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Caballero-Marcos A, Rodríguez-Bachiller L, Baroja-Mazo A, Morales Á, Fernández-Cáceres P, Fernández-Martínez M, DíazFontenla F, Velasco E, Fernández-Yunquera A, Díaz-Zorita B, Cortese S, Pérez-Peña JM, Colón-Rodríguez A, Romero-Cristóbal M, Asencio JM, Bañares R, López-Baena JÁ, Salcedo-Plaza M. Dynamics of Ischemia/Reperfusion Injury Markers During Normothermic Liver Machine Perfusion. Transplant Direct 2024; 10:e1728. [PMID: 39553741 PMCID: PMC11567704 DOI: 10.1097/txd.0000000000001728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 09/12/2024] [Indexed: 11/19/2024] Open
Abstract
Background A comprehensive mechanistic assessment of normothermic machine perfusion (NMP) is an essential step toward identifying biomarkers to assess liver viability. Although some studies have evaluated the effect of NMP on inflammation markers, there are other key pathological mechanisms involved in ischemia/reperfusion injury (IRI) that have not yet been evaluated. Methods Eight human donor livers preserved by NMP were included to analyze IRI during preservation. Concentrations of several biomarkers involved in different biological processes of IRI were measured in the perfusate. Results Perfusate levels of intercellular adhesion molecule 1, P-selectin, vascular cell adhesion molecule 1, metalloproteinase with thrombospondin motif type 1, member 13, phospholipase A2 group VII, and syndecan-1 progressively increased during NMP. Noteworthy, perfusate lactate levels showed a strong correlation with C-X-C motif chemokine ligand 10 (P = 0.001), intercellular adhesion molecule 1 (P = 0.01), and urokinase plasminogen activator (P = 0.001). Conclusions Perfusate lactate correlates with the main underlying biological mechanisms occurring in the NMP environment. Moreover, several IRI biomarkers accumulate during NMP, which may limit the extent of the benefits of this technology.
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Affiliation(s)
- Aránzazu Caballero-Marcos
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Luis Rodríguez-Bachiller
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | - Álvaro Morales
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Paloma Fernández-Cáceres
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
| | - María Fernández-Martínez
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Fernando DíazFontenla
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Enrique Velasco
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Ainhoa Fernández-Yunquera
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Benjamin Díaz-Zorita
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Sergio Cortese
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - José María Pérez-Peña
- Department of Anesthesiology, Reanimation and Intensive Care, Hospital General Universitario Gregorio Marañon, Madrid, Spain
| | - Arturo Colón-Rodríguez
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Mario Romero-Cristóbal
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - José Manuel Asencio
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Rafael Bañares
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - José Ángel López-Baena
- Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Magdalena Salcedo-Plaza
- Hepatology and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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Felli E, Felli E, Muttillo EM, Urade T, Laracca GG, Giannelli V, Famularo S, Geny B, Ettorre GM, Rombouts K, Pinzani M, Diana M, Gracia-Sancho J. Liver ischemia-reperfusion injury: From trigger loading to shot firing. Liver Transpl 2023; 29:1226-1233. [PMID: 37728488 DOI: 10.1097/lvt.0000000000000252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 08/15/2023] [Indexed: 09/21/2023]
Abstract
An ischemia-reperfusion injury (IRI) results from a prolonged ischemic insult followed by the restoration of blood perfusion, being a common cause of morbidity and mortality, especially in liver transplantation. At the maximum of the potential damage, IRI is characterized by 2 main phases. The first is the ischemic phase, where the hypoxia and vascular stasis induces cell damage and the accumulation of damage-associated molecular patterns and cytokines. The second is the reperfusion phase, where the local sterile inflammatory response driven by innate immunity leads to a massive cell death and impaired liver functionality. The ischemic time becomes crucial in patients with underlying pathophysiological conditions. It is possible to compare this process to a shooting gun, where the loading trigger is the ischemia period and the firing shot is the reperfusion phase. In this optic, this article aims at reviewing the main ischemic events following the phases of the surgical timeline, considering the consequent reperfusion damage.
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Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Emanuele Felli
- Department of Digestive Surgery and Liver Transplantation, University Hospital of Tours, France
| | - Edoardo M Muttillo
- Department of Medical Surgical Science and Translational Medicine, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Takeshi Urade
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Giovanni G Laracca
- Department of Medical Surgical Science and Translational Medicine, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Valerio Giannelli
- Department of Transplantation and General Surgery, San Camillo Hospital, Italy
| | - Simone Famularo
- Department of Biomedical Science, Humanitas University Pieve Emanuele, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Research Institute Against Cancer of the Digestive System (IRCAD), France
| | - Bernard Geny
- Institute of Physiology, EA3072 Mitochondria Respiration and Oxidative Stress, University of Strasbourg, France
| | - Giuseppe M Ettorre
- Department of Transplantation and General Surgery, San Camillo Hospital, Italy
| | - Krista Rombouts
- University College London - Institute for Liver and Digestive Health, Royal Free Hospital, NW3 2PF London, United Kingdom
| | - Massimo Pinzani
- University College London - Institute for Liver and Digestive Health, Royal Free Hospital, NW3 2PF London, United Kingdom
| | - Michele Diana
- Research Institute Against Cancer of the Digestive System (IRCAD), France
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, Hospital Clínic Barcelona, CIBEREHD, Barcelona, Spain
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Kiouptsi K, Casari M, Mandel J, Gao Z, Deppermann C. Intravital Imaging of Thrombosis Models in Mice. Hamostaseologie 2023; 43:348-359. [PMID: 37857297 DOI: 10.1055/a-2118-2932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2023] Open
Abstract
Intravital microscopy is a powerful tool to study thrombosis in real time. The kinetics of thrombus formation and progression in vivo is studied after inflicting damage to the endothelium through mechanical, chemical, or laser injury. Mouse models of atherosclerosis are also used to induce thrombus formation. Vessels of different sizes and from different vascular beds such as carotid artery or vena cava, mesenteric or cremaster arterioles, can be targeted. Using fluorescent dyes, antibodies, or reporter mouse strains allows to visualize key cells and factors mediating the thrombotic processes. Here, we review the latest literature on using intravital microscopy to study thrombosis as well as thromboinflammation following transient middle cerebral artery occlusion, infection-induced immunothrombosis, and liver ischemia reperfusion.
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Affiliation(s)
- Klytaimnistra Kiouptsi
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Martina Casari
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Jonathan Mandel
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Zhenling Gao
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Carsten Deppermann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
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Akbulut S, Yagin FH, Sahin TT, Garzali IU, Tuncer A, Akyuz M, Bagci N, Barut B, Unsal S, Sarici KB, Saritas S, Ozer A, Bentli R, Colak C, Bayindir Y, Yilmaz S. Effect of COVID-19 Pandemic on Patients Who Have Undergone Liver Transplantation: Retrospective Cohort Study. J Clin Med 2023; 12:4466. [PMID: 37445501 PMCID: PMC10342746 DOI: 10.3390/jcm12134466] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/28/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND In liver transplant (LT) recipients, immunosuppressive therapy may potentially increase the risk of severe COVID-19 and may increase the mortality in patients. However, studies have shown conflicting results, with various studies reporting poor outcomes while the others show no difference between the LT recipients and healthy population. The aim of this study is to determine the impact of the COVID-19 pandemic on survival of LT recipients. METHODS This is a retrospective cohort study analyzing the data from 387 LT recipients diagnosed with COVID-19. LT recipients were divided into two groups: survival (n = 359) and non-survival (n = 28) groups. A logistic regression model was used to determine the independent risk factors for mortality. Machine learning models were used to analyze the contribution of independent variables to the mortality in LT recipients. RESULTS The COVID-19-related mortality rate in LT recipients was 7.2%. Multivariate analysis showed that everolimus use (p = 0.012; OR = 6.2), need for intubation (p = 0.001; OR = 38.4) and discontinuation of immunosuppressive therapy (p = 0.047; OR = 7.3) were independent risk factors for mortality. Furthermore, COVID-19 vaccination reduced the risk of mortality by 100 fold and was the single independent factor determining the survival of the LT recipients. CONCLUSION The effect of COVID-19 infection on LT recipients is slightly different from the effect of the disease on the general population. The COVID-19-related mortality is lower than the general population and vaccination for COVID-19 significantly reduces the risk of mortality.
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Affiliation(s)
- Sami Akbulut
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
- Department of Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
- Department of Public Health, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Fatma Hilal Yagin
- Department of Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Tevfik Tolga Sahin
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Ibrahim Umar Garzali
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
- Department of Surgery, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
| | - Adem Tuncer
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Musap Akyuz
- Department of Surgical Nursing, Inonu University Faculty of Nursing, Malatya 44280, Turkey
| | - Nazlican Bagci
- Department of Surgical Nursing, Inonu University Faculty of Nursing, Malatya 44280, Turkey
| | - Bora Barut
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Selver Unsal
- Department of Nursing Service, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Kemal Baris Sarici
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Serdar Saritas
- Department of Surgical Nursing, Inonu University Faculty of Nursing, Malatya 44280, Turkey
| | - Ali Ozer
- Department of Public Health, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Recep Bentli
- Department of Internal Medicine, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Cemil Colak
- Department of Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Yasar Bayindir
- Department of Infectious Diseases and Clinical Microbiology, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Sezai Yilmaz
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
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Rao JS, Ivkov R, Sharma A. Nanoparticle-Based Interventions for Liver Transplantation. Int J Mol Sci 2023; 24:7496. [PMID: 37108659 PMCID: PMC10144867 DOI: 10.3390/ijms24087496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/29/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Liver transplantation is the only treatment for hepatic insufficiency as a result of acute and chronic liver injuries/pathologies that fail to recover. Unfortunately, there remains an enormous and growing gap between organ supply and demand. Although recipients on the liver transplantation waitlist have significantly higher mortality, livers are often not allocated because they are (i) classified as extended criteria or marginal livers and (ii) subjected to longer cold preservation time (>6 h) with a direct correlation of poor outcomes with longer cold ischemia. Downregulating the recipient's innate immune response to successfully tolerate a graft having longer cold ischemia times or ischemia-reperfusion injury through induction of immune tolerance in the graft and the host would significantly improve organ utilization and post-transplant outcomes. Broadly, technologies proposed for development aim to extend the life of the transplanted liver through post-transplant or recipient conditioning. In this review, we focus on the potential benefits of nanotechnology to provide unique pre-transplant grafting and recipient conditioning of extended criteria donor livers using immune tolerance induction and hyperthermic pre-conditioning.
