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1
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Ghallab A, Mandorfer M, Stirnimann G, Geyer J, Lindström E, Luedde T, van der Merwe S, Rashidi-Alavijeh J, Schmidt H, Karpen SJ, Fickert P, Trauner M, Hengstler JG, Dawson PA. Enteronephrohepatic Circulation of Bile Acids and Therapeutic Potential of Systemic Bile Acid Transporter Inhibitors. J Hepatol 2025:S0168-8278(25)02207-X. [PMID: 40414504 DOI: 10.1016/j.jhep.2025.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/27/2025]
Abstract
Together with carriers in liver and small intestine, kidney transporters function to conserve and compartmentalize bile acids in the enteronephrohepatic circulation. In patients with liver disease, systemic bile acid levels are elevated, undergo increased renal glomerular filtration, and contribute to the pathogenesis of cholemic nephropathy and acute kidney injury. In this review, we describe mechanisms for renal bile acid transport and highlight very recent discoveries that challenge current paradigms for the pathogenesis of cholemic nephropathy and renal tubule cast formation. We also discuss the therapeutic potential of inhibiting the kidney apical sodium-dependent bile acid transporter (ASBT) to redirect bile acids into urine for elimination, reduce hepatobiliary accumulation and systemic levels of bile acids, and treat cholemic nephropathy. In conclusion, a deeper understanding of the enteronephrohepatic bile acid axis is providing insights into novel strategies to protect both liver and kidney in patients with liver disease.
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Affiliation(s)
- Ahmed Ghallab
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany; Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
| | - Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, Inselspital University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Joachim Geyer
- Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany
| | | | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany
| | | | - Jassin Rashidi-Alavijeh
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Hartmut Schmidt
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Saul J Karpen
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, VA, United States
| | - Peter Fickert
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Jan G Hengstler
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany
| | - Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States.
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Alabdul Razzak I, El Naamani H, Dimitrov D, Morin R, Jaber BL. Bile cast nephropathy: A systematic review of case reports and case series. World J Hepatol 2025; 17:105120. [PMID: 40308820 PMCID: PMC12038420 DOI: 10.4254/wjh.v17.i4.105120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/27/2025] [Accepted: 03/25/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Bile cast nephropathy (BCN) is suspected in the setting of liver disease and hyperbilirubinemia and is characterized by the formation of tubular bile casts and acute tubular injury. While postmortem studies reveal a high prevalence of BCN, little is known about this orphan acute kidney injury syndrome. AIM To address this knowledge gap, we performed a systematic review of case reports and case series of BCN, focusing on risk factors, diagnostic criteria, clinical presentation, kidney biopsy findings, severity, treatment approaches, and outcomes. METHODS Electronic databases were searched to identify eligible studies of patients with possible, probable, or definite BCN, using pre-established criteria. Relevant variables were extracted and analyzed. We explored the impact of serum total bilirubin levels and alcoholic liver disease on BCN severity and outcomes by stratifying cases into total bilirubin tertiles and alcoholic vs non-alcoholic liver disease. Univariate and multivariable logistic regression analyses were used to examine factors associated with the composite outcome of dialysis requirement or death. RESULTS Sixty-seven case reports and six case series (involving 2 patients each) met the inclusion criteria, totaling 79 cases of BCN. The mean age was 48.3 years, and 83.5% were men. The most common cause of liver disease was drug-induced injury (30.4%), followed by infection (18.9%) and alcoholism (12.7%). BCN diagnosis was deemed definite, probable, and possible in 65.8%, 32.9%, and 1.3% of cases, respectively. Levels of serum creatinine, dialysis requirement, and renal recovery did not differ among the total bilirubin tertile groups. However, both initial and peak serum creatinine were significantly higher in the alcoholic liver disease group compared to the non-alcoholic group (P = 0.011 and P = 0.012, respectively). There was also a non-significant trend toward a higher incidence of dialysis requirement or death in the alcoholic liver disease group (80% vs 52%, P = 0.098). Finally, higher initial serum creatinine (per 1 mg/dL increase) was independently associated with dialysis requirement or death (adjusted odds ratio 1.291, 95% confidence interval: 1.032-1.615, P = 0.025). CONCLUSION BCN is a common and potentially serious cause of acute kidney injury in patients with liver disease. The degree of hyperbilirubinemia does not appear to correlate with BCN severity or outcomes. However, in alcoholic liver disease, BCN is associated with a greater rise in serum creatinine and a trend toward worse outcomes compared to non-alcoholic liver disease. Serum creatinine may be a valuable predictor of BCN prognosis. Further studies are needed to develop non-invasive diagnostic tools and establish effective treatments for BCN.
