1
|
Tanaka K, Uchida Y, Kadono K, Kageyama S, Kawamoto H, Ito M, Kidoguchi Y, Saga K, Kojima H, Hirao H, Nakamura K, Taura K, Terajima H, Watanabe T, Hatano E. Recipient toll-like receptor 4 determines the outcome of ischemia-reperfusion injury in steatotic liver transplantation in mice. Am J Transplant 2025; 25:1168-1179. [PMID: 40064295 DOI: 10.1016/j.ajt.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/16/2025] [Accepted: 03/04/2025] [Indexed: 04/01/2025]
Abstract
Toll-like receptor 4 (TLR4) plays a crucial role in ischemia-reperfusion injury (IRI) after liver transplantation (LT). However, the role of TLR4 in the context of steatotic grafts remains unclear. In this study, we developed a mouse model to explore IRI mechanisms in steatotic LT using TLR4 knockout mice as recipients. We successfully transplanted steatotic grafts with approximately 35% macrosteatosis and 5 hours of cold storage. Compared to normal LT, steatotic LT resulted in significantly higher serum level of alanine aminotransferase and high mobility group box 1 (HMGB1), higher transcriptional expression of inflammatory markers (C-X-C motif chemokine ligand 2, caspase-1, and caspase-11), and increased infiltration of CD11b-positive cells, correlating with lower survival. Serum HMGB1 and cleaved caspase-3 activation peaked earlier than serum alanine aminotransferase, with cold-stored steatotic grafts releasing more HMGB1. Notably, TLR4 knockout recipients demonstrated improved survival, attenuated inflammatory response, and reduced apoptosis. These findings suggest that TLR4 deficiency in recipients ameliorates IRI in steatotic LT, highlighting the importance of recipient immune modulation in mitigating steatotic graft injury.
Collapse
Affiliation(s)
- Kosuke Tanaka
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Yoichiro Uchida
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan.
| | - Kentaro Kadono
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shoichi Kageyama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Kawamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masaaki Ito
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuki Kidoguchi
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenichi Saga
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidenobu Kojima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hirofumi Hirao
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Nakamura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Hiroaki Terajima
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Takeshi Watanabe
- Division of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| |
Collapse
|
2
|
Si Z, Zhang Z, Zhao S, Chen T, Wang R, Zou G, Dong C, Wang K, Sun C, Zheng W, Wei X, Shen Z, Gao W. Definition, Prognosis, and Complication Analysis of Early Allograft Dysfunction in Pediatric Liver Transplantation: A Retrospective Cohort Study. J Pediatr Surg 2025; 60:162214. [PMID: 39933470 DOI: 10.1016/j.jpedsurg.2025.162214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 01/17/2025] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND The definition of early allograft dysfunction (EAD) varies, and has hardly been studied in pediatric transplantation (pLT) since the adult EAD definition is not easily applicable to pLT. METHODS A retrospective analysis was conducted on consecutive pLT patients aged <18 at the Department of Pediatric Transplantation of Tianjin First Central Hospital from April 2013 to December 2022. The definition of EAD explored in this study is (1) international normalized ratio ≥2.8 on day 1 and aspartate aminotransferase >1500 IU/mL within the first 7 days or (2) total bilirubin ≥5 mg/dL on day 7. The overall survival of patients and graft survival at 90 days after surgery were compared between this new definition and the adult EAD definition. RESULTS A total of 1620 pLT recipients were included in the study, of which 179 (11.0 %) recipients met the new definition of EAD for pLT. Twenty-five (13.97 %) died and 37 (20.67 %) graft lost within 90 days. The RR_death under Olthoff's EAD definition and our EAD definition are 3.45 and 9.57, respectively; The RR_graft_loss under Olthoff's EAD definition and our EAD definition are 4.18 and 11.48, respectively. A total of 97 (18.98 %) of 511 recipients who received deceased donor liver transplantation (DDLT) met the new definition of EAD, 18 (18.56 %) died and 29 (29.90 %) graft lost within 90 days. In DDLT group, the RR_death under Olthoff's EAD definition and our EAD definition are 2.29 and 10.98, respectively; The RR_graft_loss under Olthoff's EAD definition and our EAD definition are 2.34 and 11.24, respectively. CONCLUSION The broadly used Olthoff's EAD definition in adult liver transplantation is unsuitable for pLT use. The EAD definition established in this study is more suitable for patients <18 years old who received pLT, especially those <18 years old who received DDLT.
Collapse
Affiliation(s)
- Zhuyuan Si
- Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan, China; Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Zhixin Zhang
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Shengqiao Zhao
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Tianran Chen
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Ruofan Wang
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Guoyin Zou
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Chong Dong
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Kai Wang
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Chao Sun
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Weiping Zheng
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Xinzhe Wei
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Zhongyang Shen
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wei Gao
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China.
| |
Collapse
|
3
|
Sanchez-Gonzalez C, Fernández Aguilar JL, Sánchez Pérez B, Santoyo Santoyo J. Value of Factor V in the diagnosis of early graft dysfunction after liver transplantation: Internal validation. Liver Transpl 2025; 31:489-497. [PMID: 39352267 DOI: 10.1097/lvt.0000000000000500] [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: 07/14/2024] [Accepted: 09/15/2024] [Indexed: 10/03/2024]
Abstract
Primary graft dysfunction is a major early complication following liver transplantation, potentially leading to retransplantation or patient death. Coagulation Factor V (FV) and ALT have emerged as important biomarkers in assessing liver function, yet their role as early predictors of graft loss has not been fully validated. The aim of this study is to conduct an internal validation of published results on the applicability of FV and ALT for diagnosing graft dysfunction and its predictive ability for graft loss within the first 90 days. We conducted a retrospective cohort study including 513 adult recipients from 2012 to 2023 at the Regional University Hospital of Málaga. FV and ALT levels were measured on postoperative day 2, and patients were categorized based on FV <37.5 and ALT >1539. The association with 90-day graft loss was analyzed. Graft loss occurred in 43 patients (8.4%) within the first 90 days. The combination of FV <37.5 and ALT >1539 on postoperative day 2 demonstrated a specificity of 99% and a test efficiency of 94% in predicting graft loss. Patients meeting both criteria had a 74-fold increased risk of graft loss, with most losses occurring within the first week, and a median survival of 4 days. These findings suggest that FV and ALT on postoperative day 2 are reliable early markers for predicting graft loss, enabling risk stratification and guiding critical decisions regarding early retransplantation in the immediate postoperative period.
Collapse
Affiliation(s)
- Claudia Sanchez-Gonzalez
- General and Digestive Surgery Department, Regional University Hospital of Malaga, Málaga, Spain
- Medical School University of Malaga (UMA), Málaga, Spain
| | - José L Fernández Aguilar
- General and Digestive Surgery Department, Regional University Hospital of Malaga, Málaga, Spain
- Medical School University of Malaga (UMA), Málaga, Spain
| | - Belinda Sánchez Pérez
- General and Digestive Surgery Department, Regional University Hospital of Malaga, Málaga, Spain
- Medical School University of Malaga (UMA), Málaga, Spain
| | - Julio Santoyo Santoyo
- General and Digestive Surgery Department, Regional University Hospital of Malaga, Málaga, Spain
- Medical School University of Malaga (UMA), Málaga, Spain
| |
Collapse
|
4
|
Zhang JW, Ullah K, Khan N, Pan HT. Comprehensive profiling of serum microRNAs in normal and non-alcoholic fatty liver disease (NAFLD) patients. Sci Rep 2025; 15:3766. [PMID: 39885249 PMCID: PMC11782575 DOI: 10.1038/s41598-025-87791-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025] Open
Abstract
Pediatric non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide health concern with the potential to advance to cirrhosis and liver cancer. NAFLD can also directly contribute to heart problems through inflammation and insulin resistance, even in individuals without other risk factors. The pathological mechanisms of NAFLD are linked to functional differences of miRNAs in different biological environments. The miRNA in serum exosomes may reflect the pathological state of the liver and changes in systemic metabolism, while the miRNA in serum may be associated with physiological processes other than the liver. Pediatric non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide health concern with the potential to advance to cirrhosis and liver cancer. NAFLD can also directly contribute to heart problems through inflammation and insulin resistance, even in individuals without other risk factors. The pathological mechanisms of NAFLD are linked to functional differences of miRNAs in different biological environments. The miRNA in serum exosomes may reflect the pathological state of the liver and changes in systemic metabolism, while the miRNA in serum may be associated with physiological processes other than the liver. Pediatric non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide health concern with the potential to advance to cirrhosis and liver cancer. NAFLD can also directly contribute to heart problems through inflammation and insulin resistance, even in individuals without other risk factors. The pathological mechanisms of NAFLD are linked to functional differences of miRNAs in different biological environments. The miRNA in serum exosomes may reflect the pathological state of the liver and changes in systemic metabolism, while the miRNA in serum may be associated with physiological processes other than the liver. Our study identified 36 miRNAs with differential expression in the serum of NAFLD patients compared to the control group, including 21 miRNAs with significantly increased expression and 15 with decreased expression. Consistent with our previously reported data on serum-derived exosomal miRNA profiling, this study also observed a notable upregulation of serum miR-122-5p levels in NAFLD patients. PCR validation confirmed the differential expression of miR-122-5p identified through RNA sequencing. Functional analysis using GO and KEGG pathways revealed a diverse range of biological roles associated with these differentially expressed miRNAs. Notably, NAFLD significantly impacts heart health, with miR-122-5p playing a key role in regulating cardiovascular function. Furthermore, activation of the miR-122/Sirt-6/ACE2 axis may contribute to myocardial necrosis, highlighting its potential role in NAFLD-associated cardiovascular risks. Our study suggests that miR-122 plays a key role in the progression of NAFLD and its associated metabolic disturbances, which can increase the risk of cardiovascular disease. Targeting miR-122 may offer potential therapeutic benefits for improving both liver and heart health in individuals with NAFLD.