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Affiliation(s)
- Joseph Sushil Rao
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Robert Ivkov
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Department of Oncology, Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Mechanical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Anirudh Sharma
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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Amygdalos I, Czigany Z, Bednarsch J, Boecker J, Santana DAM, Meister FA, von der Massen J, Liu WJ, Strnad P, Neumann UP, Lurje G. Low Postoperative Platelet Counts Are Associated with Major Morbidity and Inferior Survival in Adult Recipients of Orthotopic Liver Transplantation. J Gastrointest Surg 2020; 24:1996-2007. [PMID: 31388889 DOI: 10.1007/s11605-019-04337-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/19/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Platelets (PLT) play an essential functional role in cellular injury and liver regeneration following partial hepatectomy and orthotopic liver transplantation (OLT). Here, we investigated the association of postoperative PLT counts with short- and long-term outcomes in adult OLT recipients. METHODS Three hundred consecutive patients from our prospective OLT database were analyzed retrospectively (May 2010-November 2017). Ninety-day post-OLT complications were graded using the Clavien-Dindo (CD) classification and quantified by the comprehensive complication index (CCI). To determine the prognostic accuracy of PLT counts, the area under the receiver operating characteristic curve (AUROC) was calculated for major complications (CD ≥ 3b). Parametric and non-parametric tests were applied for subgroup analyses. Uni- and multivariable logistic regression analyses were performed to identify risk factors for major complications. Graft and patient survival were analyzed using the Kaplan-Meier method as well as uni- and multivariable Cox regression analyses. RESULTS Postoperative day 6 PLT counts < 70 × 109/L (POD6-70) were identified as the best cutoff for predicting major complications (AUROC = 0.7; p < 0.001; Youden index 0.317). The stratification of patients into low- (n = 113) and high-PLT (n = 187) groups highlighted significant differences in major complications (CCI 68 ± 29 vs. 43 ± 28, p < 0.001); length of hospital and intensive care unit (ICU) stay (53 ± 43 vs. 31 ± 25, p < 0.001; 21 ± 29 vs. 7 ± 11, p < 0.001, respectively) and estimated procedural costs. POD6-70 was associated with inferior 5-year graft survival. Multivariable logistic regression analysis identified POD6-70 as an independent predictor of major complications (odds ratio 2.298, confidence intervals 1.179-4.478, p = 0.015). CONCLUSION In OLT patients, a PLT count on POD6 of less than 70 × 109/L bears a prognostic significance warranting further investigations.
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Affiliation(s)
- Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Joerg Boecker
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | | | - Franziska Alexandra Meister
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Jelena von der Massen
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Wen-Jia Liu
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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Czigany Z, Lurje I, Schmelzle M, Schöning W, Öllinger R, Raschzok N, Sauer IM, Tacke F, Strnad P, Trautwein C, Neumann UP, Fronek J, Mehrabi A, Pratschke J, Schlegel A, Lurje G. Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications. J Clin Med 2020; 9:E846. [PMID: 32244972 PMCID: PMC7141496 DOI: 10.3390/jcm9030846] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP-which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion-will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Isabella Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Pavel Strnad
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Christian Trautwein
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Jiri Fronek
- Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic;
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Andrea Schlegel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK;
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
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8
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Coagulation, hemostasis, and transfusion during liver transplantation. Best Pract Res Clin Anaesthesiol 2020; 34:79-87. [DOI: 10.1016/j.bpa.2020.03.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 12/12/2022]
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Czigany Z, Lurje I, Tolba RH, Neumann UP, Tacke F, Lurje G. Machine perfusion for liver transplantation in the era of marginal organs-New kids on the block. Liver Int 2019; 39:228-249. [PMID: 30129192 DOI: 10.1111/liv.13946] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/26/2018] [Accepted: 08/16/2018] [Indexed: 12/12/2022]
Abstract
In the face of a critical organ shortage in the Western world, various strategies are employed to expand the donor pool for orthotopic liver transplantation (OLT). Among them is the transplantation of organs from extended criteria donors, a valuable source of liver allografts, however, characterized by potential risks for post-OLT complications and inferior outcomes. In recent years, machine perfusion (MP) of the explanted donor liver as well as regional perfusion techniques has witnessed significant advancements. Here, we aim to discuss different modes of dynamic organ preservation in OLT. These include hypothermic and normothermic MP, hypothermic oxygenated machine perfusion (HOPE), controlled oxygenated rewarming as well as regional perfusion protocols. Over recent years, multiple feasibility trials have demonstrated the clinical prospects of MP. In the context of OLT using organs from extended criteria donors, MP has numerous advantages compared to conventional cold storage, some of which include the preservation and reconditioning of borderline transplantable organs and the viability assessment of high-risk donor allografts. This review aims to address the topic of liver allograft MP, highlighting particularly the current trends in clinical applications and future perspectives. Furthermore, different approaches of liver storage and reconditioning are reviewed in the context of ongoing research.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Isabella Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Rene H Tolba
- Institute for Laboratory Animal Science, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.,Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Frank Tacke
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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10
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Beltrame P, Rodriguez S, Brandão ABDM. Low platelet count: Predictor of death and graft loss after liver transplantation. World J Hepatol 2019; 11:99-108. [PMID: 30705722 PMCID: PMC6354122 DOI: 10.4254/wjh.v11.i1.99] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/20/2018] [Accepted: 01/01/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The impact of platelets on liver transplantation (LT) is well recognized, but not completely understood. Platelets exert dichotomous effects on the graft and on the patient. On the one hand, they are essential for primary hemostasis and tissue repair and regeneration. On the other hand, they support ischemia/reperfusion injury and inflammatory processes. Recent evidence has shown a new role for platelet count (PC) in predicting outcomes after LT.
AIM To evaluate if low PC is a predictor of short- and long-term outcomes after LT.
METHODS Four hundred and eighty consecutive LT patients were retrospectively assessed. PC from the preoperative to the seventh postoperative day (POD) were considered. C-statistic analysis defined the ideal cutoff point for PC. Cox regression was performed to check whether low PC was a predictor of death, retransplantation or primary changes in graft function within one year after LT.
RESULTS The highest median PC was 86 × 109/L [interquartile range (IQR) = 65–100 × 109/L] on seventh POD, and the lowest was 51 × 109/L (IQR = 38–71 × 109/L) on third POD. The C-statistic defined a PC < 70 × 109/L on fifth POD as the ideal cutoff point for predicting death and retransplantation. In the multivariate analysis, platelets < 70 × 109/L on 5POD was an independent risk factor for death at 12 mo after LT [hazard ratio (HR) = 2.01; 95% confidence interval (CI) 1.06-3.79; P = 0.031]. In the Cox regression, patients with PC < 70 × 109/L on 5POD had worse graft survival rates up to one year after LT (HR = 2.76; 95%CI 1.52-4.99; P = 0.001).
CONCLUSION PC < 70 × 109/L on 5POD is an independent predictor of death in the first year after LT. These results are in agreement with other studies that indicate that low PC after LT is associated with negative outcomes.
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Affiliation(s)
- Pedro Beltrame
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-170, Brazil
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90035-072, Brazil
| | - Santiago Rodriguez
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-170, Brazil
| | - Ajacio Bandeira de Mello Brandão
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-170, Brazil
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90035-072, Brazil
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11
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Gwiasda J, Schrem H, Klempnauer J, Kaltenborn A. Identifying independent risk factors for graft loss after primary liver transplantation. Langenbecks Arch Surg 2017; 402:757-766. [PMID: 28573420 DOI: 10.1007/s00423-017-1594-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Accepted: 05/23/2017] [Indexed: 12/21/2022]
Abstract
PURPOSE The aim of the study is the identification of independent risk factors for re-transplantation after primary liver transplantation beyond the occurrence of hepatic artery thrombosis. METHODS Eight hundred thirty-four adult patients undergoing primary liver transplantation were analyzed. A propensity score was developed using multivariable binary logistic regression with hepatic artery thrombosis as the dependent variable. The logit link function of the propensity score was included into multivariable Cox regression analysis for graft survival to adjust the study population. RESULTS Graft loss was observed in 134 patients (16.1%). Independent significant risk factors for graft loss were recipient platelet count (p = 0.040; HR: 1.002; 95%-CI: 1.000-1.003), preoperative portal vein thrombosis (p = 0.032; HR: 1.797; 95%-CI: 1.054-2.925), donor age (p < 0.001; HR: 1.026; 95%-CI: 1.012-1.040), percentage of macrovesicular steatosis of the graft (p = 0.011; HR: 1.037; 95%-CI: 1.009-1.061), early complications leading to revision surgery (p < 0.001; HR: 2.734; 95%-CI: 1.897-3.956), duration of the transplant procedure (p < 0.001; HR: 1.005; 95%-CI: 1.003-1.007) as well as transplantation of a split liver graft (p = 0.003; HR: 2.637; 95%-CI: 1.420-4.728). The logit of the propensity score did not reach statistical significance in the final multivariable Cox regression model (p = 0.111) indicating good adjustment for the occurrence of hepatic artery thrombosis. CONCLUSION Liver transplant programs might benefit from regular donor organ biopsies to assess the amount of macrovesicular steatosis. An elevated recipient platelet count can promote reperfusion injury leading to graft loss. A liver graft from an elderly donor should not be split or be transplanted in a recipient with detected portal vein thrombosis.