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Affiliation(s)
- Iyiad Alabdul Razzak
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States.
| | - Hind El Naamani
- Department of Medicine, St. Elizabeth's Medical Center, Boston, MA 02135, United States
| | - Dimo Dimitrov
- Department of Medicine, St. Elizabeth's Medical Center, Boston, MA 02135, United States
| | - Rebecca Morin
- Department of Research and Instruction, Tufts University, Boston, MA 02111, United States
| | - Bertrand L Jaber
- Department of Medicine, St. Elizabeth's Medical Center, Boston, MA 02135, United States
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Bangera A, Basthi PM, Musunuri B, Nagaraju SP, Shetty S, Rao IR. The Kidney and Extracorporeal Therapies in Acute-on-Chronic Liver Failure: What the Nephrologist Needs to Know. Nephrology (Carlton) 2025; 30:e70034. [PMID: 40243165 DOI: 10.1111/nep.70034] [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: 09/18/2024] [Revised: 01/01/2025] [Accepted: 04/06/2025] [Indexed: 04/18/2025]
Abstract
In this review, we discuss the pathophysiology and management of acute kidney injury (AKI) in the setting of acute-on-chronic liver failure (ACLF). ACLF is characterised by the occurrence of acute hepatic and/or extrahepatic organ failure, induced by immune dysregulation and systemic inflammation in patients with chronic liver disease. Kidney involvement is common, with AKI occurring in 30% to > 95% of ACLF patients, depending on the definition used. Since there is a lack of kidney biopsy data in these patients, the underlying pathophysiological basis of AKI remains incompletely understood, and systemic inflammation is believed to be the primary driver of organ injury. The management of AKI has been largely extrapolated from studies in decompensated cirrhosis, and there is little data specifically in the ACLF setting. However, available evidence suggests that structural kidney injury is more common in ACLF than in decompensated CLD, and therefore, AKI in ACLF is less likely to respond to volume repletion and vasopressors. Treatment options remain limited for those who are non-responsive to intravenous fluids and vasopressors. Liver transplantation (LT), with or without kidney transplantation, is the definitive treatment for these patients. At present, extracorporeal therapies such as therapeutic plasma exchange and kidney replacement therapies play a supportive role in ACLF as a bridge to LT; however, the optimal timing and dosing remain unclear. While theoretically, extracorporeal therapies have the potential to reverse or halt progression of organ damage in ACLF, there is limited evidence currently.
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Affiliation(s)
- Ashika Bangera
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Pooja Mohan Basthi
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Balaji Musunuri
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Indu Ramachandra Rao
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Xia Y, Ye Z, Li B, Yan X, Yuan T, Li L, Song B, Yu W, Rao T, Ning J, Zhu J, Li X, Mei S, Mao Z, Zhou X, Cheng F. EZH2-mediated macrophage-to-myofibroblast transition contributes to calcium oxalate crystal-induced kidney fibrosis. Commun Biol 2025; 8:286. [PMID: 39987296 PMCID: PMC11846861 DOI: 10.1038/s42003-025-07735-3] [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: 05/14/2024] [Accepted: 02/13/2025] [Indexed: 02/24/2025] Open
Abstract
Long-term nephrocalcinosis leads to kidney injury, fibrosis, and even chronic kidney disease (CKD). Macrophage-to-myofibroblast transition (MMT) has been identified as a new mechanism in CKD, however, the effect of MMT in calcium oxalate (CaOx)-induced kidney fibrosis remains unclear. In this study, abundant MMT cells are identified by immunofluorescence (IF) and flow cytometry in kidney tissues of patients with CaOx-related CKD, a male mouse model, and CaOx-treated macrophages. Clodronate liposome (CLO)-mediated macrophage depletion attenuates fibrosis in male nephrocalcinosis mice. Transcriptomic sequencing reveals that histone methyltransferase (HMTs), EZH2, is highly expressed in nephrocalcinosis. Ezh2 inducible knock-out or inhibition by GSK-126 attenuates MMT and renal fibrosis. Mechanistically, ChIP and transcriptomic sequencing show that EZH2 inhibition reduces the enrichment of H3K27me3 on the Dusp23 gene promoter and elevates Dusp23 expression. The Co-IP and molecular docking analysis shows that DUSP23 mediates the dephosphorylation of pSMAD3 (Ser423/425). Thus, our study found that EZH2 promotes kidney fibrosis by meditating MMT via the DUSP23/SMAD3 pathway in nephrocalcinosis.