Collapse
Affiliation(s)
- Jian-Wei Zhang
- Shaoxing Maternity and Child Health Care Hospital, No. 222 Fenglin East Road, Shaoxing, 312000, Zhejiang, China
- Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Kamran Ullah
- Department of Biology, The University of Haripur, Haripur, KP, Pakistan
| | - Nauman Khan
- College of Animal Science and Technology, Northwest A & F University, Yangling, 712100, Shaanxi, China
| | - Hai-Tao Pan
- Shaoxing Maternity and Child Health Care Hospital, No. 222 Fenglin East Road, Shaoxing, 312000, Zhejiang, China.
- Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China.
| |
Collapse
|
5
|
Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab 2024; 15:20420188241242937. [PMID: 38628492 PMCID: PMC11020731 DOI: 10.1177/20420188241242937] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/22/2024] [Indexed: 04/19/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.
Collapse
Affiliation(s)
- Waleed Alghamdi
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh A. Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| |
Collapse
|
6
|
Dugbartey GJ. Cellular and molecular mechanisms of cell damage and cell death in ischemia-reperfusion injury in organ transplantation. Mol Biol Rep 2024; 51:473. [PMID: 38553658 PMCID: PMC10980643 DOI: 10.1007/s11033-024-09261-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 01/16/2024] [Indexed: 04/02/2024]
Abstract
Ischemia-reperfusion injury (IRI) is a critical pathological condition in which cell death plays a major contributory role, and negatively impacts post-transplant outcomes. At the cellular level, hypoxia due to ischemia disturbs cellular metabolism and decreases cellular bioenergetics through dysfunction of mitochondrial electron transport chain, causing a switch from cellular respiration to anaerobic metabolism, and subsequent cascades of events that lead to increased intracellular concentrations of Na+, H+ and Ca2+ and consequently cellular edema. Restoration of blood supply after ischemia provides oxygen to the ischemic tissue in excess of its requirement, resulting in over-production of reactive oxygen species (ROS), which overwhelms the cells' antioxidant defence system, and thereby causing oxidative damage in addition to activating pro-inflammatory pathways to cause cell death. Moderate ischemia and reperfusion may result in cell dysfunction, which may not lead to cell death due to activation of recovery systems to control ROS production and to ensure cell survival. However, prolonged and severe ischemia and reperfusion induce cell death by apoptosis, mitoptosis, necrosis, necroptosis, autophagy, mitophagy, mitochondrial permeability transition (MPT)-driven necrosis, ferroptosis, pyroptosis, cuproptosis and parthanoptosis. This review discusses cellular and molecular mechanisms of these various forms of cell death in the context of organ transplantation, and their inhibition, which holds clinical promise in the quest to prevent IRI and improve allograft quality and function for a long-term success of organ transplantation.
Collapse
Affiliation(s)
- George J Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana.
- Department of Physiology & Pharmacology, Accra College of Medicine, East Legon, Accra, Ghana.
| |
Collapse
|
7
|
Xu Y, Xue W, Gao H, Cui J, Zhao L, You C. Association of toll-like receptors single nucleotide polymorphisms with HBV and HCV infection: research status. PeerJ 2022; 10:e13335. [PMID: 35462764 PMCID: PMC9029363 DOI: 10.7717/peerj.13335] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 04/04/2022] [Indexed: 01/13/2023] Open
Abstract
Background Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have become increasingly severe worldwide and are a threat to public health. There have been a number of studies conducted recently on the relationship of single nucleotide polymorphisms (SNPs) to innate immune receptor genes such as toll-like receptors (TLRs). Some literature suggests that SNPs of TLRs are associated with HBV and HCV infection. We summarized the role of TLRs gene polymorphisms associated with HBV and HCV infections and explored their possible mechanisms of action. Methodology PubMed and Web of Science were used to perform the literature review. Related articles and references were identified and used to analyze the role of TLRs gene polymorphism in HBV and HCV infection. Results TLRs gene polymorphisms may have beneficial or detrimental effects in HBV and HCV infection, and some SNPs can affect disease progression or prognosis. They affect the disease state by altering gene expression or protein synthesis; however, the mechanism of action is not clearly understood. Conclusions Single nucleotide polymorphisms of TLRs play a role in HBV and HCV infection, but the mechanism of action still needs to be explored in future studies.
Collapse
Affiliation(s)
- Yaxin Xu
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Wentao Xue
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Hongwei Gao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Jiabo Cui
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Lingzhi Zhao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| | - Chongge You
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China
| |
Collapse
|
8
|
Abstract
Severe allograft dysfunction, as opposed to the expected immediate function, following liver transplantation is a major complication, and the clinical manifestations of such that lead to either immediate retransplant or death are the catastrophic end of the spectrum. Primary nonfunction (PNF) has declined in incidence over the years, yet the impact on patient and healthcare teams, and the burden on the organ pool in case of the need for retransplant should not be underestimated. There is no universal test to define the diagnosis of PNF, and current criteria are based on various biochemical parameters surrogate of liver function; moreover, a disparity remains within different healthcare systems on selecting candidates eligible for urgent retransplantation. The impact on PNF from traditionally accepted risk factors has changed somewhat, mainly driven by the rising demand for organs, combined with the concerted approach by clinicians on the in-depth understanding of PNF, optimal graft recipient selection, mitigation of the clinical environment in which a marginal graft is reperfused, and postoperative management. Regardless of the mode, available data suggest machine perfusion strategies help reduce the incidence further but do not completely avert the risk of PNF. The mainstay of management relies on identifying severe allograft dysfunction at a very early stage and aggressive management, while excluding other identifiable causes that mimic severe organ dysfunction. This approach may help salvage some grafts by preventing total graft failure and also maintaining a patient in an optimal physiological state if retransplantation is considered the ultimate patient salvage strategy.
Collapse
Affiliation(s)
- Hermien Hartog
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | | | | |
Collapse
|
9
|
Wei Q, Zhou J, Wang K, Zhang X, Chen J, Lu D, Wei X, Zheng S, Xu X. Combination of Early Allograft Dysfunction and Protein Expression Patterns Predicts Outcome of Liver Transplantation From Donation After Cardiac Death. Front Med (Lausanne) 2021; 8:775212. [PMID: 34957150 PMCID: PMC8692269 DOI: 10.3389/fmed.2021.775212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/12/2021] [Indexed: 11/13/2022] Open
Abstract
Early allograft dysfunction (EAD) after liver transplantation (LT) accompanies poor prognosis. This study aims to explore the relationship between pretransplant intrahepatic proteins and the incidence of EAD, and the value of combined EAD and protein profiles for predicting recipient and graft survival prognosis. Liver biopsy specimens of 105 pretransplant grafts used for LT were collected and used for immunohistochemistry analysis of 5 proteins. And matched clinical data of donor, recipient, transplantation, and prognosis were analyzed. The incidence of EAD was 41.9% (44/105) in this cohort. Macrovesicular steatosis (P = 0.016), donor body mass index (P = 0.013), recipients' pretransplant serum creatinine (P = 0.036), and intrahepatic expression of heme oxygenase 1 (HO1) (P = 0.015) and tumor necrosis factor α (TNF-α) (P = 0.039) were independent predictors of EAD. Inferior graft and recipient prognosis were observed in patients who experienced EAD (P = 0.028 and 0.031) or received grafts with higher expression of sirtuin 1 (P = 0.005 and 0.013). The graft and recipient survival were worst in patients with both EAD and high expression of sirtuin 1 (P = 0.001 and 0.004). In conclusion, pretransplant intrahepatic expression of HO1 and TNF-α are associated with the incidence of EAD. The combination of EAD and EAD-unrelated proteins showed superiority in distinguishing recipients with worse prognosis.
Collapse
Affiliation(s)
- Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,National Health Commission Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Junbin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,National Health Commission Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Kun Wang
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xuanyu Zhang
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,National Health Commission Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junli Chen
- China Liver Transplant Registery, Hangzhou, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,National Health Commission Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,National Health Commission Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Shusen Zheng
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,National Health Commission Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,National Health Commission Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
10
|
Salum GM, el Meguid MA, Abelhafez TH, Medhat E, Abdel Aziz AO, Dawood R. Evaluation of seven gene signature for predicting HCV recurrence post-liver transplantation. J Genet Eng Biotechnol 2021; 19:174. [PMID: 34757522 PMCID: PMC8581076 DOI: 10.1186/s43141-021-00266-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 10/05/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Orthotropic liver transplantation (OLT) offers a therapeutic choice for hepatocellular carcinoma (HCC) patients. The poor outcome of liver transplantation is HCV recurrence. Several genome-wide associated studies (GWAS) have reported many genetic variants to be associated with HCV recurrence. Seven gene polymorphisms formed a cirrhosis risk score (CRS) signature that could be used to distinguish chronic HCV patients at high risk from those at low risk for cirrhosis in non-transplant patients. This study aims to examine the association of CRS score and other clinical parameters with the probability for HCC emergence and/or the rate of HCV recurrence following liver transplantation. RESULTS Seven gene polymorphisms, forming the CRS, were genotyped by real-time PCR using allelic discrimination protocol in 199 end-stage liver disease patients (79 child A, 43 child B, and 77child C), comprising 106 patients who encountered liver transplantation. Recipient CRS scores were correlated with HCV recurrence (HCV-Rec) at the end of the third year after OLT. Around 81% (39) recipients with low steatosis (LS; < 3.5%) donor percentage revealed no HCV recurrence (non-Rec) (p<0.001). CRS score could distinguish between child A, child B, and child C only at the low-risk group. Among the HCV Rec group 27% (8/30), 40% (12/30), and 33% (10/30) fell into the high, moderate, and low CRS risk groups, respectively. Stepwise logistic regression evinced two features more likely to be seen in HCV-Rec patients: abnormal ALT [OR, 1.1; 95% CI, 1.02-1.2] and donor steatosis >3.5% [OR, 46.07; 95% CI, 1.5-1407.8]. CONCLUSIONS Accordingly, the CRS score seems to be less useful to predict HCV recurrence after OLT. ALT and donor steatosis (exceed 3.5%) can significantly promote the HCV recurrence post-OLT. Moreover, the combination of MMF and CNI positively heightens HCV recurrence.