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Affiliation(s)
- Jill Gwiasda
- Core Facility Quality Management and Health Technology Assessment in Transplantation, Integrated Research and Treatment Center-Transplantation (IFB-Tx), Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
| | - Harald Schrem
- Core Facility Quality Management and Health Technology Assessment in Transplantation, Integrated Research and Treatment Center-Transplantation (IFB-Tx), Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.,Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Jürgen Klempnauer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Alexander Kaltenborn
- Core Facility Quality Management and Health Technology Assessment in Transplantation, Integrated Research and Treatment Center-Transplantation (IFB-Tx), Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.,Department of Trauma and Orthopaedic Surgery, Federal Armed Forces Hospital Westerstede, Westerstede, Germany
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12
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Hayashi H, Takamura H, Ohbatake Y, Nakanuma S, Tajima H, Fushida S, Onishi I, Tani T, Shimizu K, Ohta T. Postoperative changes in neutrophil-to-lymphocyte ratio and platelet count: A simple prognostic predictor for adult-to-adult living donor liver transplantation. Asian J Surg 2017; 41:341-348. [PMID: 28365200 DOI: 10.1016/j.asjsur.2017.02.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 02/06/2017] [Accepted: 02/13/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/OBJECTIVE The neutrophil-to-lymphocyte ratio (NLR) is a simple index that represents systemic inflammatory change. The number of platelets is also known to reflect both post-transplant graft regeneration and dysfunction. Thus, we aimed to investigate the usefulness of NLR and platelet number in predicting the clinical course after adult-to-adult living donor liver transplantation (AA-LDLT) in the acute postoperative period in recipients. METHODS Between January 1999 and December 2013, 61 patients underwent their first AA-LDLT at our institute. We retrospectively analyzed their clinical data, including NLR and number of platelets, until postoperative day 14, and evaluated their ability to predict prognosis after AA-LDLT. RESULTS The optimal cutoff values of postoperative maximum NLR and maximum platelets to predict prognosis were 50 and 80 × 103/μL, respectively. The 1- and 5-year survival rates were 87.5% and 79.1% in the normal maximum NLR group, respectively, and 46.2% for both in the high maximum NLR group (p = 0.0033). The 1- and 5-year survival rates, respectively, were 90.9% and 84.1% in the high maximum platelets group and 47.1% and 41.2% in the low maximum platelets group (p < 0.0001). In multivariate analysis, maximum NLR ≥ 50 and maximum platelets < 80 × 103/μL were independently associated with 1-year mortality. CONCLUSION A high NLR and a low platelet count during acute postoperative period might correlate with poor prognosis after AA-LDLT.
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Affiliation(s)
- Hironori Hayashi
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan.
| | - Hiroyuki Takamura
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan
| | - Yoshinao Ohbatake
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan
| | - Shinichi Nakanuma
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan
| | - Hidehiro Tajima
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan
| | - Sachio Fushida
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan
| | - Ichiro Onishi
- Department of Surgery, National Hospital Organization Kanazawa Medical Center, 1-1 Shimoishibiki-machi, Kanazawa, Ishikawa 920-8650, Japan
| | - Takashi Tani
- Department of Surgery, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, Ishikawa 924-0865, Japan
| | - Koichi Shimizu
- Department of Surgery, Toyama Prefectural Central Hospital, 2-2-78 Nishinagae, Toyama, Toyama 930-8550, Japan
| | - Tetsuo Ohta
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan
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13
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Akamatsu N, Sugawara Y, Kanako J, Arita J, Sakamoto Y, Hasegawa K, Kokudo N. Low Platelet Counts and Prolonged Prothrombin Time Early After Operation Predict the 90 Days Morbidity and Mortality in Living-donor Liver Transplantation. Ann Surg 2017; 265:166-172. [PMID: 28009742 DOI: 10.1097/sla.0000000000001634] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The aim of the study was to investigate the association between platelet count/prothrombin time early after transplant and short-term outcomes among living-donor liver transplant (LDLT) recipients. BACKGROUND Postoperative platelet count and prothrombin time-international normalized ratio (PT-INR) were critical biomarkers in LDLT. METHODS The study participants consisted of 445 initial LDLT recipients, and perioperative variables, including platelet count and PT-INR, were assessed for their association with severe complications (Clavien-Dindo classification grade IIIb/IV) and mortality within 90 days after operation. RESULTS Severe complications and operative mortality occurred in 161 (36%) and 23 patients (5%), respectively. Cox regression analysis revealed that a high body mass index [hazard ratio (HR) 1.2; 95% confidence interval (CI), 1.1-1.4; P = 0.004] and low platelet count on postoperative day (POD)3 (HR 0.88; 95% CI, 0.57-0.97; P < 0.001) were independent predictors for grade IIIb/IV complications after LDLT, whereas high PT-INR on POD5 (HR 1.1; 95% CI, 1.1-1.3; P = 0.021) was the only independent factor for operative mortality. In addtion, the progonostic scoring with low platelet count (<50 × 10/L) and prolonged prothrombin time (PT-INR >1.6) within POD5, 1 point for each, was demonstrated to be useful in predicting the development of Clavien-Dindo grade IIIb/IV/V complications after LDLT (30% for score 0, 46% for score 1, and 72% for score 2: 0 vs 1, P = 0.004; 0 vs 2, P < 0.001; 1 vs 2, P = 0.002). CONCLUSIONS PT-INR above 1.6 and platelet count below 50 × 10/L within POD5 were useful predictors of mortality and severe complications after LDLT.
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Affiliation(s)
- Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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14
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Pamecha V, Mahansaria SS, Kumar S, Bharathy KGS, Sasturkar SV, Sinha PK, Kumar N, Kumar V. Association of thrombocytopenia with outcome following adult living donor liver transplantation. Transpl Int 2016; 29:1126-35. [PMID: 27429066 DOI: 10.1111/tri.12819] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 04/03/2016] [Accepted: 07/15/2016] [Indexed: 12/15/2022]
Abstract
This study aimed to evaluate the association of postoperative thrombocytopenia with outcome following adult living donor liver transplantation (LDLT) for end-stage liver disease (ESLD). It was a prospective study of 120 consecutive adult LDLT from September 2012 to May 2015. Preoperative platelet counts (PLTs) and postoperative PLTs were recorded at regular intervals till 3 months after LDLT. Univariate and multivariate analyses were performed. The median pretransplant PLT was 61 × 10(9) /l. The lowest median PLT after LDLT was observed on POD 3. Patients were stratified into low platelet group (n = 83) with PLT <30 × 10(9) /l and high platelet group (n = 37) with PLT ≥30 × 10(9) /l. Patients with PLT <30 × 10(9) /l had statistically significant higher grade III/IV complication (P = 0.001), early graft dysfunction (P = 0.01), sepsis (P = 0.001), and prolonged ascites drainage (P = 0.002). On multivariate analysis, PLT<30 × 10(9) /l was identified as an independent risk factor for grade III/IV complications (P = 0.005). Overall, patients survival was significantly different between two groups (P = 0.04), but this predictive value was lost in patients who survived more than 90 days (P = 0.37). Postoperative PLT of <30 × 10(9) /l was a strong predictor of major postoperative complications and is associated with early graft dysfunction, prolonged ascites drainage, and sepsis. The perioperative mortality rate was high in the thrombocytopenia group.
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Affiliation(s)
- Viniyendra Pamecha
- Department of Liver Transplantation and Hepato Pancreatico Biliary Surgery, Institute of Liver & Biliary Sciences, New Delhi, India.
| | - Shyam Sunder Mahansaria
- Department of Liver Transplantation and Hepato Pancreatico Biliary Surgery, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Senthil Kumar
- Department of Liver Transplantation and Hepato Pancreatico Biliary Surgery, Institute of Liver & Biliary Sciences, New Delhi, India
| | | | - Shridhar Vasantrao Sasturkar
- Department of Liver Transplantation and Hepato Pancreatico Biliary Surgery, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Piyush Kumar Sinha
- Department of Liver Transplantation and Hepato Pancreatico Biliary Surgery, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Niteen Kumar
- Department of Liver Transplantation and Hepato Pancreatico Biliary Surgery, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Vaibhaw Kumar
- Department of Liver Transplantation and Hepato Pancreatico Biliary Surgery, Institute of Liver & Biliary Sciences, New Delhi, India
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15
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Mechanisms of platelet-mediated liver regeneration. Blood 2016; 128:625-9. [PMID: 27297793 DOI: 10.1182/blood-2016-04-692665] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 05/31/2016] [Indexed: 12/15/2022] Open
Abstract
Platelets have multiple functions beyond their roles in thrombosis and hemostasis. Platelets support liver regeneration, which is required after partial hepatectomy and acute or chronic liver injury. Although it is widely assumed that platelets stimulate liver regeneration by local excretion of mitogens stored within platelet granules, definitive evidence for this is lacking, and alternative mechanisms deserve consideration. In-depth knowledge of mechanisms of platelet-mediated liver regeneration may lead to new therapeutic strategies to treat patients with failing regenerative responses.
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16
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Hide D, Ortega-Ribera M, Garcia-Pagan JC, Peralta C, Bosch J, Gracia-Sancho J. Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy. Sci Rep 2016; 6:22107. [PMID: 26905693 PMCID: PMC4764954 DOI: 10.1038/srep22107] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 02/08/2016] [Indexed: 02/08/2023] Open
Abstract
Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR, and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype, and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.
