] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 09/27/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers, is the second leading cause of cancer-related deaths and the leading cause of death in patients with cirrhosis. Liver transplantation (LT) represents the ideal treatment for selected patients as it removes both the tumor and the underlying cirrhotic liver with 5-year survival rates higher than 70%. Unfortunately, due to tumor characteristics, patient co-morbidities or shortage of organs available for transplant, only 20% of patients can undergo curative treatment. Ex situ machine perfusion (MP) is a technology recently introduced that might potentially improve organ preservation, allow graft assessment and increase the pool of available organs. The purpose of this review is to provide an update on the current role of ex situ liver MP in liver transplantation for HCC patients.
Collapse
Affiliation(s)
- Davide Ghinolfi
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Erion Rreka
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Daniele Pezzati
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Franco Filipponi
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| | - Paolo De Simone
- Division of Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Tuscany, Italy
| |
Collapse
|
|
48
|
Junger HH, Schlitt HJ, Geissler EK, Fichtner-Feigl S, Brunner SM. Bile duct regeneration and immune response by passenger lymphocytes signals biliary recovery versus complications after liver transplantation. Liver Transpl 2017; 23:1422-1432. [PMID: 28779549 DOI: 10.1002/lt.24836] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/30/2017] [Accepted: 07/24/2017] [Indexed: 01/05/2023]
Abstract
This study aimed to elucidate the impact of epithelial regenerative responses and immune cell infiltration on biliary complications after liver transplantation. Bile duct (BD) damage after cold storage was quantified by a BD damage score and correlated with patient outcome in 41 patients. Bacterial infiltration was determined by fluorescence in situ hybridization (FISH). BD samples were analyzed by immunohistochemistry for E-cadherin, cytokeratin, CD56, CD14, CD4, CD8, and double-immunofluorescence for cytokine production and by messenger RNA (mRNA) microarray. Increased mRNA levels of adherens junctions (P < 0.01) were detected in damaged BDs from patients without complications compared with damaged BDs from patients with biliary complications. Immunohistochemistry showed increased expression of E-cadherin and cytokeratin in BDs without biliary complications (P = 0.03; P = 0.047). FISH analysis demonstrated translocation of bacteria in BDs. However, mRNA analysis suggested an enhanced immune response in BDs without biliary complications (P < 0.01). Regarding immune cell infiltration, CD4+ and CD8+ cells were significantly increased in patients without complications compared with those with complications (P = 0.02; P = 0.01). In conclusion, following BD damage during cold storage, we hypothesize that the functional regenerative capacity of biliary epithelium and enhanced local adaptive immune cell infiltration are crucial for BD recovery. Such molecular immunological BD analyses therefore could help to predict biliary complications in cases of "major" epithelial damage after cold storage.Liver Transplantation 23 1422-1432 2017 AASLD.
Collapse
Affiliation(s)
- Henrik H Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Hans J Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Edward K Geissler
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Stefan Fichtner-Feigl
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany.,Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany
| | - Stefan M Brunner
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| |
Collapse
|
|
49
|
Trivedi PJ, Scalera I, Slaney E, Laing RW, Gunson B, Hirschfield GM, Schlegel A, Ferguson J, Muiesan P. Clinical outcomes of donation after circulatory death liver transplantation in primary sclerosing cholangitis. J Hepatol 2017; 67:957-965. [PMID: 28690174 DOI: 10.1016/j.jhep.2017.06.027] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 06/23/2017] [Accepted: 06/27/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIM Primary sclerosing cholangitis (PSC) is a progressive fibro-inflammatory cholangiopathy for which liver transplantation is the only life-extending intervention. These patients may benefit from accepting liver donation after circulatory death (DCD), however their subsequent outcome is unknown. The aim of this study was to determine the clinical impact of using DCD liver grafts in patients specifically undergoing transplantation for PSC. METHODS Clinical outcomes were prospectively evaluated in PSC patients undergoing transplantation from 2006 to 2016 stratified by donor type (DCD, n=35 vs. donation after brainstem death [DBD], n=108). RESULTS In liver transplantation for PSC; operating time, days requiring critical care support, total ventilator days, incidence of acute kidney injury, need for renal replacement therapy (RRT) or total days requiring RRT were not significantly different between DCD vs. DBD recipients. Although the incidence of ischaemic-type biliary lesions was greater in the DCD group (incidence rate [IR]: 4.4 vs. 0 cases/100-patient-years; p<0.001) there was no increased risk of post-transplant biliary strictures overall (hazard ratio [HR]: 1.20, 0.58-2.46; p=0.624), or in sub-analysis specific to anastomotic strictures or recurrent PSC, between donor types. Graft loss and mortality rates were not significantly different following transplantation with DCD vs. DBD livers (IR: 3.6 vs. 3.1 cases/100-patient-years, p=0.34; and 3.9 vs. 4.7, p=0.6; respectively). DCD liver transplantation in PSC did not impart a heightened risk of graft loss (HR: 1.69, 0.58-4.95, p=0.341) or patient mortality (0.75, 0.25-2.21, p=0.598). CONCLUSION Transplantation with DCD (vs. DBD) livers in PSC patients does not impact graft loss or patient survival. In an era of organ shortage, DCD grafts represent a viable therapeutic option for liver transplantation in PSC patients. Lay summary: This study examines the impact of liver transplantation in primary sclerosing cholangitis (PSC) with organs donated after circulatory death (DCD), compared to donation after brainstem death (DBD). We show that in appropriately selected patients, the outcomes for DCD transplantation mirror those using DBD livers, with no significant differences in complication rate, patient survival or transplanted liver survival. In an era of organ shortage and increasing wait-list times, DCD livers represent a potential treatment option for transplantation in PSC.
Collapse
Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK
| | - Irene Scalera
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK
| | - Emma Slaney
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK
| | - Richard W Laing
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK
| | - Bridget Gunson
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK
| | - Gideon M Hirschfield
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK
| | - Andrea Schlegel
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK; Department of Surgery and Transplantation, University Hospital Zürich, Zürich, Switzerland
| | - James Ferguson
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK.
| | - Paolo Muiesan
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, UK; Department of Liver Surgery, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
| |
Collapse
|
|
50
|
Bohorquez H, Seal JB, Cohen AJ, Kressel A, Bugeaud E, Bruce DS, Carmody IC, Reichman TW, Battula N, Alsaggaf M, Therapondos G, Bzowej N, Tyson G, Joshi S, Nicolau-Raducu R, Girgrah N, Loss GE. Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy. Am J Transplant 2017; 17:2155-2164. [PMID: 28276658 DOI: 10.1111/ajt.14261] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 02/14/2017] [Accepted: 02/22/2017] [Indexed: 02/06/2023]
Abstract
Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.
Collapse
Affiliation(s)
- H Bohorquez
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - J B Seal
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - A J Cohen
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - A Kressel
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
| | - E Bugeaud
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
| | - D S Bruce
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
| | - I C Carmody
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - T W Reichman
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
| | - N Battula
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
| | - M Alsaggaf
- School of Medicine, University of Queensland, New Orleans, LA
| | - G Therapondos
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - N Bzowej
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - G Tyson
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - S Joshi
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - R Nicolau-Raducu
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
| | - N Girgrah
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| | - G E Loss
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA.,School of Medicine, University of Queensland, New Orleans, LA
| |
Collapse
|