Collapse
Affiliation(s)
- Ghada M. Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, Dokki, P.O. 12622, Giza, Egypt
| | - Mai Abd el Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, Dokki, P.O. 12622, Giza, Egypt
| | - Tawfeek H. Abelhafez
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, Dokki, P.O. 12622, Giza, Egypt
| | - Eman Medhat
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ashraf O. Abdel Aziz
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Reham Dawood
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, Dokki, P.O. 12622, Giza, Egypt
| |
Collapse
|
11
|
Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation. Genes Immun 2021; 22:35-43. [PMID: 33627833 PMCID: PMC7903020 DOI: 10.1038/s41435-021-00122-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 01/19/2021] [Accepted: 01/27/2021] [Indexed: 02/01/2023]
Abstract
UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.
Collapse
|
12
|
Chen Q, Wang Y, Jiao F, Shi C, Pei M, Wang L, Gong Z. Betaine inhibits Toll-like receptor 4 responses and restores intestinal microbiota in acute liver failure mice. Sci Rep 2020; 10:21850. [PMID: 33318565 PMCID: PMC7736280 DOI: 10.1038/s41598-020-78935-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
Previous research has revealed that the gut microbiome has a marked impact on acute liver failure (ALF). Here, we evaluated the impact of betaine on the gut microbiota composition in an ALF animal model. The potential protective effect of betaine by regulating Toll-like receptor 4 (TLR4) responses was explored as well. Both mouse and cell experiments included normal, model, and betaine groups. The rat small intestinal cell line IEC-18 was used for in vitro experiments. Betaine ameliorated the small intestine tissue and IEC-18 cell damage in the model group by reducing the high expression of TLR4 and MyD88. Furthermore, the intestinal permeability in the model group was improved by enhancing the expression of the (ZO)-1 and occludin tight junction proteins. There were 509 operational taxonomic units (OTUs) that were identified in mouse fecal samples, including 156 core microbiome taxa. Betaine significantly improved the microbial communities, depleted the gut microbiota constituents Coriobacteriaceae, Lachnospiraceae, Enterorhabdus and Coriobacteriales and markedly enriched the taxa Bacteroidaceae, Bacteroides, Parabacteroides and Prevotella in the model group. Betaine effectively improved intestinal injury in ALF by inhibiting the TLR4/MyD88 signaling pathway, improving the intestinal mucosal barrier and maintaining the gut microbiota composition.
Collapse
Affiliation(s)
- Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Fangzhou Jiao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Chunxia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Maohua Pei
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Luwen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| |
Collapse
|
13
|
Zhou J, Chen J, Wei Q, Saeb-Parsy K, Xu X. The Role of Ischemia/Reperfusion Injury in Early Hepatic Allograft Dysfunction. Liver Transpl 2020; 26:1034-1048. [PMID: 32294292 DOI: 10.1002/lt.25779] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/15/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022]
Abstract
Liver transplantation (LT) is the only available curative treatment for patients with end-stage liver disease. Early allograft dysfunction (EAD) is a life-threatening complication of LT and is thought to be mediated in large part through ischemia/reperfusion injury (IRI). However, the underlying mechanisms linking IRI and EAD after LT are poorly understood. Most previous studies focused on the clinical features of EAD, but basic research on the underlying mechanisms is insufficient, due, in part, to a lack of suitable animal models of EAD. There is still no consensus on definition of EAD, which hampers comparative analysis of data from different LT centers. IRI is considered as an important risk factor of EAD, which can induce both damage and adaptive responses in liver grafts. IRI and EAD are closely linked and share several common pathways. However, the underlying mechanisms remain largely unclear. Therapeutic interventions against EAD through the amelioration of IRI is a promising strategy, but most approaches are still in preclinical stages. To further study the mechanisms of EAD and promote collaborations between LT centers, optimized animal models and unified definitions of EAD are urgently needed. Because IRI and EAD are closely linked, more attention should be paid to the underlying mechanisms and the fundamental relationship between them. Ischemia/reperfusion-induced adaptive responses may play a crucial role in the prevention of EAD, and more preclinical studies and clinical trials are urgently needed to address the current limitation of available therapeutic interventions.
Collapse
Affiliation(s)
- Junbin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Jian Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom.,Cambridge National Institute of Health Research Biomedical research Centre, Cambridge, United Kingdom
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| |
Collapse
|
14
|
Risk factors, surgical complications and graft survival in liver transplant recipients with early allograft dysfunction. Hepatobiliary Pancreat Dis Int 2019; 18:423-429. [PMID: 30853253 DOI: 10.1016/j.hbpd.2019.02.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 02/18/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Early allograft dysfunction (EAD) is a severe complication after liver transplantation. The associated risk factors and complications have re-gained recent interest. This study investigated risk factors, survival and complications associated with EAD in a large liver transplant center in Latin America. METHODS Retrospective, unicenter, cohort, based on data from adult patients undergoing first deceased-donor liver transplant from January 2009 to December 2013. EAD was defined by one or more of the following: (i) bilirubin ≥10 mg/dL on postoperative day 7; (ii) international normalized ratio ≥1.6 on postoperative day 7, and (iii) alanine aminotransferase or aspartate aminotransferase >2000 IU/L within the first seven days after transplant. RESULTS A total of 602 patients were included; of these 34.2% developed EAD. Donor risk factors were male (P = 0.007), age between 50 and 59 years (P = 0.034), overweight (P = 0.028) or grade I obesity (P = 0.012), sodium >157 mmol/L (P = 0.002) and grade IV ischemia/reperfusion injury (P = 0.002). Cold ischemia time ≥10 h (P = 0.008) and warm ischemia time ≥40 min (P = 0.013) were the surgical factors. Male (P <0.001) was the only recipient protective factor. Compared with the non-EAD group, patients with EAD were submitted to more reoperations (24.3% vs. 13.4%, P = 0.001) and had higher graft loss rates (37.9% vs. 21.2%, P <0.001), with similar patient survival rates (P = 0.238). CONCLUSIONS EAD risk factors are related to donor, surgical procedure and recipient. Donor risk factors for EAD were male, age between 50 and 59 years, donor overweight or grade I obesity, sodium >157 mmol/L and grade IV ischemia/reperfusion injury. Cold ischemia time ≥10 h and warm ischemia time ≥40 min were the surgical risk factors. Male was the only recipient protective factor. Patients with EAD had higher reoperations and graft loss rates.
Collapse
|
15
|
Aragonès G, Colom-Pellicer M, Aguilar C, Guiu-Jurado E, Martínez S, Sabench F, Antonio Porras J, Riesco D, Del Castillo D, Richart C, Auguet T. Circulating microbiota-derived metabolites: a "liquid biopsy? Int J Obes (Lond) 2019; 44:875-885. [PMID: 31388096 DOI: 10.1038/s41366-019-0430-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/08/2019] [Accepted: 06/30/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND/OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, from simple steatosis (SS) to cirrhosis. SS and non-alcoholic steatohepatitis (NASH) cannot be distinguished by clinical or laboratory features. Dysregulation of the gut microbiota is involved in NASH pathogenesis. The aim of this study was to assess the relationship between microbiota-derived metabolites and the degrees of NAFLD; also, to investigate whether these metabolites could be included in a panel of NASH biomarkers. SUBJECTS/METHODS We used liquid chromatography coupled to triple-quadrupole-mass spectrometry (LC-QqQ) analysis to quantify choline and its derivatives, betaine, endogenous ethanol, bile acids, short-chain fatty acids and soluble TLR4 in serum from women with normal weight (n = 29) and women with morbid obesity (MO) (n = 82) with or without NAFLD. We used real-time polymerase chain reaction (RT-PCR) analysis to evaluate the hepatic and intestinal expression level of all genes studied (TLR2, TLR4, TLR9, LXRα, SREBP1C, ACC1, FAS, PPARα, CPT1α, CROT, SREBP2, ABCA1, ABCG1 and FXR in the liver; TLR2, TLR4, TLR5, TLR9, GLP-1R, DPP-4, FXR and PPARɣ in the jejunum) in 82 women with MO with normal liver histology (NL, n = 29), SS (n = 32), and NASH (n = 21). RESULTS Hepatic FAS, TLR2, and TLR4 expression were overexpressed in NAFLD patients. TLR2 was overexpressed in NASH patients. In women with MO with NAFLD, we found upregulation of intestinal TLR9 expression and downregulation of intestinal FXR expression in women with NASH. Circulating TMAO, glycocholic acid and deoxycholic acid levels were significantly increased in NAFLD patients. Endogenous circulating ethanol levels were increased in NASH patients in comparison to those in SS patients. CONCLUSIONS These findings suggest that the intestine participates in the progression of NAFLD. Moreover, levels of certain circulating microbiota-related metabolites are associated with NAFLD severity and could be used as a "liquid biopsy" in the noninvasive diagnosis of NASH.