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Affiliation(s)
- Diana Hide
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | - Martí Ortega-Ribera
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | - Juan-Carlos Garcia-Pagan
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | | | - Jaime Bosch
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
| | - Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute – Hospital Clinic de Barcelona – CIBEREHD. Barcelona, Spain
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17
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The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors. PLoS One 2016; 11:e0148815. [PMID: 26863224 PMCID: PMC4749185 DOI: 10.1371/journal.pone.0148815] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 01/22/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIMS The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD). The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD), we aimed to understand how ischemia/reperfusion (I/R) injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration. METHODS Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13) and DBD (n = 10) livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22) and DBD (n = 13) livers. RESULTS When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05) and C22 ceramide (p<0.05) were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST) of DCD allografts had significantly increased. CONCLUSION These data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation.
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18
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Miyashita T, Nakanuma S, Ahmed AK, Makino I, Hayashi H, Oyama K, Nakagawara H, Tajima H, Takamura H, Ninomiya I, Fushida S, Harmon JW, Ohta T. Ischemia reperfusion-facilitated sinusoidal endothelial cell injury in liver transplantation and the resulting impact of extravasated platelet aggregation. Eur Surg 2015; 48:92-98. [PMID: 27110233 PMCID: PMC4830883 DOI: 10.1007/s10353-015-0363-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 09/28/2015] [Accepted: 09/29/2015] [Indexed: 12/13/2022]
Abstract
Background The exact sequence of events leading to ultimate hepatocellular damage following ischemia/reperfusion (I/R) is incompletely understood. In this article, we review a mechanism of organ dysfunction after hepatic I/R or immunosuppressive treatment, in addition to the potential of liver sinusoidal endothelial cell (LSEC) protection and antiplatelet treatment for the suppression of hepatocellular damage. Methods A review of the literature, utilizing PubMed-NCBI, was used to provide information on the components necessary for the development of hepatocellular damage following I/R. Results It is well-established that LSECs damage following hepatic I/R or immunosuppressive treatment followed by extravasated platelet aggregation (EPA) is the root cause of organ dysfunction in liver transplantation. We have classified three phases, from LSECs damage to organ dysfunction, utilizing the predicted pathogenic mechanism of sinusoidal obstruction syndrome. The first phase is detachment of LSECs and sinusoidal wall destruction after LSECs injury by hepatic I/R or immunosuppressive treatment. The second phase is EPA, accomplished by sinusoidal wall destruction. The various growth factors, including thromboxane A2, serotonin, transforming growth factor-beta and plasminogen activator inhibitor-1, released by EPA in the Disse’s space of zone three, induce portal hypertension and the progression of hepatic fibrosis. The third phase is organ dysfunction following portal hypertension, hepatic fibrosis, and suppressed liver regeneration through various growth factors secreted by EPA. Conclusion We suggest that EPA in the space of Disse, initiated by LSECs damage due to hepatic I/R or immunosuppressive treatment, and activated platelets may primarily contribute to liver damage in liver transplantation. Endothelial protective therapy or antiplatelet treatment may be useful in the treatment of hepatic I/R following EPA.
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Affiliation(s)
- T Miyashita
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - S Nakanuma
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - A K Ahmed
- Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, 21224 Baltimore, MD USA
| | - I Makino
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Hayashi
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - K Oyama
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Nakagawara
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Tajima
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Takamura
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - I Ninomiya
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - S Fushida
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - J W Harmon
- Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, 21224 Baltimore, MD USA
| | - T Ohta
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
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19
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Ed Rainger G, Chimen M, Harrison MJ, Yates CM, Harrison P, Watson SP, Lordkipanidzé M, Nash GB. The role of platelets in the recruitment of leukocytes during vascular disease. Platelets 2015. [PMID: 26196409 PMCID: PMC4673595 DOI: 10.3109/09537104.2015.1064881] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Besides their role in the formation of thrombus during haemostasis, it is becoming clear that platelets contribute to a number of other processes within the vasculature. Indeed, the integrated function of the thrombotic and inflammatory systems, which results in platelet-mediated recruitment of leukocytes, is now considered to be of great importance in the propagation, progression and pathogenesis of atherosclerotic disease of the arteries. There are three scenarios by which platelets can interact with leukocytes: (1) during haemostasis, when platelets adhere to and are activated on sub-endothelial matrix proteins exposed by vascular damage and then recruit leukocytes to a growing thrombus. (2) Platelets adhere to and are activated on stimulated endothelial cells and then bridge blood borne leukocytes to the vessel wall and. (3) Adhesion between platelets and leukocytes occurs in the blood leading to formation of heterotypic aggregates prior to contact with endothelial cells. In the following review we will not discuss leukocyte recruitment during haemostasis, as this represents a physiological response to tissue trauma that can progress, at least in its early stages, in the absence of inflammation. Rather we will deal with scenarios 2 and 3, as these pathways of platelet–leukocyte interactions are important during inflammation and in chronic inflammatory diseases such as atherosclerosis. Indeed, these interactions mean that leukocytes possess means of adhesion to the vessel wall under conditions that may not normally be permissive of leukocyte–endothelial cell adhesion, meaning that the disease process may be able to bypass the regulatory pathways which would ordinarily moderate the inflammatory response.
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Affiliation(s)
- G Ed Rainger
- Centre for Cardiovascular Sciences, Institute for Biomedical Research, The Medical School, The University of Birmingham , Birmingham , UK and
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20
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Aliakbarian M, Nikeghbalian S, Ghaffaripour S, Bahreini A, Shafiee M, Rashidi M, Rajabnejad Y. Effects of N-Acetylcysteine Addition to University of Wisconsin Solution on the Rate of Ischemia-Reperfusion Injury in Adult Orthotopic Liver Transplant. EXP CLIN TRANSPLANT 2015; 15:432-436. [PMID: 26114393 DOI: 10.6002/ect.2014.0263] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES One of the main concerns in liver transplant is the prolonged ischemia time, which may lead to primary graft nonfunction or delayed function. N-acetylcysteine is known as a hepato-protective agent in different studies, which may improve human hepatocyte viability in steatotic donor livers. This study investigated whether N-acetylcysteine can decrease the rate of ischemia-reperfusion syndrome and improve short-term outcome in liver transplant recipients. MATERIALS AND METHODS This was a double-blind, randomized, control clinical trial of 115 patients. Between April 2012 and January 2013, patients with orthotopic liver transplant were randomly divided into 2 groups; in 49 cases N-acetylcysteine was added to University of Wisconsin solution as the preservative liquid (experimental group), and in 66 cases standard University of Wisconsin solution was used (control group). We compared postreperfusion hypotension, inotrope requirement before and after portal reperfusion, intermittent arterial blood gas analysis and potassium measurement, pathological review of transplanted liver, in-hospital complications, morbidity, and mortality. RESULTS There was no significant difference between the groups regarding time to hepatic artery reperfusion, hospital stay, vascular complications, inotrope requirement before and after portal declamping, and blood gas analysis. Hypotension after portal reperfusion was significantly more common in experimental group compared with control group (P = .005). Retransplant and in-hospital mortality were comparable between the groups. CONCLUSIONS Preservation of the liver inside Univer-sity of Wisconsin solution plus N-acetylcysteine did not change the rate of ischemia reperfusion injury and short-term outcome in liver transplant recipients.
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Affiliation(s)
- Mohsen Aliakbarian
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Jawan B, Wang CH, Chen CL, Huang CJ, Cheng KW, Wu SC, Shih TH, Yang SC. Review of anesthesia in liver transplantation. ACTA ACUST UNITED AC 2014; 52:185-96. [PMID: 25477262 DOI: 10.1016/j.aat.2014.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 09/26/2014] [Indexed: 01/10/2023]
Abstract
Liver transplantation (LT) is a well-accepted treatment modality of many end-stage liver diseases. The main issue in LT is the shortage of deceased donors to accommodate the needs of patients waiting for such transplants. Live donors have tremendously increased the pool of available liver grafts, especially in countries where deceased donors are not common. The main ethical concern of this procedure is the safety of healthy donors, who undergo a major abdominal surgery not for their own health, but to help cure others. The first part of the review concentrates on live donor selection, preanesthetic evaluation, and intraoperative anesthetic care for living liver donors. The second part reviews patient evaluation, intraoperative anesthesia monitoring, and fluid management of the recipient. This review provides up-to-date information to help improve the quality of anesthesia, and contribute to the success of LT and increase the long-term survival of the recipients.
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Affiliation(s)
- Bruno Jawan
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Chih-Hsien Wang
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplant Program, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chia-Jung Huang
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kwok-Wai Cheng
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shao-Chun Wu
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hsiao Shih
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Chun Yang
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Chin JL, Hisamuddin SH, O'Sullivan A, Chan G, McCormick PA. Thrombocytopenia, Platelet Transfusion, and Outcome Following Liver Transplantation. Clin Appl Thromb Hemost 2014; 22:351-60. [PMID: 25430936 DOI: 10.1177/1076029614559771] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Thrombocytopenia affects patients undergoing liver transplantation. Intraoperative platelet transfusion has been shown to independently influence survival after liver transplantation at 1 and 5 years. We examined the impact of thrombocytopenia and intraoperative platelet transfusion on short-term graft and overall survival after orthotopic liver transplantation (OLT). A total of 399 patients undergoing first OLT were studied. Graft and overall survival in patients with different degrees of thrombocytopenia and with or without intraoperative platelet transfusion were described. The degree of thrombocytopenia prior to OLT did not affect graft or overall survival after transplant. However, graft survival in patients receiving platelets was significantly reduced at 1 year (P= .023) but not at 90 days (P= .093). Overall survival was significantly reduced at both 90 days (P= .040) and 1 year (P= .037) in patients receiving platelets. We conclude that a consistently lower graft and overall survival were observed in patients receiving intraoperative platelet transfusion.