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Affiliation(s)
- Yuqi Xia
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zehua Ye
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Bojun Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xinzhou Yan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tianhui Yuan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Lei Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Baofeng Song
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Weimin Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jinzhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jiefu Zhu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xing Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shuqin Mei
- Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhiguo Mao
- Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiangjun Zhou
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
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Jiménez-Esquivel N, Piñeiro G, Carpio A, Ortiz O, Lozano M, Rodríguez-Carunchio L, Salgado MDC, Toapanta D, Cid J, Bassegoda O, Cuadrado-Payán E, Sanz M, Charry P, Poch E, Fernández J, Reverter E. Bilirubin Removal with Therapeutic Plasma Exchange or Molecular Adsorbent Recirculating System as Treatment for Cholemic Nephropathy in Patients with Cirrhosis and Acute-on-Chronic Liver Failure: A Case Series. Blood Purif 2025; 54:160-166. [PMID: 39827849 PMCID: PMC11949189 DOI: 10.1159/000543619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 01/12/2025] [Indexed: 01/22/2025]
Abstract
INTRODUCTION Cholemic nephropathy is an overlooked cause of acute kidney injury (AKI) in patients with cirrhosis and high bilirubin plasma levels (usually above 20 mg/dL), due to bilirubin and bile acid deposition in the kidneys. Those deposits have been hypothesized to cause tubular injury. It has no standardized diagnostic criteria or therapeutic strategies. METHOD We present a series of 15 patients with cirrhosis, acute-on-chronic liver failure (ACLF), and severe cholemic AKI, diagnosed by microscopic urinary cast visualization after excluding and treating other causes of AKI. Bilirubin plasma removal was performed with Molecular Adsorbent Recirculating System (MARS®, n = 3) or therapeutic plasma exchange (TPE, n = 12) to treat and prevent further kidney deterioration. RESULTS Kidney function improved in most of the patients; 5 patients also required transient hemodialysis, with only 1 patient evolving to end-stage chronic kidney disease needing liver-kidney transplant. Five patients underwent extended TPE sessions as a bridge to liver transplantation. Survival at 30 days and 1 year was 80% and 73%, respectively, with 10 patients undergoing transplantation along this year. CONCLUSION In this highly selected cohort of patients with cirrhosis, ACLF, and severe cholemic AKI, extracorporeal plasma removal techniques seem to improve kidney function and overall prognosis. Larger prospective and controlled studies are required to better understand this condition. INTRODUCTION Cholemic nephropathy is an overlooked cause of acute kidney injury (AKI) in patients with cirrhosis and high bilirubin plasma levels (usually above 20 mg/dL), due to bilirubin and bile acid deposition in the kidneys. Those deposits have been hypothesized to cause tubular injury. It has no standardized diagnostic criteria or therapeutic strategies. METHOD We present a series of 15 patients with cirrhosis, acute-on-chronic liver failure (ACLF), and severe cholemic AKI, diagnosed by microscopic urinary cast visualization after excluding and treating other causes of AKI. Bilirubin plasma removal was performed with Molecular Adsorbent Recirculating System (MARS®, n = 3) or therapeutic plasma exchange (TPE, n = 12) to treat and prevent further kidney deterioration. RESULTS Kidney function improved in most of the patients; 5 patients also required transient hemodialysis, with only 1 patient evolving to end-stage chronic kidney disease needing liver-kidney transplant. Five patients underwent extended TPE sessions as a bridge to liver transplantation. Survival at 30 days and 1 year was 80% and 73%, respectively, with 10 patients undergoing transplantation along this year. CONCLUSION In this highly selected cohort of patients with cirrhosis, ACLF, and severe cholemic AKI, extracorporeal plasma removal techniques seem to improve kidney function and overall prognosis. Larger prospective and controlled studies are required to better understand this condition.