Collapse
Affiliation(s)
- Gemma Aragonès
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain
| | - Marina Colom-Pellicer
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain
| | - Carmen Aguilar
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain
| | - Esther Guiu-Jurado
- IFB-Adiposity Diseases, Leipzig University, Liebigstraße 19-21, 04103, Leipzig, Germany
| | - Salomé Martínez
- Servei Anatomia Patològica, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - Fàtima Sabench
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, Avinguda Doctor Josep Laporte, 2, 43204, Reus, Spain
| | - José Antonio Porras
- Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - David Riesco
- Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - Daniel Del Castillo
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, Avinguda Doctor Josep Laporte, 2, 43204, Reus, Spain
| | - Cristóbal Richart
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain.,Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - Teresa Auguet
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain. .,Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain.
| |
Collapse
|
16
|
Shi S, Verstegen MMA, Mezzanotte L, de Jonge J, Löwik CWGM, van der Laan LJW. Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective. Liver Transpl 2019; 25:1091-1104. [PMID: 31077562 PMCID: PMC6617733 DOI: 10.1002/lt.25488] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/22/2019] [Indexed: 12/13/2022]
Abstract
Cell death is a natural process for the turnover of aged cells, but it can also arise as a result of pathological conditions. Cell death is recognized as a key feature in both acute and chronic hepatobiliary diseases caused by drug, alcohol, and fat uptake; by viral infection; or after surgical intervention. In the case of chronic disease, cell death can lead to (chronic) secondary inflammation, cirrhosis, and the progression to liver cancer. In liver transplantation, graft preservation and ischemia/reperfusion injury are associated with acute cell death. In both cases, so-called programmed cell death modalities are involved. Several distinct types of programmed cell death have been described of which apoptosis and necroptosis are the most well known. Parenchymal liver cells, including hepatocytes and cholangiocytes, are susceptible to both apoptosis and necroptosis, which are triggered by distinct signal transduction pathways. Apoptosis is dependent on a proteolytic cascade of caspase enzymes, whereas necroptosis induction is caspase-independent. Moreover, different from the "silent" apoptotic cell death, necroptosis can cause a secondary inflammatory cascade, so-called necroinflammation, triggered by the release of various damage-associated molecular patterns (DAMPs). These DAMPs activate the innate immune system, leading to both local and systemic inflammatory responses, which can even cause remote organ failure. Therapeutic targeting of necroptosis by pharmacological inhibitors, such as necrostatin-1, shows variable effects in different disease models.
Collapse
Affiliation(s)
- Shaojun Shi
- Department of SurgeryErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
| | | | - Laura Mezzanotte
- Department of RadiologyErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
| | - Jeroen de Jonge
- Department of SurgeryErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
| | | | | |
Collapse
|
17
|
Early graft dysfunction after liver transplant: Comparison of different diagnostic criteria in a single-center prospective cohort. Med Intensiva 2018; 44:150-159. [PMID: 30528954 DOI: 10.1016/j.medin.2018.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/23/2018] [Accepted: 09/05/2018] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Comparison of different diagnostic criteria for early liver allograft dysfunction (EAD) and their capability to predict mortality. DESIGN Single-center, prospective, cohort study. SETTINGS ICU in a Regional Hospital with a liver transplant program since 1997. PATIENTS 253 consecutive patients admitted to our ICU immediately after liver transplantation between 2009 and 2015. VARIABLES OF INTEREST Differences in the incidence of EAD and its relation with ICU, Hospital and 2-year mortality depending on the definition applied using as comparator the UNOS (United Network for Organ Sharing) primary non-function criterion. RESULTS The incidence of early liver allograft dysfunction according to UNOS was 13.8%, to Makowka 6.3%, to Ardite 10.7%, to Nanashima 20.6%, to Dhillon 30.8% and to MEAF 13.4%. Kappa test did not show a good correlation among these criteria. EAD was related with ICU mortality for all diagnostic criteria except Dhillon but only UNOS, Makowka and MEAF were associated with 2-year mortality. Hospital mortality was poorly predicted by all criteria except for the MEAF score. CONCLUSION We found a poor agreement between different criteria analyzed for the diagnosis of EAD. In our population, the MEAF score showed the best relationship with short- and long-term mortality.
Collapse
|
18
|
Zhang R, Zhu ZJ, Sun LY, Wei L, Qu W. Outcomes of Liver Transplantation Using Pediatric Deceased Donor Livers: A Single-Center Analysis of 102 Donors. Chin Med J (Engl) 2018; 131:677-683. [PMID: 29521290 PMCID: PMC5865313 DOI: 10.4103/0366-6999.226901] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The outcome of pediatric deceased donor liver transplantation (LT) has not been well studied, especially pediatric deceased donor livers used in adult transplantation. This study aimed to evaluate the efficacy of LT using pediatric deceased donor livers and compare the outcomes between pediatric-to-pediatric LT and pediatric-to-adult LT. METHODS A retrospective review of LT using pediatric deceased donor livers from June 2013 to August 2016 was performed. The patients were divided into the pediatric-to-pediatric LT group and pediatric-to-adult LT group based on the ages of the recipients. The survival and incidence of early vascular complications (VCs) were observed between the two groups. We also analyzed the risk factors of early VCs in pediatric LT and the effect of donor hypernatremia on the prognosis of recipients. RESULTS There were 102 cases of LT using pediatric deceased donor livers in our hospital from June 2013 to August 2016, 83 pediatric-to-pediatric LT (recipients' age ≤13 years) and 19 pediatric-to-adult LT (recipients' age ≥19 years). The ratio of early VC was similar in the two groups (19.3% vs. 10.6%, P = 0.514). Low body weight of recipient was an independent risk factor of early VC in pediatric LT (odds ratio: 0.856, 95% confidence interval: 0.752-0.975, P = 0.019). The 1-year cumulative survival rates of grafts and patients were 89.16% and 91.57% in pediatric-to-pediatric LT and 89.47% and 94.74% in pediatric-to-adult LT, respectively (all P > 0.05). In all cases, patients using donors with hypernatremia (serum sodium levels ≥150 mmol/L) had worse graft survival (χ2=4.330, P = 0.037). CONCLUSIONS Pediatric-to-pediatric LT group has similar graft and patient survival rates with those of pediatric-to-adult LT group. Low body weight of recipients is an independent risk factor of early VC in pediatric LT. Patients using donors with hypernatremia have worse graft survival.
Collapse
Affiliation(s)
- Rui Zhang
- Liver Transplantation Center, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- Department of Hepatobiliary and Pancreatic Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, China
| | - Zhi-Jun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Li-Ying Sun
- Liver Transplantation Center, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lin Wei
- Liver Transplantation Center, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wei Qu
- Liver Transplantation Center, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| |
Collapse
|
19
|
Kim JS, Kwon JH, Kim KW, Kim SY, Choi SH, Song GW, Lee SG. Low Graft Attenuation at Unenhanced CT: Association with 1-Month Mortality or Graft Failure after Liver Transplantation. Radiology 2017; 287:167-175. [PMID: 29267144 DOI: 10.1148/radiol.2017171144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Purpose To investigate whether low graft attenuation at unenhanced computed tomography (CT) is associated with 1-month mortality or graft failure after liver transplant and determine its diagnostic performance. Materials and Methods Included were 663 recipients who underwent CT imaging within 7 days after liver transplant between December 2014 and August 2016. Initial poor function (IPF) was diagnosed by using a combination of laboratory values within 7 days after liver transplant and subdivided patients into primary and secondary IPF. At 1 month after the operation, mortality and graft failure or survival in recipients was categorized. Two radiologists who were blinded to clinical data retrospectively and independently evaluated graft attenuation on unenhanced CT images (high or isoattenuation, graft attenuation greater than or equal to that of spleen; low, graft attenuation less than that of spleen). The interobserver agreement was evaluated by using intraclass correlation coefficient and κ statics. Incidence of low graft attenuation between recipients with IPF and those with normal function was compared by using χ2 test. The relationship between graft attenuation and outcome in primary and secondary IPF was evaluated by using log-rank test. Results Of 663 recipients, 114 had IPF (80 primary; 34 secondary). After 1 month, 11 had graft failure or died, whereas 652 survived. Low graft attenuation was more common in patients with IPF than in normal-function patients (P < .001). In the primary group (those without identifiable cause), 15 patients had low graft attenuation, which led to mortality or graft failure within 1 month in seven of those patients. No recipient with high or isoattenuation had 1-month mortality or graft failure (P < .001). The secondary group (those with identifiable cause) showed no significant association between graft attenuation and 1-month mortality and graft failure (P = .181). Values of low graft attenuation for 1-month mortality and graft failure in primary IPF were positive predictive value, 46.7%; negative predictive value, 100%; sensitivity, 100%; specificity, 89.0%; and accuracy, 90.0%. There was excellent interobserver agreement in the assessment of graft attenuation (intraclass correlation coefficient, 0.957; κ = 1.00). Conclusion Low graft attenuation can be associated with 1-month mortality or graft failure in liver graft recipients with primary IPF. © RSNA, 2017.