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Affiliation(s)
- Jun Liong Chin
- Liver Unit, St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | | | - Aoife O'Sullivan
- Blood bank, St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Grace Chan
- Liver Unit, St Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - P Aiden McCormick
- Liver Unit, St Vincent's University Hospital, University College Dublin, Dublin, Ireland
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23
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Lesurtel M, Clavien PA. Platelet-derived serotonin: translational implications for liver regeneration. Hepatology 2014; 60:30-3. [PMID: 24700245 DOI: 10.1002/hep.27067] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 02/07/2014] [Indexed: 01/17/2023]
Affiliation(s)
- Mickaël Lesurtel
- Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Zurich, Switzerland
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25
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Nowatari T, Murata S, Fukunaga K, Ohkohchi N. Role of platelets in chronic liver disease and acute liver injury. Hepatol Res 2014; 44:165-72. [PMID: 23841688 DOI: 10.1111/hepr.12205] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 07/03/2013] [Accepted: 07/07/2013] [Indexed: 12/13/2022]
Abstract
Platelets contain not only hemostatic factors but also many growth factors that play important roles in wound healing and tissue repair. Platelets have already been used for the promotion of tissue regeneration in the clinical setting, such as dental implantation and plastic surgery. Thrombocytopenia, which is frequently found in patients with chronic liver disease and cirrhosis, is due to various causes such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism. However, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in chronic liver disease are poorly understood. In acute liver injury, it is reported that platelets are recruited to the liver and contribute to liver damage by promoting the induction of chemotactic factors and the accumulation of leukocytes in the liver, whereas platelets or mediators released by platelets can have a protective effect against liver injury. In this review, we highlight the recent accumulated knowledge concerning the role of platelets in chronic liver disease and acute liver injury.
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Affiliation(s)
- Takeshi Nowatari
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery, and Organ Transplantation, University of Tsukuba, Tsukuba, Japan
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26
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Lesurtel M, Raptis DA, Melloul E, Schlegel A, Oberkofler C, El-Badry AM, Weber A, Mueller N, Dutkowski P, Clavien PA. Low platelet counts after liver transplantation predict early posttransplant survival: the 60-5 criterion. Liver Transpl 2014; 20:147-55. [PMID: 24123804 DOI: 10.1002/lt.23759] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 09/19/2013] [Indexed: 02/06/2023]
Abstract
Platelets play a critical role in liver injury and regeneration. Thrombocytopenia is associated with increases in postoperative complications after partial hepatectomy, but it is unknown whether platelet counts could also predict outcomes after transplantation, a procedure that is often performed in thrombocytopenic patients. Therefore, the aim of this study was to evaluate whether platelet counts could be indicators of short- and long-term outcomes after liver transplantation (LT). Two hundred fifty-seven consecutive LT recipients (January 2003-December 2011) from our prospective database were analyzed. Preoperative and daily postoperative platelet counts were recorded until postoperative day 7 (POD7). Univariate and multivariate analyses were performed to assess whether low perioperative platelet counts were a risk factor for postoperative complications and graft and patient survival. The median pretransplant platelet count was 88 × 10(9) /L [interquartile range (IQR) = 58-127 × 10(9) /L]. The lowest platelet counts occurred on POD3: the median was 56 × 10(9) /L (IQR = 41-86 × 10(9) /L). Patients with low platelet counts on POD5 had higher rates of severe (grade IIIb/IV) complications [39% versus 29%, odds ratio (OR) = 1.09 (95% CI = 1.1-3.3), P = 0.02] and 90-day mortality [16% versus 8%, OR = 2.25 (95% CI = 1.0-5.0), P = 0.05]. In the multivariate analysis, POD5 platelet counts < 60 × 10(9) /L were identified as an independent risk factor for grade IIIb/IV complications [OR = 1.96 (95% CI = 1.07-3.56), P = 0.03)], graft survival [hazard ratio (HR) = 2.0 (95% CI = 1.1-3.6), P = 0.03)], and patient survival [HR = 2.2 (95% CI = 1.1-4.6), P = 0.03)]. The predictive value of platelet counts for graft and patient survival was lost in patients who survived 90 days. In conclusion, after LT, platelet counts < 60 × 10(9) /L on POD5 (the 60-5 criterion) are an independent factor associated with severe complications and early graft and patient survival. These findings may help us to develop protective strategies or specific interventions for high-risk patients.
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Affiliation(s)
- Mickaël Lesurtel
- Swiss Hepatopancreatobiliary and Transplantation Center, Department of Surgery, University Hospital of Zurich, Zurich, Switzerland
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27
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Graham JA, Guarrera JV. Looking into the crystal ball: the 60-5 criterion--a newly proposed predictor of severe complications after liver transplantation. Liver Transpl 2014; 20:127-9. [PMID: 24307500 DOI: 10.1002/lt.23805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 11/24/2013] [Indexed: 02/07/2023]
Affiliation(s)
- Jay A. Graham
- Center for Liver Disease and Transplantation, Department of Surgery; Columbia University College of Physicians and Surgeons; New York NY
| | - James V. Guarrera
- Center for Liver Disease and Transplantation, Department of Surgery; Columbia University College of Physicians and Surgeons; New York NY
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Fayed NA, Abdallah AR, Khalil MK, Marwan IK. Therapeutic rather than prophylactic platelet transfusion policy for severe thrombocytopenia during liver transplantation. Platelets 2013; 25:576-86. [PMID: 24246132 DOI: 10.3109/09537104.2013.849335] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Platelet transfusion (PTx) has been identified as an important risk factor for morbidity and mortality after liver transplantation (LTx). Our aim was to evaluate the safety of therapeutic rather than prophylactic PTx policy in severe thrombocytopenic patients undergoing LTx. Recipients of LTx were divided into two groups: group I (GI) (n = 76) platelet count (PC) ≥ 50 × 10(9)/l and group II (GII) PC < 50 × 109/l (n = 76). Platelets were transfused following a thromboelastometry protocol and clinical signs of diffuse bleeding. Both groups were compared regarding hemoglobin (Hb), international normalized ratio (INR), fibrinogen level, blood loss (BL), blood products required, percentage of bloodless surgery, duration of mechanical ventilation, ICU stay, and vascular complications. Each group was further subdivided according to PTx into (GI NPTx and GII NPTx) with no platelet transfusion (NPTx) and (GI PTx and GII PTx) received PTx. These subgroups were further compared for some variables. Base line Hb was significantly higher while INR was significantly lower in GI.75% avoided PTx in GII. Comparisons of BL, packed red blood cells (PRBCs), and cryoprecipitate transfusion were insignificant. Fresh frozen plasma (FFP) transfusion was higher and the percentage of bloodless surgery was lower in GII. In GII, PC increased after start of surgery. Two cases of hepatic artery thrombosis in GI and one in GII were recorded. Recovery of platelets was quicker, and duration of mechanical ventilation and ICU stay was shorter in NPTx patients regardless the base line PC. Cut-off values of PC 30 × 10(9)/l (with sensitivity 73.7% and specificity 78.8%, p < 0.01), BL of 3750 ml in GI (sensitivity of 75% and specificity of 69%, p < 0.01) and of 3250 ml in GII (sensitivity of 84.2% and specificity of 87.7% (p < 0.01)) could indicate the need of PTx. With therapeutic approach, 75% of patients in GII could avoid unnecessary PTx with its hazards without excessive bleeding. PC in GII increased intraoperatively, PTx may lead to delayed recovery of platelets, increased duration of mechanical ventilation and ICU stay. The given cut-off values may help to guide PTx.
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Affiliation(s)
- Nirmeen A Fayed
- Department of Anesthesia, National Liver Institute, Menoufeya University , Shebeen El-Kom , Egypt
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Peralta C, Jiménez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol 2013; 59:1094-1106. [PMID: 23811302 DOI: 10.1016/j.jhep.2013.06.017] [Citation(s) in RCA: 465] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 06/17/2013] [Accepted: 06/18/2013] [Indexed: 12/16/2022]
Abstract
Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction post-transplantation. Cellular and biochemical processes occurring during hepatic ischemia-reperfusion are diverse and complex, and include the deregulation of the healthy phenotype of all liver cellular components. Nevertheless, a significant part of these processes are still unknown or unclear. The present review aims at summarizing the current knowledge in liver ischemia-reperfusion, but specifically focusing on liver cell phenotype and paracrine interaction deregulations. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field will be described. Finally, the importance of considering the subclinical situation of liver grafts when translating basic knowledge to the bedside is discussed.