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Affiliation(s)
| | - Gastón Piñeiro
- Nephrology and Kidney Transplant Department, Hospital Clinic de Barcelona, Barcelona, Spain
- Red de Investigación Renal (REDinREN), Madrid, Spain
- Institut d'Indvestigacions Biomèdiques August Pi i Sunyer, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Adrià Carpio
- Liver and Digestive ICU, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Oswaldo Ortiz
- Liver and Digestive ICU, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Miquel Lozano
- Institut d'Indvestigacions Biomèdiques August Pi i Sunyer, IDIBAPS, University of Barcelona, Barcelona, Spain
- Apheresis & Cellular Therapy Unit, Department of Hemotherapy and Hemostasis, Clinical Institute of Hematology and Oncology, Hospital Clinic de Barcelona, Barcelona, Spain
| | | | | | - David Toapanta
- Liver and Digestive ICU, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Joan Cid
- Institut d'Indvestigacions Biomèdiques August Pi i Sunyer, IDIBAPS, University of Barcelona, Barcelona, Spain
- Apheresis & Cellular Therapy Unit, Department of Hemotherapy and Hemostasis, Clinical Institute of Hematology and Oncology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Octavi Bassegoda
- Liver and Digestive ICU, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Elena Cuadrado-Payán
- Nephrology and Kidney Transplant Department, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Miquel Sanz
- Liver and Digestive ICU, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Paola Charry
- Institut d'Indvestigacions Biomèdiques August Pi i Sunyer, IDIBAPS, University of Barcelona, Barcelona, Spain
- Apheresis & Cellular Therapy Unit, Department of Hemotherapy and Hemostasis, Clinical Institute of Hematology and Oncology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Esteban Poch
- Nephrology and Kidney Transplant Department, Hospital Clinic de Barcelona, Barcelona, Spain
- Red de Investigación Renal (REDinREN), Madrid, Spain
- Institut d'Indvestigacions Biomèdiques August Pi i Sunyer, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Javier Fernández
- Liver and Digestive ICU, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Indvestigacions Biomèdiques August Pi i Sunyer, IDIBAPS, University of Barcelona, Barcelona, Spain
- EF-Clif Consortium, Barcelona, Spain
| | - Enric Reverter
- Liver and Digestive ICU, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Indvestigacions Biomèdiques August Pi i Sunyer, IDIBAPS, University of Barcelona, Barcelona, Spain
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6
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Maiwall R, Sharma F. AKI in ACLF: navigating the complex therapeutic puzzle. Expert Rev Gastroenterol Hepatol 2025; 19:165-180. [PMID: 39825627 DOI: 10.1080/17474124.2025.2456121] [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: 07/04/2024] [Accepted: 01/16/2025] [Indexed: 01/20/2025]
Abstract
INTRODUCTION Acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) is driven by the severity of systemic inflammation, acute portal hypertension driving circulatory dysfunction, hyperbilirubinemia, and toxicity of bile acids. The spectrum is mostly structural, associated with reduced response to vasoconstrictors. The progression is rapid, and need of renal replacement therapy and extracorporeal therapies may be required for the management. The development of renal failure is usually considered when defining the syndrome of ACLF. AREAS COVERED In the current review we discuss the pathophysiological basis, natural course, and response to the current therapeutic modalities and challenges in assessing and managing AKI in patients with ACLF. We conducted a comprehensive search of electronic databases such as PubMed, Web of Science, and Scopus using keywords like lactate, NGAL, and PHTN, as well as CRRT, PLEX, ACLF, and AKI phases for our review. Peer-reviewed English papers that addressed our issue were considered. EXPERT OPINION The difficulties and specific management strategies for AKI in ACLF patients are discussed emphasizing the importance of customized protocols, risk assessment guided by biomarkers, and investigation of extracorporeal therapies that target bile acids.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Fagun Sharma
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
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7
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Fuchs CD, Simbrunner B, Baumgartner M, Campbell C, Reiberger T, Trauner M. Bile acid metabolism and signalling in liver disease. J Hepatol 2025; 82:134-153. [PMID: 39349254 DOI: 10.1016/j.jhep.2024.09.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 10/02/2024]
Abstract
Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.