Collapse
Affiliation(s)
- Jin Sil Kim
- From the Department of Radiology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea (J.S.K.); Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery (J.H.K., G.W.S., S.G.L.), and Department of Radiology and Research Institute of Radiology (K.W.K., S.Y.K., S.H.C.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
| | - Jae Hyun Kwon
- From the Department of Radiology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea (J.S.K.); Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery (J.H.K., G.W.S., S.G.L.), and Department of Radiology and Research Institute of Radiology (K.W.K., S.Y.K., S.H.C.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
| | - Kyoung Won Kim
- From the Department of Radiology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea (J.S.K.); Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery (J.H.K., G.W.S., S.G.L.), and Department of Radiology and Research Institute of Radiology (K.W.K., S.Y.K., S.H.C.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
| | - So Yeon Kim
- From the Department of Radiology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea (J.S.K.); Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery (J.H.K., G.W.S., S.G.L.), and Department of Radiology and Research Institute of Radiology (K.W.K., S.Y.K., S.H.C.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
| | - Sang Hyun Choi
- From the Department of Radiology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea (J.S.K.); Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery (J.H.K., G.W.S., S.G.L.), and Department of Radiology and Research Institute of Radiology (K.W.K., S.Y.K., S.H.C.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
| | - Gi Won Song
- From the Department of Radiology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea (J.S.K.); Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery (J.H.K., G.W.S., S.G.L.), and Department of Radiology and Research Institute of Radiology (K.W.K., S.Y.K., S.H.C.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
| | - Sung Gyu Lee
- From the Department of Radiology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea (J.S.K.); Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery (J.H.K., G.W.S., S.G.L.), and Department of Radiology and Research Institute of Radiology (K.W.K., S.Y.K., S.H.C.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
| |
Collapse
|
20
|
Song JL, Yang J, Yan LN, Yang JY, Wen TF, Li B, Zeng Y, Wu H, Wang WT, Xu MQ, Chen ZY, Wei YG, Jiang L. A new index predicts early allograft dysfunction following living donor liver transplantation: A propensity score analysis. Dig Liver Dis 2017; 49:1225-1232. [PMID: 28750872 DOI: 10.1016/j.dld.2017.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 06/08/2017] [Accepted: 06/12/2017] [Indexed: 01/10/2023]
Abstract
OBJECTIVE/AIM The aim of this study was to identify a new index to predict early allograft dysfunction following living donor liver transplantation. METHODS The study enrolled 260 adult living donor liver transplantation recipients. Postoperative laboratory variables were assessed for their association with the prevalence of early allograft dysfunction using the inverse probability of treatment weighting and propensity-score matching (n=93 pairs) analysis. RESULTS Forty-seven recipients (18.1%) developed early allograft dysfunction. In multivariable analysis, the alanine aminotransferase and gamma-glutamyl transpeptidase levels on postoperative day 1 were independent predictors of early allograft dysfunction. The alanine aminotransferase to gamma-glutamyl transpeptidase ratio (AGR) was developed. All cases were divided into two groups (Group 1 [AGR≥8.47, n=103] and Group 2 [AGR<8.47, n=157]). AGR≥8.47 (OR 10.345, 95%CI 4.502-23.772, p<0.001), hepatorenal syndrome (OR 3.016, 95%CI 1.119-8.125, p=0.029), and graft to recipient weight ratio <0.8% (OR 2.155, 95%CI 1.004-4.624, p=0.049) were independent risk factors for early allograft dysfunction. The prevalence of early allograft dysfunction was higher in group 1 (after adjusting for inverse probability of treatment weighting [n=39; 37.9% vs n=8; 5.1%] and propensity-score matching [n=33; 35.5% vs n=2; 2.2%]) than that in group 2 (p<0.001). CONCLUSIONS The postoperative AGR is a practical index for predicting early allograft dysfunction after living donor liver transplantation.
Collapse
Affiliation(s)
- Jiu-Lin Song
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Jian Yang
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Lu-Nan Yan
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Jia-Yin Yang
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Tian-Fu Wen
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Bo Li
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Yong Zeng
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Hong Wu
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Wen-Tao Wang
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Ming-Qing Xu
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Zhe-Yu Chen
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Yong-Gang Wei
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Li Jiang
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China.
| |
Collapse
|
21
|
Abstract
The Wingless-type MMTV integration site family member 2b (Wnt2b) has been found to be a principal mediator of liver development and regeneration. However, the significance of Wnt2b in the pathogenesis of fibrosis-related liver diseases remains undefined. Here, we report that Wnt2b was highly expressed in the fibrotic liver tissues, exhibiting protective effects against activation of hepatic stellate cells (HSCs) and fibrosis progression. We identified a negative regulation of Wnt2b on the toll-like receptor 4 (TLR4) activation-mediated pro-fibrogenic effects. Wnt2b was shown not only to directly suppress LPS-induced HSCs activation, but also to inhibit TLR4-enhanced the sensitivity of HSCs to transforming growth factor beta (TGF-β). Mechanistic study showed that Wnt2b suppresses TLR4 signaling through inhibiting the expression of TLR4 as well as the activation of NF-κB and MAPKs. These findings provided new insights into the pathophysiology of liver fibrosis by characterizing Wnt2b as a novel endogenous suppressor of TLR4 signaling, maintaining tissue homeostasis during the early stage of hepatic fibrosis-associated liver diseases.
Collapse
|
22
|
Li X, Wu Y, Zhang W, Gong J, Cheng Y. Pre-conditioning with tanshinone IIA attenuates the ischemia/reperfusion injury caused by liver grafts via regulation of HMGB1 in rat Kupffer cells. Biomed Pharmacother 2017; 89:1392-1400. [PMID: 28320107 DOI: 10.1016/j.biopha.2017.03.022] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/27/2017] [Accepted: 03/07/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE We have evaluated the protective mechanism of tanshinone IIA in ischemia/reperfusion injury (IRI) induced by liver grafts, revealing novel supplementary immunotherapy for liver transplantation. METHODS The tanshinone IIA preconditioning group (TP group) was pretreated with tanshinone IIA via intraperitoneal injection for 1 week before receiving orthotopic liver transplantation with hepatic arterial ischemia for 30min. The sham-operation group (SO group), control graft group (CG group) and IRI group were pretreated with an equivalent volume of normal saline. The IRI group and CG group received orthotopic liver transplantation with or without hepatic arterial ischemia. Rats were sacrificed at each time point, serum was collected for ELISA detection, and Kupffer cells (KCs) were isolated to extract total protein and RNA for western blotting and real-time PCR, respectively. RESULTS The levels of TNF-α and IL-4 in the TP group were significantly lower than those of in the IRI group; meanwhile the IL-10 and TGF-β levels were significantly higher than in the IRI group. The protein and mRNA expression levels of HMGB1 were significantly lower in TP group than in the IRI group at each time point. The TLR-4, Myd88, NLRP3 and p-NF-κb p65 expression levels in the TP groups were significantly lower than those in the IRI group, while the PTEN, PI3K and AKT phosphorylation levels in the TP groups were significantly higher than those in the IRI group. CONCLUSIONS Tanshinone IIA attenuates IRI caused by liver grafts via down-regulation of the HMGB1-TLR-4/NF-κb pathway in KCs and activation of PTEN/PI3K/AKT pathway, suggesting a potential role for prevention of liver cell IRI during liver transplantation.
Collapse
Affiliation(s)
- Xuanfei Li
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Yakun Wu
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan, 629000, PR China
| | - Wenfeng Zhang
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China
| | - Jianping Gong
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
| | - Yao Cheng
- Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
| |
Collapse
|
23
|
Neves DB, Rusi MB, Diaz LGG, Salvalaggio P. Primary graft dysfunction of the liver: definitions, diagnostic criteria and risk factors. ACTA ACUST UNITED AC 2016; 14:567-572. [PMID: 27783749 DOI: 10.1590/s1679-45082016rw3585] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/09/2016] [Indexed: 12/11/2022]
Abstract
Primary graft dysfunction is a multifactorial syndrome with great impact on liver transplantation outcomes. This review article was based on studies published between January 1980 and June 2015 and retrieved from PubMed database using the following search terms: "primary graft dysfunction", "early allograft dysfunction", "primary non-function" and "liver transplantation". Graft dysfunction describes different grades of graft ischemia-reperfusion injury and can manifest as early allograft dysfunction or primary graft non-function, its most severe form. Donor-, surgery- and recipient-related factors have been associated with this syndrome. Primary graft dysfunction definition, diagnostic criteria and risk factors differ between studies. RESUMO A disfunção primária do enxerto hepático é uma síndrome multifatorial com grande impacto no resultado do transplante de fígado. Foi realizada uma ampla revisão da literatura, consultando a base de dados PubMed, em busca de estudos publicados entre janeiro de 1980 e junho de 2015. Os termos descritivos utilizados foram: "primary graft dysfunction", "early allograft dysfunction", "primary non-function" e "liver transplantation". A disfunção traduz graus diferentes da lesão de isquemia e reperfusão do órgão, e pode se manifestar como disfunção precoce ou, na forma mais grave, pelo não funcionamento primário do enxerto. Fatores relacionados ao doador, ao transplante e ao receptor contribuem para essa síndrome. Existem definições diferentes na literatura quanto ao diagnóstico e aos fatores de risco associados à disfunção primária.