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Affiliation(s)
- Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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30
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Serotonin: a key molecule in acute and chronic liver injury! Clin Res Hepatol Gastroenterol 2012; 36:319-22. [PMID: 22749697 DOI: 10.1016/j.clinre.2012.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Revised: 05/17/2012] [Accepted: 05/21/2012] [Indexed: 02/04/2023]
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Tamura T, Kondo T, Pak S, Nakano Y, Murata S, Fukunaga K, Ohkohchi N. Interaction between Kupffer cells and platelets in the early period of hepatic ischemia-reperfusion injury--an in vivo study. J Surg Res 2012; 178:443-51. [PMID: 22480836 DOI: 10.1016/j.jss.2011.12.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 11/25/2011] [Accepted: 12/06/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatic ischemia-reperfusion (I/R) leads to activation of Kupffer cells (KCs). The activated KCs cause platelet and leukocyte adhesion to the sinusoidal endothelium. Previously, we reported that platelet-endothelium interactions occur earlier than leukocyte responses. The aim of this study was to evaluate the interaction between platelets and KCs in the hepatic microcirculation after I/R. MATERIALS AND METHODS Sprague-Dawley rats were divided into three groups: the no-ischemia group (control group; n = 6); the 20-min ischemia group (I/R group; n = 6); and the 20-min ischemia + anti-rat platelet serum group (APS group; n = 6). KCs were labeled using the liposome entrapment method. The number of adherent platelets was observed for up to 120 min after reperfusion by intravital microscopy. To investigate the effects of platelets on I/R injury, rats were injected intravenously with rabbit APS for platelet depletion. RESULTS In the I/R group, the number of adherent platelets increased significantly after I/R. More than 50% of the adherent platelets adhered to KCs. Electron microscopy indicated that the platelets attached to the KCs after hepatic ischemia. The histologic findings indicated liver damage and apoptosis of hepatocytes in zone 1. In the I/R group, but not in the control and APS groups, serum ALT increased immediately after reperfusion. CONCLUSIONS We succeeded in visualizing the dynamics of both KCs and platelets in the hepatic sinusoids. Liver ischemia induced the adhesion of platelets to KCs in the early period, which could play a key role in reperfusion injury of the liver.
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Affiliation(s)
- Takafumi Tamura
- Department of Surgery, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
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Lisman T, Leuvenink HGD, Porte RJ, Ploeg RJ. Activation of hemostasis in brain dead organ donors: an observational study. J Thromb Haemost 2011; 9:1959-65. [PMID: 21762465 DOI: 10.1111/j.1538-7836.2011.04442.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Brain death is associated with a systemic inflammatory response resulting in diminished organ function in individuals transplanted with organs from brain dead donors. As inflammation is accompanied by activation of coagulation, we hypothesized that activation of hemostasis occurs in brain dead organ donors. OBJECTIVES To assess the hemostatic status in brain dead organ donors. PATIENTS AND METHODS In this study, we systematically assessed the hemostatic system in samples taken from 30 brain dead donors. As controls, blood samples from 30 living kidney donors were included. RESULTS AND CONCLUSIONS Compared with the living donors, brain dead donors showed significant platelet activation (assessed by glycocalicin plasma levels), and a profound dysbalance in the von Willebrand factor/ADAMTS13 axis, which is key in platelet attachment to damaged vasculature. Furthermore, compared with the living donors, brain dead donors showed a significantly increased activation of secondary hemostasis with formation of fibrin (assessed by plasma levels of prothrombin fragment 1 + 2, fibrinopeptide A and D-dimer). Finally, brain dead donors showed profound hypofibrinolysis as assessed by a global clot lysis assay, which was attributed to substantially elevated plasma levels of plasminogen activator inhibitor type 1. Collectively, our results show activation of hemostasis and dysregulated fibrinolysis in brain dead organ donors. This prothrombotic state may contribute to formation of microthrombi in transplantable organs, which potentially contributes to deterioration of organ function.
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Affiliation(s)
- T Lisman
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Ripoche J. Blood platelets and inflammation: their relationship with liver and digestive diseases. Clin Res Hepatol Gastroenterol 2011; 35:353-7. [PMID: 21482218 DOI: 10.1016/j.clinre.2011.02.012] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 02/17/2011] [Accepted: 02/22/2011] [Indexed: 02/04/2023]
Abstract
An expansion of knowledge from basic and clinical research has highlighted the critical role of platelets in inflammation and tissue repair in addition to their established contribution to hemostasis. Activated platelets are a rich source of mediators participating to inflammation and tissue regeneration. Platelet-derived microparticles recapitulate essential platelet functions and their contribution to the pathogenesis of inflammatory diseases has been emphasized. Recent findings suggest that platelets are both friends and foes for the liver. Platelets are essential to liver regeneration, platelet-derived serotonin being critical. However platelets can also exacerbate liver damage, as in immune-mediated injury. The dual role of platelets has recently been exemplified in animal models of liver fibrosis. Platelets release profibrogenic mediators, such as CXC Chemokine Ligand 4, that is instrumental in the progression of liver fibrosis. On the other hand, thrombocytopenia aggravates liver fibrosis, an outcome linked to the downregulation of hepatic stellate cell collagen production by platelet derived hepatocyte growth factor. CD154, a key molecule in inflammation, is expressed by platelets and is a pathogenic mediator in inflammatory bowel disease. Here, we summarize some of the mechanisms linking platelets with inflammation and comment few recent articles indicating why platelets may prove to be important pathogenic mediators in liver and gastrointestinal diseases.
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Affiliation(s)
- J Ripoche
- Inserm U889, université Victor-Segalen-Bordeaux, 146, rue Léo-Saignat, 33076 Bordeaux, France.
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Rice MJ, Wendling A, Firpi RJ, Hemming AW, Nelson DR, Schwab WK, Gravenstein N, Morey TE. Transfusion has no effect on recurrence in hepatitis C after liver transplantation. Acta Anaesthesiol Scand 2010; 54:1224-32. [PMID: 21069900 DOI: 10.1111/j.1399-6576.2010.02313.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND The literature suggests that blood product transfusions have a negative impact on the survival of liver transplant patients. We investigated the impact of intraoperative blood product usage on the survival of liver transplantation patients being transplanted for hepatitis C-related end-stage liver disease. In addition, we analyzed a potentially more sensitive metric, namely disease recurrence and fibrosis progression, obtained from follow-up liver biopsies. METHODS We retrospectively studied 194 consecutive patients with hepatitis C virus (HCV) undergoing liver transplantation. To investigate the effect of red blood cell (RBC) or platelet transfusions on post-transplant HCV recurrence, hepatic biopsy data from 4 months and 1 year after transplantation were studied. In addition, survival data were analyzed. RESULTS There was no effect of intraoperative RBC or platelet transfusion on either 1- or 5-year patient survival following liver transplantation. There was no difference in HCV disease recurrence or progression of hepatic fibrosis at 4 months or 1 year attributable either to RBC or to platelet transfusion. CONCLUSION This study was not able to confirm an effect on the survival of HCV-infected liver transplant patients related to intraoperative transfusion of RBCs or platelets. In addition, these transfusions had no effect on HCV recurrence or fibrosis progression. This is not to condone a liberal transfusion practice, but rather to reassure that when clinically indicated, transfusion does not have a significant impact on patient survival or disease recurrence in HCV-infected liver transplant patients.
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Affiliation(s)
- M J Rice
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, USA.
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35
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Kim J, Yi NJ, Shin WY, Kim T, Lee KU, Suh KS. Platelet transfusion can be related to liver regeneration after living donor liver transplantation. World J Surg 2010; 34:1052-8. [PMID: 20151125 DOI: 10.1007/s00268-010-0464-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Although liver regeneration is a fundamental aspect of living donor liver transplantation (LDLT), the factors that affect liver regeneration during the early post-transplantation period have not been thoroughly investigated. Recently it was suggested that platelets contribute to liver regeneration. The aim of the present study was to identify the major factors that affect liver graft regeneration during the early post-transplantation period. MATERIALS AND METHODS Eighty-seven right liver grafted, adult-to-adult LDLT patients were retrospectively analyzed. Liver regeneration was assessed by volumetry from computed tomographic (CT) scans obtained between the 9th and 11th postoperative days. The authors investigated relationships between clinical variables and liver graft regeneration rates, and they conducted multiple regression analysis on factors found to be significant by univariate analysis. RESULTS Mean graft weight at operation was 722.9 +/- 109.7 g, and mean graft volume assessed by follow-up CT was 1,042.2 +/- 155.6 ml, reflecting a mean liver graft regeneration of 45.9 +/- 22.3%. The graft regeneration was found to correlate inversely with graft-to-recipient weight ratio (GRWR, r = -0.406, p < 0.001) and directly with portal flow velocity (cm/s; r = 0.307; p = 0.004) and splenic index (cm(3); r = 0.282; p = 0.009). Moreover, the total amount (units) of platelets transfused was found to be significantly associated with graft regeneration (r = 0.293; p = -.006). Stepwise regression analysis showed that GRWR (beta = -33.124; p = 0.001), total amount of platelets transfused (beta = 0.771; p = 0.012), and splenic index (beta = -0.010; p = 0.049) were independently associated with graft regeneration. CONCLUSIONS The results of the present study suggest that platelets play a significant role in human liver regeneration after LDLT.
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Affiliation(s)
- Joohyun Kim
- Department of Surgery, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul, 130-702, Republic of Korea
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Esch JSA, Jurk K, Knoefel WT, Roeder G, Voss H, Tustas RY, Schmelzle M, Krieg A, Eisenberger CF, Topp S, Rogiers X, Fischer L, Aken HV, Kehrel BE. Platelet activation and increased tissue factor expression on monocytes in reperfusion injury following orthotopic liver transplantation. Platelets 2010; 21:348-59. [DOI: 10.3109/09537101003739897] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Uchida Y, Ke B, Freitas MCS, Ji H, Zhao D, Benjamin ER, Najafian N, Yagita H, Akiba H, Busuttil RW, Kupiec-Weglinski JW. The emerging role of T cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse. Hepatology 2010; 51:1363-72. [PMID: 20091883 PMCID: PMC3066468 DOI: 10.1002/hep.23442] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The T cell immunoglobulin and mucin domain-containing molecules (TIM) protein family, which is expressed by T cells, plays a crucial role in regulating host adaptive immunity and tolerance. However, its role in local inflammation, such as innate immunity-dominated organ ischemia-reperfusion injury (IRI), remains unknown. Liver IRI occurs frequently after major hepatic resection or liver transplantation. Using an antagonistic anti-TIM-1 antibody (Ab), we studied the role of TIM-1 signaling in the model of partial warm liver ischemia followed by reperfusion. Anti-TIM-1 Ab monotherapy ameliorated the hepatocellular damage and improved liver function due to IR, as compared with controls. Histological examination has revealed that anti-TIM-1 Ab treatment decreased local neutrophil infiltration, inhibited sequestration of T lymphocytes, macrophages, TIM-1 ligand-expressing TIM-4(+) cells, and reduced liver cell apoptosis. Intrahepatic neutrophil activity and induction of proinflammatory cytokines/chemokines were also reduced in the treatment group. In parallel in vitro studies, anti-TIM-1 Ab suppressed interferon-gamma (IFN-gamma) production in concanavalin A (conA)-stimulated spleen T cells, and diminished tumor necrosis factor alpha (TNF-alpha)/interleukin (IL)-6 expression in a macrophage/spleen T cell coculture system. This is the first study to provide evidence for the novel role of TIM-1 signaling in the mechanism of liver IRI. TIM-1 regulates not only T for the role of cell activation but may also affect macrophage function in the local inflammation response. These results provide compelling data for further investigation of TIM-1 pathway in the mechanism of IRI, to improve liver function, expand the organ donor pool, and improve the overall success of liver transplantation.