Collapse
Affiliation(s)
- Douglas Bastos Neves
- Hospital Federal dos Servidores do Estado, Rio de Janeiro, RJ, Brazil; Hospital São Vicente de Paulo, Rio de Janeiro, RJ, Brazil.,Programa de Pós-graduação em Ciências da Saúde, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | | | | | | |
Collapse
|
24
|
Kim JS, Kwon JH, Kim KW, Kim J, Kim SY, Jeong WK, Park SH, Yu E, Lee J, Lee SJ, Lee JS, Kim HJ, Song GW, Lee SG. CT Features of Primary Graft Nonfunction after Liver Transplantation. Radiology 2016; 281:465-473. [PMID: 27152552 DOI: 10.1148/radiol.2016152157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Purpose To determine computed tomographic (CT) features of primary graft nonfunction (PNF) after liver transplantation in comparison with those of early graft failure or death by identifiable causes. Materials and Methods Institutional review board approval was obtained and informed consent was waived. Among 3947 adult liver transplantations performed in one institution between May 2002 and May 2015, 72 patients died or had graft failure within 10 days, and 38 of them were evaluated with CT. PNF was diagnosed in 21 patients. The other 17 patients who died or had early graft failure were considered the non-PNF control group. On unenhanced CT images, graft attenuation was compared qualitatively. Graft attenuation was measured quantitatively and, if available, the difference between preoperative and postoperative CT (interval change) attenuation was evaluated. Unenhanced CT was evaluated for relative parenchymal enhancement. Statistical analyses included the Fisher exact and χ2 tests with Yates correction and the Student t test. Results On unenhanced CT images, grafts with PNF more commonly showed low (eight of 26 [31%]) or extremely low (18 of 26 [69%]) qualitative attenuation compared with grafts in the non-PNF group (three of 21 [14%], one of 21 [5%]; P < .001). The mean attenuation value (30.5 HU ± 10.8) was significantly lower and the mean interval change (24.7 HU ± 12.5) was significantly higher in the PNF group than in the non-PNF group (49.7 HU ± 8.0 and 9.7 HU ± 10.1, respectively; P < .001 and P = .001). There was no significant difference in the proportion of grafts that showed poor enhancement on postcontrast CT images between the PNF group and the non-PNF group (nine of 24 [38%] vs two of 20 [10%], respectively; P = .08). Conclusion Recipients with PNF after liver transplantation tended to show low or extremely low attenuation on unenhanced CT images, and this finding was seen more frequently in patients with PNF than in those who died of identifiable causes and in those with early graft failure. © RSNA, 2016 Online supplemental material is available for this article.
Collapse
Affiliation(s)
- Jin Sil Kim
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Jae Hyun Kwon
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Kyoung Won Kim
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Jihun Kim
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - So Yeon Kim
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Woo Kyoung Jeong
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - So Hyun Park
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Eunsil Yu
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Jeongjin Lee
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - So Jung Lee
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Jong Seok Lee
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Hyoung Jung Kim
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Gi Won Song
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| | - Sung Gyu Lee
- From the Department of Radiology (J.S.K., K.W.K., S.Y.K., S.H.P., S.J.L., J.S.L., H.J.K.), Division of Liver Transplantation and Hepatobiliary Surgery, and Departments of Surgery (J.H.K., G.W.S., S.G.L.) and Pathology (J.K., E.Y.), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea; Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (W.K.J.); and School of Computer Science and Engineering, Soongsil University, Seoul, Korea (J.L.)
| |
Collapse
|
25
|
Bolondi G, Mocchegiani F, Montalti R, Nicolini D, Vivarelli M, De Pietri L. Predictive factors of short term outcome after liver transplantation: A review. World J Gastroenterol 2016; 22:5936-5949. [PMID: 27468188 PMCID: PMC4948266 DOI: 10.3748/wjg.v22.i26.5936] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/17/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1(th) and the 5(th) day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function.
Collapse
|
26
|
Citores MJ, Pérez-Pulgar S, Duca A, Crespo G, de la Fuente S, Vilches C, Navasa M, Cuervas-Mons V. Rapidity of fibrosis progression in liver transplant recipients with recurrent hepatitis C is influenced by toll-like receptor 3 polymorphism. Clin Transplant 2016; 30:810-818. [PMID: 27101936 DOI: 10.1111/ctr.12754] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2016] [Indexed: 02/05/2023]
Abstract
Liver transplantation activates the innate immune system through toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single-nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two-center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real-time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (-1237T/C and -1486C/T). The CC genotype of TLR3 Leu412Phe in liver recipients was associated with severe recurrence (odds ratio (OR) = 2.01, 95% confidence interval (95% CI) = 1.02-3.93, p = 0.04). We also analyzed this polymorphism in 72 of their donors but no association was found with severity of HCV recurrence (p = 0.89). Multivariate analysis showed donor age older than 40 yr (OR=2.93; 95% CI = 1.49-5.8, p = 0.002) and the TLR3 Leu412Phe CC genotype (OR=2.02, 95%CI=1.01-4.05, p = 0.046) were independently associated with severe HCV recurrence. Our results show that the TLR3 Leu412Phe CC genotype is independently associated with severity of hepatitis C recurrence after LT.
Collapse
Affiliation(s)
- Maria J Citores
- Servicio de Medicina Interna, Instituto de Investigación Sanitaria Puerta de Hierro-Majadahonda (IDIPHIM), Madrid, Spain
| | - Sofia Pérez-Pulgar
- Unidad de Trasplante Hepático, Hospital Clinic, IDIBAPS, CIBERedh, Barcelona, Spain
| | - Ana Duca
- Unidad de Trasplante Hepático, Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Gonzalo Crespo
- Unidad de Trasplante Hepático, Hospital Clinic, IDIBAPS, CIBERedh, Barcelona, Spain
| | - Sara de la Fuente
- Unidad de Trasplante Hepático, Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Carlos Vilches
- Grupo de Inmunogenética e Histocompatibilidad, Servicio de Inmunología, Instituto de Investigación Sanitaria Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Miquel Navasa
- Unidad de Trasplante Hepático, Hospital Clinic, IDIBAPS, CIBERedh, Barcelona, Spain
| | - Valentin Cuervas-Mons
- Unidad de Trasplante Hepático, Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
- Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| |
Collapse
|
27
|
Braza F, Brouard S, Chadban S, Goldstein DR. Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat Rev Nephrol 2016; 12:281-90. [PMID: 27026348 DOI: 10.1038/nrneph.2016.41] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances--damage-associated molecular patterns (DAMPs)--that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.
Collapse
Affiliation(s)
- Faouzi Braza
- Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 2780-156 Oeiras, Portugal
| | - Sophie Brouard
- INSERM, UMR 1064, CHU de Nantes, ITUN, 30 Bd Jean Monnet Nantes F-44093, France
| | - Steve Chadban
- Renal Medicine and Transplantation, Royal Prince Alfred Hospital, Missenden Road Camperdown, NSW 2050, Sydney, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Missenden Road, Camperdown, NSW 2093, Australia
| | - Daniel R Goldstein
- Department of Internal Medicine, 333 Cedar St, Yale School of Medicine, New Haven, Connecticut 06525, USA.,Department of Immunobiology, 300 Cedar St, Yale School of Medicine, New Haven, Connecticut 06525, USA
| |
Collapse
|
28
|
Verna EC. Hepatitis viruses and liver transplantation: evolving trends in antiviral management. Clin Liver Dis 2014; 18:575-601. [PMID: 25017077 DOI: 10.1016/j.cld.2014.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Viral hepatitis is both a leading indication for liver transplant (LT) and an important cause of posttransplant graft loss and mortality. Treatment and prevention of hepatitis B virus in LT recipients, with the observed corresponding improvement in post-LT outcomes, is among the great success stories in transplantation. By comparison, treatment of hepatitis C virus with safe and effective regimens is only just becoming a reality. Chronic hepatitis E virus infection in LT recipients represents a newly described phenomenon that can also lead to graft loss; early diagnosis and treatment may be key in the management of these patients.
Collapse
Affiliation(s)
- Elizabeth C Verna
- Division of Digestive and Liver Diseases, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032, USA.
| |
Collapse
|
29
|
Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:7381-7391. [PMID: 24966608 PMCID: PMC4064083 DOI: 10.3748/wjg.v20.i23.7381] [Citation(s) in RCA: 281] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 01/07/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease (NAFLD). The change in gut microbiota may alter nutritional absorption and storage. In addition, gut microbiota are a source of Toll-like receptor (TLR) ligands, and their compositional change can also increase the amount of TLR ligands delivered to the liver. TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD. The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been considered a potential underlying mechanism of obesity and NAFLD, but the role of these microbiota in NAFLD remains unknown. Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD. For instance, a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability, which allows the leakage of bacterial components. Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD. In children, the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis (NASH) compared with those in obese control. Escherichia can produce ethanol, which promotes gut permeability. Thus, normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD. In addition, TLR signaling in the liver is activated, and its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To data, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment.
Collapse
|
30
|
Wang Z, Wu S, Chen D, Guo F, Zhong L, Fan J, Peng Z. Influence of TLR4 rs1927907 locus polymorphisms on tacrolimus pharmacokinetics in the early stage after liver transplantation. Eur J Clin Pharmacol 2014; 70:925-31. [DOI: 10.1007/s00228-014-1673-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Accepted: 03/24/2014] [Indexed: 11/30/2022]
|
31
|
Abstract
BACKGROUND Primary graft dysfunction (PGD) causes complications in liver transplantation, which result in poor prognosis. Recipients who develop PGD usually experience a longer intensive care unit and hospital stay and have higher mortality and graft loss rates compared with those without graft dysfunction. However, because of the lack of universally accepted definition, early diagnosis of graft dysfunction is difficult. Additionally, numerous factors affect the allograft function after transplantation, making the prediction of PGD more difficult. The present review was to analyze the literature available on PGD and to propose a definition. DATA SOURCE A search of PubMed (up to the end of 2012) for English-language articles relevant to PGD was performed to clarify the characteristics, risk factors, and possible treatments or interventions for PGD. RESULTS There is no pathological diagnostic standard; many documented definitions of PGD are different. Many factors, such as donor status, procurement and transplant process and recipient illness may affect the function of graft, and ischemia-reperfusion injury is considered the direct cause. Potential managements which are helpful to improve graft function were investigated. Some of them are promising. CONCLUSIONS Our analyses suggested that the definition of PGD should include one or more of the following variables: (1) bilirubin ≥ 10 mg/dL on postoperative day 7; (2) international normalized ratio ≥ 1.6 on postoperative day 7; and (3) alanine aminotransferase or aspartate aminotransferase >2000 IU/L within 7 postoperative days. Reducing risk factors may decrease the incidence of PGD. A majority of the recipients could recover from PGD; however, when the graft progresses into primary non-function, the patients need to be treated with re-transplantation.