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Affiliation(s)
- Yoichiro Uchida
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Bibo Ke
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Maria Cecilia S Freitas
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Haofeng Ji
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Danyun Zhao
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Elizabeth R Benjamin
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Nader Najafian
- Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Hideo Yagita
- Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hisaya Akiba
- Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
| | - Ronald W Busuttil
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA,Address correspondence to: Jerzy W. Kupiec-Weglinski, MD, PhD. Dumont - UCLA Transplant Center 77-120 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095. Phone: (310) 825-4196; Fax: (310) 267-2358;
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Zaouali MA, Ben Abdennebi H, Padrissa-Altés S, Mahfoudh-Boussaid A, Roselló-Catafau J. Pharmacological strategies against cold ischemia reperfusion injury. Expert Opin Pharmacother 2010; 11:537-555. [PMID: 20163266 DOI: 10.1517/14656560903547836] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
IMPORTANCE OF THE FIELD Good organ preservation is a determinant of graft outcome after revascularization. The necessity of increasing the quality of organ preservation, as well as of extending cold storage time, has made it necessary to consider the use of pharmacological additives. AREAS COVERED IN THIS REVIEW The complex physiopathology of cold-ischemia-reperfusion (I/R) injury--and in particular cell death, mitochondrial injury and endoplasmic reticulum stress--are reviewed. Basic principles of the formulation of the different preservation solutions are discussed. WHAT THE READER WILL GAIN Current strategies and new trends in static organ preservation using additives such as trimetazidine, polyethylene glycols, melatonin, trophic factors and endothelin antagonists in solution are presented and discussed. The benefits and mechanisms responsible for enhancing organ protection against I/R injury are also discussed. Graft preservation was substantially improved when additives were added to the preservation solutions. TAKE HOME MESSAGE Enrichment of preservation solutions by additives is clinically useful only for short periods. For longer periods of cold ischemia, the use of such additives becomes insufficient because graft function deteriorates as a result of ischemia. In such conditions, the preservation strategy should be changed by the use of machine perfusion in normothermic conditions.
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Affiliation(s)
- Mohamed Amine Zaouali
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, C/Rosselló 161, 7th floor, E-08036-Barcelona, Spain.
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Schulte am Esch J, Akyildiz A, Tustas RY, Ganschow R, Schmelzle M, Krieg A, Robson SC, Topp SA, Rogiers X, Knoefel WT, Fischer L. ADP-dependent platelet function prior to and in the early course of pediatric liver transplantation and persisting thrombocytopenia are positively correlated with ischemia/reperfusion injury. Transpl Int 2010; 23:745-52. [PMID: 20136783 DOI: 10.1111/j.1432-2277.2010.01054.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Little is known about the role of platelets in relation to ischemia/reperfusion injury (IRI) of the liver graft especially in children. Thrombocyte function was prospectively analysed in 21 consecutive pediatric liver transplantation (pLT) patients by platelet aggregometry secondary to adenosine diphosphate (ADP), collagen, and the von Willebrand factor activator ristocetin (VWF:rco). Post-OP serum levels of ALT were used to divide patients into groups with high (highHD, n = 8) and low (lowHD, n = 13) hepatocellular damage. Clinically, highHD-patients showed impaired plasmatic coagulation and elevated serum bilirubin levels early after pLT when compared with lowHD-patients. Further, platelet counts markedly decreased between pre-OP and postreperfusion (postrep.) in the highHD group (P = 0.003) and did not recuperate by POD6. In lowHD individuals thrombocytopenia improved from both pre-OP (P < 0.05) and postrep. (P < 0.001) respectively towards POD6. Experimental thrombocyte testing revealed that before graft reperfusion only ADP-dependent platelet aggregation correlated with reperfusion injury, thrombocytopenia and early graft function. During the first 48 h after graft reperfusion, all inducers tested demonstrated elevated platelet aggregation levels in the highHD group. Our data suggest a possible role of platelets and their aggregative status in liver IRI subsequent to clinical pLT. Reperfusion-independent ADP-triggered platelet function may be a determinant for IRI in the pediatric hepatic graft recipient.
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Affiliation(s)
- Jan Schulte am Esch
- Department of Visceral, General and Pediatric Surgery, University Hospital Düsseldorf, Düsseldorf, Germany.
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Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 2009; 89:1269-339. [PMID: 19789382 DOI: 10.1152/physrev.00027.2008] [Citation(s) in RCA: 372] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.
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Affiliation(s)
- Brigitte Vollmar
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
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de Rougemont O, Lehmann K, Clavien PA. Preconditioning, organ preservation, and postconditioning to prevent ischemia-reperfusion injury to the liver. Liver Transpl 2009; 15:1172-82. [PMID: 19790166 DOI: 10.1002/lt.21876] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ischemia and reperfusion lead to injury of the liver. Ischemia-reperfusion injury is inevitable in liver transplantation and trauma and, to a great extent, in liver resection. This article gives an overview of the mechanisms involved in this type of injury and summarizes protective and treatment strategies in clinical use today. Intervention is possible at different time points: during harvesting, during the period of preservation, and during implantation. Liver preconditioning and postconditioning can be applied in the transplant setting and for liver resection. Graft optimization is merely possible in the period between the harvest and the implantation. Given that there are 3 stages in which a surgeon can intervene against ischemia-reperfusion injury, we have structured the review as follows. The first section reviews the approaches using surgical interventions, such as ischemic preconditioning, as well as pharmacological applications. In the second section, static organ preservation and machine perfusion are addressed. Finally, the possibility of treating the recipient or postconditioning is discussed.
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Affiliation(s)
- Olivier de Rougemont
- Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland
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Topp SA, Krieg A, Koch A, Tidden CM, Ramp U, Hohlfeld T, Macher A, Schulte am Esch J, Eisenberger CF, Stoecklein NH, Knoefel WT. Hemoglobin-Glutamer 200 Reduces Reperfusion Injury of the Cold Preserved Rat Liver by Induction of Heme Oxygenase-1. J Surg Res 2008; 150:243-54. [DOI: 10.1016/j.jss.2008.02.033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2007] [Revised: 02/04/2008] [Accepted: 02/12/2008] [Indexed: 02/01/2023]
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Hart ML, Much C, Gorzolla IC, Schittenhelm J, Kloor D, Stahl GL, Eltzschig HK. Extracellular adenosine production by ecto-5'-nucleotidase protects during murine hepatic ischemic preconditioning. Gastroenterology 2008; 135:1739-1750.e3. [PMID: 18804111 DOI: 10.1053/j.gastro.2008.07.064] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Revised: 06/26/2008] [Accepted: 07/24/2008] [Indexed: 02/02/2023]
Abstract
BACKGROUND & AIMS The liver tolerates ischemia/reperfusion (IR) poorly. The discovery of ischemic preconditioning (IP) has raised hopes that natural pathways could be activated to increase hepatic resistance to ischemia. However, mechanisms of hepatic IP remain largely unknown. Extracellular adenosine has been implicated as an innate anti-inflammatory metabolite, particularly during ischemia. We investigated whether ecto-5'-nucleotidase (CD73), the "pacemaker" enzyme of extracellular adenosine production, is critical for hepatic protection by IP. METHODS Mice were subjected to 4 cycles of portal triad occlusion and reperfusion (3 minutes of ischemia/3 minutes of reperfusion) prior to IR or IR alone. RESULTS Hepatic IP was associated with a significant induction of CD73 transcript and protein. Targeted gene deletion or pharmacologic inhibition of CD73 abolished hepatic protection by IP as measured by lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase serum levels or histologic injury. Increases in extracellular adenosine with IP were significantly attenuated in cd73-deficient (cd73(-/-)) mice. Reconstitution of cd73(-/-) mice with soluble 5'-nucleotidase resulted in complete restoration of hepatoprotection by IP, and hepatic injury following ischemia was attenuated by treatment of WT mice with soluble 5'-nucleotidase. Mice deficient in CD73 did not demonstrate the same degree of IP-dependent inhibition of acute phase complement gene expression/activation as did wild-type mice suggesting that extracellular adenosine attenuates hepatic IR via complement regulation. CONCLUSIONS Extracellular adenosine production by CD73 mediates protection during murine hepatic IP. Use of soluble 5'-nucleotidase may be a potential therapeutic for hepatic ischemia.
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Affiliation(s)
- Melanie L Hart
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Abstract
Apart from the well-known role of blood platelets in hemostasis, there is emerging evidence that platelets have various nonhemostatic properties that play a critical role in inflammation, angiogenesis, tissue repair and regeneration, and ischemia/reperfusion (I/R) injury. All these processes may be involved in the (patho)physiological alterations occurring in patients undergoing liver transplantation. Experimental and clinical research points toward a dualistic role of platelets in patients undergoing liver transplantation, resulting in both beneficial and detrimental effects. Although a low platelet count is generally considered a risk factor for perioperative bleeding, recent studies have indicated that platelet function in patients with cirrhosis may not be as abnormal as previously assumed. Platelet transfusions are frequently considered in liver transplant recipients to correct low platelet counts and to prevent bleeding; however, evidence-based transfusion thresholds are lacking, and the other detrimental and nonhemostatic properties of platelets are generally not weighed in this respect. First, platelets have been shown to contribute to I/R injury of the liver graft via induction of sinusoidal endothelial cell apoptosis. Second, platelet transfusion has been identified as an independent risk factor for reduced survival via mechanisms that are not completely understood yet. On the other hand, recent studies indicate that platelets are critically involved in restoration after liver injury and in liver regeneration via serotonin-mediated mechanisms. These findings make platelets both friend and foe in liver transplantation. The scientific challenge will be to further dissect the mechanisms and clinical relevance of these contrasting roles of platelets in liver transplantation.
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Affiliation(s)
- Ilona T A Pereboom
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Montalvo-Jave EE, Escalante-Tattersfield T, Ortega-Salgado JA, Piña E, Geller DA. Factors in the pathophysiology of the liver ischemia-reperfusion injury. J Surg Res 2008; 147:153-9. [PMID: 17707862 PMCID: PMC2443391 DOI: 10.1016/j.jss.2007.06.015] [Citation(s) in RCA: 286] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2007] [Revised: 05/29/2007] [Accepted: 06/05/2007] [Indexed: 12/16/2022]
Abstract
Hepatic ischemia-reperfusion injury is commonplace in liver surgery, particularly in hepatic transplantation, hepatic resection, and trauma. The signaling events contributing to local hepatocellular damage are diverse and complex and involve the interaction between hepatocytes, sinusoidal endothelial cells, Kupffer cells, as well as infiltrating neutrophils, macrophages, and platelets. Signaling mediators include cytokines, reactive oxygen and nitrogen species, calcium, complement, and several transcription factors. The purpose of this review article was to summarize the factors that contribute to the pathophysiology of hepatic ischemia-reperfusion injury.
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Affiliation(s)
- Eduardo E. Montalvo-Jave
- Department of Surgery, Faculty of Medicine and National Autonomous, University of Mexico (UNAM). Mexico City, Mexico and “Hospital General de Mexico OD”
- Department of Biochemistry, Faculty of Medicine and National Autonomous, University of Mexico (UNAM). Mexico City, Mexico and “Hospital General de Mexico OD”
- Transplantation Biology Program. Department of Surgery. Mayo Clinic. Rochester, Minnesota. USA
| | - Tomas Escalante-Tattersfield
- Department of Surgery, Faculty of Medicine and National Autonomous, University of Mexico (UNAM). Mexico City, Mexico and “Hospital General de Mexico OD”
| | - Jose A. Ortega-Salgado
- Department of Surgery, Faculty of Medicine and National Autonomous, University of Mexico (UNAM). Mexico City, Mexico and “Hospital General de Mexico OD”
| | - Enrique Piña
- Department of Biochemistry, Faculty of Medicine and National Autonomous, University of Mexico (UNAM). Mexico City, Mexico and “Hospital General de Mexico OD”
| | - David A. Geller
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA. USA
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Intrahepatic complement activation, sinusoidal endothelial injury, and lactic acidosis are associated with initial poor function of the liver after transplantation. Transplantation 2008; 85:718-25. [PMID: 18337666 DOI: 10.1097/tp.0b013e3181663366] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Changes in glucose metabolism in the liver during transplantation have been recently described using microdialysis. Here, these findings are correlated with histopathologic, immunohistochemical, and ultrastructural changes in liver. METHODS Microdialysis catheters were inserted into 15 human livers, which were perfused with isotonic solution, and samples of perfusate were analyzed before harvest, after storage, and after reperfusion. At each stage Menghini needle biopsy samples were taken and each studied using light and electron microscopy. RESULTS Six livers showed serum biochemical evidence of initial poor function. These livers had significantly more staining for complement fragment 4d (C4d) of both lobular and periportal hepatocytes. C4d-positive hepatocytes were also found in the liver during cold storage (3 of 15). These periportal hepatocytes also showed evidence of necrosis and were found to have intracellular neutrophils. Hepatocyte rounding in zone III, necrosis, and C4d staining in recipient were also significantly correlated with the degree of lactic acidosis during this phase. Intrahepatic lactic acidosis at all time points was significantly associated with sinusoidal endothelial cell injury after reperfusion. There were no correlations between glucose, pyruvate, and glycerol levels and histopathologic changes in the liver. DISCUSSION In the patients studied, the degree of C4d staining correlated with initial poor function and was associated with intrahepatic lactic acidosis in the donor during cold storage and after reperfusion. Complement activity in the liver during cold storage may be after in situ activation. Intrahepatic lactic acidosis is associated with sinusoidal endothelial cell and hepatocyte injury. The role of intrahepatic neutrophils is uncertain and could possibly be in response to cell necrosis.
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Principles of Organ Preservation. Surgery 2008. [DOI: 10.1007/978-0-387-68113-9_83] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Nakano Y, Kondo T, Matsuo R, Hashimoto I, Kawasaki T, Kohno K, Myronovych A, Tadano S, Hisakura K, Ikeda O, Watanabe M, Murata S, Fukunaga K, Ohkohchi N. Platelet dynamics in the early phase of postischemic liver in vivo. J Surg Res 2007; 149:192-8. [PMID: 18468625 DOI: 10.1016/j.jss.2007.09.016] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2007] [Revised: 08/27/2007] [Accepted: 09/17/2007] [Indexed: 12/13/2022]
Abstract
BACKGROUND In liver surgery, ischemia/reperfusion injury occasionally leads to liver failure by activating Kupffer cells (KCs) and leukocytes. However, few reports have demonstrated a relationship between KCs and platelets in vivo. This study investigated the relationship between these cells using intravital microscopy. MATERIALS AND METHODS Male Wistar rats were divided into two groups: (1) KC+ group, receiving 1 mL saline; and (2) KC- group, intravenously injected with liposome-encapsulated dichloromethylene disphosphonate for elimination of KCs. At 48 h after administration, 20 min of total normothermic hepatic ischemia was induced. Rhodamine-6G-labeled platelets and sinusoidal alterations were monitored using intravital microscopy up to 120 min after reperfusion. P-selectin, accumulated leukocytes and morphological damage, and alanine aminotransferase were evaluated. RESULTS In the KC+ group, numbers of adherent platelets increased significantly within 30 min after reperfusion. Endothelial cells of sinusoids in which KCs were mainly located were destroyed and the sinusoids were significantly constricted after reperfusion. Conversely, in the KC- group, adherent platelets in sinusoids were suppressed, and sinusoidal perfusion, endothelial cell damage and serum alanine aminotransferase levels were significantly improved. P-selectin on sinusoidal endothelial cells was not observed up to 120 min after reperfusion in either group. CONCLUSIONS Adherent platelets appear to reflect activation of KCs and lead to leukocyte accumulation, resulting in sinusoidal perfusion disturbance and liver failure. Evaluation of adherent platelets in the microcirculation offers an important marker of hepatic injury.
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Affiliation(s)
- Yoritaka Nakano
- Department of Surgery, Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
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Canedo LF, Machado MAC, Coelho AMM, Sampietre SN, Bachella T, Machado MCC. Efeito protetor de antagonista das gliproteínas IIb/IIa nas alterações hepáticas e pulmonares secundárias à isquemia e reperfusão do fígado em ratos. ARQUIVOS DE GASTROENTEROLOGIA 2007; 44:276-81. [DOI: 10.1590/s0004-28032007000300018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2006] [Accepted: 05/10/2007] [Indexed: 11/22/2022]
Abstract
RACIONAL: A lesão de isquemia e reperfusão hepática é um evento comum e responsável por considerável morbidade e mortalidade. OBJETIVO: Avaliar efeitos de inibidor da glicoproteína IIb/IIIa, cloridrato de tirofiban, nas alterações hepáticas e pulmonares da lesão de isquemia e reperfusão de fígado de ratos. MÉTODO: Vinte e três ratos Wistar divididos em três grupos: laparotomia (n = 6), isquemia e reperfusão que receberam solução fisiológica (n = 8), e submetidos a isquemia e reperfusão e tratados com o cloridrato de tirofiban (n = 9). Foram realizadas dosagens das aminotransferases e análise histológica hepática. Avaliação pulmonar foi realizada pelo teste do azul de Evans e pela dosagem tecidual da mieloperoxidase no parênquima pulmonar. A oxidação e fosforilação mitocondrial das células hepáticas também foram avaliadas. RESULTADOS: O grupo tratado com cloridrato de tirofiban apresentou menores níveis de aminotransferases, assim como alterações histológicas menos intensas. Avaliação pulmonar demonstrou diminuição no teste de azul de Evans no grupo tratado com cloridrato de tirofiban. Grupo tratado com cloridrato de tirofiban apresentou aumento significativo do estado 3 da respiração mitocondrial e das relações adenosina difosfato utilizado para fosforilação sobre o oxigênio consumido na reação e de coeficiente respiratório. CONCLUSÕES: O uso do cloridrato de tirofiban exerceu papel protetor da lesão hepática de isquemia e reperfusão e impediu o aumento da permeabilidade vascular secundária à lesão de reperfusão hepática.
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