Collapse
Affiliation(s)
- Xiao-Bo Chen
- Department of Liver and Vascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
| | | |
Collapse
|
32
|
Abstract
PURPOSE OF REVIEW Beyond their crucial role in host defence against invading pathogens, Toll-like receptors (TLRs) are now known to be key mediators of the 'sterile' innate immune response triggered by tissue injury. Here, we will review recent evidence examining the role of TLRs in determining the fate of the transplanted organ. RECENT FINDINGS Experimental studies have delineated a crucial role for TLRs in the pathogenesis of ischaemia-reperfusion injury (IRI). Following transplantation, experimental models and observational human studies have confirmed TLRs as mediators of IRI but also suggest that TLRs modify the subsequent adaptive alloimmune response, which determines whether an organ is rejected or accepted. SUMMARY As a key determinant of organ damage following ischaemia-reperfusion and as a modulator of the adaptive alloimmune response, we propose that TLR-mediated innate immune responses represent a potential therapeutic target to improve organ outcomes following transplantation.
Collapse
|
33
|
Verhelst XPD, Troisi RI, Colle I, Geerts A, van Vlierberghe H. Biomarkers for the diagnosis of acute cellular rejection in liver transplant recipients: A review. Hepatol Res 2013. [PMID: 23186289 DOI: 10.1111/hepr.12012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The gold standard for the diagnosis of acute cellular rejection (ACR) is a liver biopsy. The quest for an alternative non-invasive biomarkers has been long and is ongoing. However, an efficient and useful biomarker has not been developed yet. In this manuscript, we review all possible candidate biomarkers that have been studied in recent years, starting with cytokines and ending with an overview of different newly discovered "omics". Promising paths are being explored but a valid non-invasive biomarker has not been discovered yet.
Collapse
Affiliation(s)
- Xavier P D Verhelst
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | | | | | | | | |
Collapse
|
34
|
Oetting WS, Guan W, Schladt DP, Leduc RE, Jacobson PA, Matas AJ, Chinnakotla S, Schröppel B, Murphy BT, Israni AK. Donor polymorphisms of toll-like receptor 4 associated with graft failure in liver transplant recipients. Liver Transpl 2012; 18:1399-405. [PMID: 22987288 PMCID: PMC3518641 DOI: 10.1002/lt.23549] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 08/22/2012] [Indexed: 12/14/2022]
Abstract
There have been many reports showing significant associations between recipient genetic variants and allograft outcomes, including acute rejection and graft failure, but less is known about the contribution of the donor genotype. We analyzed 37 single-nucleotide polymorphisms (SNPs) within the toll-like receptor 4 (TLR4) gene from deceased donor liver allografts transplanted into 738 recipients to determine their effects on liver graft failure (LGF). Two SNPs exhibited a significant association with LGF after adjustments for donor race and recipient race and corrections for multiple test comparisons: rs11536865 [hazard ratio (HR) = 2.5, P = 0.0003] and rs5030717 (HR = 1.67, P = 0.0008). An additional SNP, rs913930, exhibited a significant association in Caucasian donors (HR = 1.62, P = 0.0006), and 2 SNPs exhibited a suggestive association in African American donors: rs11536865 (HR = 2.45, P = 0.002) and rs5030717 (HR = 2.32, P = 0.002). Additionally, the liver donor risk index (HR = 2.56, 95% confidence interval = 1.54-4.26, P = 0.0003) and the recipient hepatitis C virus (HCV) status (HR = 1.53, 95% confidence interval = 1.04-2.24, P = 0.032) increased the risk of all-cause LGF in a Cox proportional hazards model adjusted for recipient race. Donor polymorphisms in TLR4 could be important factors in modulating TLR4 activity and, therefore, affect the risk of graft loss. Additionally, there is a suggestion of an interaction between polymorphisms within TLR4 and the HCV status.
Collapse
Affiliation(s)
- William S. Oetting
- College of Pharmacy, University of Minnesota, Minneapolis, MN,Institute of Human Genetics, University of Minnesota, Minneapolis, MN
| | - Weihua Guan
- Division of Biostatistics, University of Minnesota, Minneapolis, MN
| | - David P. Schladt
- Division of Biostatistics, University of Minnesota, Minneapolis, MN
| | - Robert E. Leduc
- Division of Biostatistics, University of Minnesota, Minneapolis, MN
| | | | - Arthur J. Matas
- Department of Surgery, University of Minnesota, Minneapolis, MN
| | | | | | | | - Ajay K. Israni
- Department of Medicine, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN
| |
Collapse
|
35
|
do O NT, Eurich D, Schmitz P, Schmeding M, Heidenhain C, Bahra M, Trautwein C, Neuhaus P, Neumann UP, Wasmuth HE. A 7-gene signature of the recipient predicts the progression of fibrosis after liver transplantation for hepatitis C virus infection. Liver Transpl 2012; 18:298-304. [PMID: 22139994 DOI: 10.1002/lt.22475] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Fibrosis recurrence after liver transplantation (LT) for hepatitis C virus (HCV) is a universal event and strongly determines a patient's prognosis. The recipient risk factors for fibrosis recurrence are still poorly defined. Here we assess a genetic risk score as a predictor of fibrosis after LT. The cirrhosis risk score (CRS), which comprises allele variants in 7 genes (adaptor-related protein complex 3 S2, aquaporin 2, antizyme inhibitor 1, degenerative spermatocyte homolog 1 lipid desaturase, syntaxin binding protein 5-like, toll-like receptor 4, and transient receptor potential cation channel M5), was calculated for 137 patients who underwent LT for HCV infection and experienced HCV reinfection of the graft. The patients were stratified into 3 CRS categories: <0.5, 0.5 to 0.7, and >0.7. All patients underwent protocol biopsy after LT (median follow-up = 5 years), and liver fibrosis was assessed according to the Desmet and Scheuer score. The data were analyzed with univariate and multivariate analyses. The results showed that the highest CRS category was strongly associated with the presence of F2 or F3 fibrosis in protocol biopsy samples 1, 3, and 5 years after LT (P = 0.006, P = 0.001, and P = 0.02, respectively). Overall, 75.0% of the patients with a CRS > 0.7 developed at least F2 fibrosis, whereas 51.5% developed F3 fibrosis during follow-up. The predictive value of the CRS for fibrosis progression was independent of known clinical risk factors, including the age of the donor, the sex of the recipient, and the occurrence of acute rejection. A Kaplan-Meier analysis confirmed the prognostic value of the CRS with respect to the recurrence of severe liver fibrosis in HCV-infected patients after LT (log rank = 6.23, P = 0.03). In conclusion, the genetic signature of the recipient predicts the likelihood of severe liver fibrosis in the graft after HCV recurrence. The CRS might help with early clinical decision making (eg, the selection of patients for antiviral therapy after LT).
Collapse
Affiliation(s)
- Nicole T do O
- Medical Department III, Charité University Hospital, Berlin, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
36
|
Leventhal JS, Schröppel B. Toll-like receptors in transplantation: sensing and reacting to injury. Kidney Int 2012; 81:826-32. [PMID: 22297675 DOI: 10.1038/ki.2011.498] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Toll-like receptors (TLRs) are a family of transmembrane proteins that have a major role in pathogen-induced inflammation and orchestrating an organism's defense against infection. Data are emerging that the TLRs play an important role as a first response to tissue injury linking the innate with the adaptive immune system. The recognition that TLRs are expressed on nonimmune cells including renal and liver cells, and that endogenous, cell-derived ligands (damage-associated molecular patterns) can signal through specific TLRs has expanded the understanding of how these receptors impact a variety of diseases. This review focuses on recent findings elucidating the ability of TLRs to affect transplant outcomes. Specifically, observations demonstrating the link between endogenous TLR ligands and IR injury, how this can affect alloimmunity and transplant tolerance, and therapeutic implications will be discussed.
Collapse
Affiliation(s)
- Jeremy S Leventhal
- Division of Nephrology, Mount Sinai School of Medicine, New York, New York 10029, USA
| | | |
Collapse
|
37
|
Sawhney R, Visvanathan K. Polymorphisms of toll-like receptors and their pathways in viral hepatitis. Antivir Ther 2011; 16:443-58. [PMID: 21685532 DOI: 10.3851/imp1820] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) are an important part of the innate immune response to a variety of pathogens including hepatic viral infections. Activation of TLRs stimulates a complex intracellular signalling cascade that results in production of proinflammatory cytokines and interferons important for antiviral responses as well as induction of the adaptive arm of the immune system. There is substantial evidence for an important role for TLRs and TLR-mediated signalling in the pathogenesis and outcomes of hepatitis B and C in particular, but it might also influence responses to other viral hepatitis infections. Several single nucleotide polymorphisms (SNPs) of TLRs, relevant adaptor molecules and cytokines mediated by TLR signalling have been described that alter innate immune responses and have been implicated in a variety of human diseases including viral and other infections. There is now significant evidence that a number of TLR SNPs can affect various clinical outcomes in Caucasian patients with chronic HCV. However, the role of these polymorphisms in acute and other chronic hepatitis infections, including HBV as well as in non-Caucasian populations, has not been elucidated. In addition, results for SNPs downstream of TLR activation, such as in relevant cytokines, are inconsistent and their influence requires further investigation to determine the clinical significance of genetic variations in these mediators.
Collapse
Affiliation(s)
- Rohit Sawhney
- Innate Immunity Laboratory, Department of Medicine, Monash University, Melbourne, Australia
| | | |
Collapse
|
38
|
Jiang N, Zhang X, Zheng X, Chen D, Zhang Y, Siu LKS, Xin HB, Li R, Zhao H, Riordan N, Ichim TE, Quan D, Jevnikar AM, Chen G, Min W. Targeted gene silencing of TLR4 using liposomal nanoparticles for preventing liver ischemia reperfusion injury. Am J Transplant 2011; 11:1835-44. [PMID: 21794086 DOI: 10.1111/j.1600-6143.2011.03660.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
RNAi-based therapy is a promising strategy for the prevention of ischemia-reperfusion injury (IRI). However, systemic administration of small interfering RNA (siRNA) may cause globally nonspecific targeting of all tissues, which impedes clinical use. Here we report a hepatocyte-specific delivery system for the treatment of liver IRI, using galactose-conjugated liposome nanoparticles (Gal-LipoNP). Heptocyte-specific targeting was validated by selective in vivo delivery as observed by increased Gal-LipoNP accumulation and gene silencing in the liver. Gal-LipoNP TLR4 siRNA treatment resulted in a significant decrease of serum alanine transferase (ALT) and aspartate transaminase (AST) in a hepatic IRI model. Histopathology displayed an overall reduction of the injury area in the Gal-LipoNP TLR4 siRNA treated mice. Additionally, neutrophil accumulation and lipid peroxidase-mediated tissue injury, detected by MPO, MDA and ROS respectively, were attenuated after Gal-LipoNP TLR4 siRNA treatment. Moreover, therapeutic effects of Gal-LipoNP TLR4 siRNA were associated with suppression of the inflammatory cytokines IL-1 and TNF-α. Taken together, this study is the first demonstration of liver IRI treatment using liver-specific siRNA delivery.
Collapse
Affiliation(s)
- N Jiang
- Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
39
|
Neumann U. Impact of IL-28B polymorphism on outcome in patients with hepatitis C after liver transplantation. Expert Rev Gastroenterol Hepatol 2011; 5:429-31. [PMID: 21780887 DOI: 10.1586/egh.11.54] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
|
40
|
Citores MJ, Baños I, Noblejas A, Rosado S, Castejon R, Cuervas-Mons V. Toll-like receptor 3 L412F polymorphism may protect against acute graft rejection in adult patients undergoing liver transplantation for hepatitis C-related cirrhosis. Transplant Proc 2011; 43:2224-2226. [PMID: 21839239 DOI: 10.1016/j.transproceed.2011.05.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Liver transplantation activates the innate immune system by toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. The aim of this study was to evaluate the possible association of different single nucleotide polymorphisms (SNPs) in several TLR genes with the incidence of acute graft rejection in liver transplant recipients for hepatitis C virus (HCV)-related cirrhosis. This is a single-center study of 100 adult patients who received a first whole only liver graft from deceased donors at our institution between 1988 and 2009 for cirrhosis due to HCV infection. We examined 10 SNPs in the TLR1 (S6021), TLR2 (R753Q), TLR3 (L412F), TLR4 (D299G and T399I), TLR5 (R392X), TLR6 (S249P), TLR7 (Q11L), and TLR9 (-1237T/C and -1486C/T) genes. Genotyping was carried out with the LightSNiP typing assay (TIB-MolBiol, Berlin, Germany) by analyzing the melting curves with the LightCycler 480 system (Roche Applied Science, Mannheim, Germany). Recipient allelic and genotypic distributions for each SNP were compared among patients with and without acute rejection within the first 3 months after transplantation. We found the homozygous mutant TT genotype for TLR3 L412F was associated with a lower rate of acute rejection when compared with the homozygous wild-type genotype [odds ratio (OR) = 0.1, 95% confidence interval (95% CI) = 0.01-0.86; P = .017], and showed a trend toward a lower graft rejection rate when compared with patients carrying one or two C alleles (OR = 0.15, 95% CI = 0.02-1.2, P = .05). No other associations with acute rejection rates were found for any other SNP evaluated. This preliminary study suggests an important role for SNP TLR3 L412F in acute rejection in liver transplant patients for HCV-related cirrhosis. Nevertheless, these findings must be prospectively validated in other cohorts of patients as well as in patients after liver transplantation for other etiologies than HCV.
Collapse
Affiliation(s)
- M J Citores
- Laboratorio de Medicina Interna, Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
| | | | | | | | | | | |
Collapse
|
41
|
Roedder S, Vitalone M, Khatri P, Sarwal MM. Biomarkers in solid organ transplantation: establishing personalized transplantation medicine. Genome Med 2011; 3:37. [PMID: 21658299 PMCID: PMC3218811 DOI: 10.1186/gm253] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Technological advances in molecular and in silico research have enabled significant progress towards personalized transplantation medicine. It is now possible to conduct comprehensive biomarker development studies of transplant organ pathologies, correlating genomic, transcriptomic and proteomic information from donor and recipient with clinical and histological phenotypes. Translation of these advances to the clinical setting will allow assessment of an individual patient's risk of allograft damage or accommodation. Transplantation biomarkers are needed for active monitoring of immunosuppression, to reduce patient morbidity, and to improve long-term allograft function and life expectancy. Here, we highlight recent pre- and post-transplantation biomarkers of acute and chronic allograft damage or adaptation, focusing on peripheral blood-based methodologies for non-invasive application. We then critically discuss current findings with respect to their future application in routine clinical transplantation medicine. Complement-system-associated SNPs present potential biomarkers that may be used to indicate the baseline risk for allograft damage prior to transplantation. The detection of antibodies against novel, non-HLA, MICA antigens, and the expression of cytokine genes and proteins and cytotoxicity-related genes have been correlated with allograft damage and are potential post-transplantation biomarkers indicating allograft damage at the molecular level, although these do not have clinical relevance yet. Several multi-gene expression-based biomarker panels have been identified that accurately predicted graft accommodation in liver transplant recipients and may be developed into a predictive biomarker assay.
Collapse
Affiliation(s)
- Silke Roedder
- Department of Pediatrics and Immunology, Stanford University, G306 300 Pasteur Drive, Palo Alto, CA 94304, USA.
| | | | | | | |
Collapse
|
42
|
Vasileiou I, Kostopanagiotou G, Katsargyris A, Klonaris C, Perrea D, Theocharis S. Toll-like receptors: a novel target for therapeutic intervention in intestinal and hepatic ischemia-reperfusion injury? Expert Opin Ther Targets 2010; 14:839-53. [PMID: 20568914 DOI: 10.1517/14728222.2010.500286] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
IMPORTANCE OF THE FIELD Toll-like receptors (TLRs) are transmembrane proteins that act mainly as sensors of microbes, orchestrating an organism's defense against infections, while they sense also host tissue injury by recognizing products of dying cells. Ischemia-reperfusion injury (IRI) represents one of these tissue damage states in which TLR-mediated mechanisms might be implicated. AREAS COVERED IN THIS REVIEW The most recent data on TLR signaling and the latest knowledge regarding the involvement of TLRs in the pathogenesis and progression of intestinal and hepatic IRI are presented. The potential effectiveness of TLR-modulating therapy in intestinal and liver IRI is also analyzed. WHAT THE READER WILL GAIN A comprehensive summary of the data suggesting TLR involvement in intestinal and hepatic IRI. Knowledge required for developing TLR modulation strategies against intestinal and hepatic IRI. TAKE HOME MESSAGE TLRS play a significant role in both intestinal and hepatic IRI pathophysiology. Better understanding of TLR involvement in such processes may enable the invention of novel TLR-based therapies for IRI in the intestine and liver.
Collapse
Affiliation(s)
- Ioanna Vasileiou
- University of Athens, Medical School, Department of Forensic Medicine and Toxicology, Athens, Greece.
| | | | | | | | | | | |
Collapse
|
43
|
Guo J, Friedman SL. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. FIBROGENESIS & TISSUE REPAIR 2010; 3:21. [PMID: 20964825 PMCID: PMC2984459 DOI: 10.1186/1755-1536-3-21] [Citation(s) in RCA: 240] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 10/21/2010] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.
Collapse
Affiliation(s)
- Jinsheng Guo
- Division of Liver Diseases, Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY, USA.
| | | |
Collapse
|
44
|
Innate pathways of immune activation in transplantation. J Transplant 2010; 2010. [PMID: 20871653 PMCID: PMC2939398 DOI: 10.1155/2010/826240] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2010] [Accepted: 07/22/2010] [Indexed: 01/04/2023] Open
Abstract
Studies of the immune mechanisms of allograft rejection have predominantly focused on the adaptive immune system that includes T cells and B cells. Recent investigations into the innate immune system, which recognizes foreign antigens through more evolutionarily primitive pathways, have demonstrated a critical role of the innate immune system in the regulation of the adaptive immune system. Innate immunity has been extensively studied in its role as the host's first-line defense against microbial pathogens; however, it is becoming increasingly recognized for its ability to also recognize host-derived molecules that result from tissue damage. The capacity of endogenous damage signals acting through the innate immune system to lower immune thresholds and promote immune recognition and rejection of transplant grafts is only beginning to be appreciated. An improved understanding of these pathways may reveal novel therapeutic targets to decrease graft alloreactivity and increase graft longevity.
Collapse
|