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Affiliation(s)
- Claudia D Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximillian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Clarissa Campbell
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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8
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Huang H, Li J, Chen T, Lu M, Zhuoma G, Chen L, Gan Y, Ye H. The correlation between blood lipids and intrahepatic cholestasis syndrome during pregnancy. J OBSTET GYNAECOL 2024; 44:2369929. [PMID: 38963226 DOI: 10.1080/01443615.2024.2369929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 06/13/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND To analyse changes in lipid levels during the development of intrahepatic cholestasis of pregnancy (ICP) and identify new biomarkers for predicting ICP. METHODS A retrospective case-control study was conducted to analyse 473 pregnant women who underwent regular prenatal examinations and delivered at the Women and Children's Hospital, School of Medicine, Xiamen University, between June 2020 and June 2023, including 269 normal pregnancy controls and 204 pregnant women with cholestasis. RESULTS Patients with ICP with gestational diabetes mellitus (GDM) have lower high-density lipoprotein (HDL) levels than in those without GDM. Total bile acid (TBA) levels were significantly higher in pregnant women with GDM than those without. The apolipoprotein A (APOA) level was lower in patients with ICP and hypothyroidism than those without hypothyroidism. TBA levels were significantly higher in pregnant women with hypothyroidism than those without. Triglyceride (TG) levels were significantly higher in patients with preeclampsia (PE) than those without. HDL and APOA levels were lower in women with ICP complicated by preterm delivery than those with normal delivery. The AUC (area under the curve) of the differential diagnosis of cholestasis of pregnancy for the APOA/APOB (apolipoprotein B) ratio was 0.727, with a sensitivity of 85.9% and specificity of 47.5%. CONCLUSIONS The results suggested that dyslipidaemia is associated with an increased risk of ICP and its complications. The timely detection of blood lipid and bile acid levels can assist in the diagnosis of ICP and effectively prevent ICP and other complications.
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Affiliation(s)
- Huibin Huang
- Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen City, China
| | - Juan Li
- Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen City, China
| | - Tianhua Chen
- Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen City, China
| | - Meidan Lu
- Department of obstetrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen City, China
| | - Gunsang Zhuoma
- School of Public Health, Xiamen University, Xiamen City, China
| | - Lijin Chen
- Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen City, China
| | - Yuebin Gan
- Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen City, China
| | - Huiming Ye
- Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen City, China
- Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen City, China
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9
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Zhuang Y, Ortega-Ribera M, Szabo G. Reply: Exercise greater caution in bile acid research. Hepatology 2024; 80:E73. [PMID: 39018556 DOI: 10.1097/hep.0000000000001017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 06/17/2024] [Indexed: 07/19/2024]
Affiliation(s)
- Yuan Zhuang
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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10
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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11
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Scilletta S, Leggio S, Di Marco M, Miano N, Musmeci M, Marrano N, Natalicchio A, Giorgino F, Bosco G, Di Giacomo Barbagallo F, Scamporrino A, Di Mauro S, Filippello A, Scicali R, Russello M, Spadaro L, Purrello F, Piro S, Di Pino A. Acute hyperbilirubinemia determines an early subclinical renal damage: Evaluation of tubular biomarkers in cholemic nephropathy. Liver Int 2024; 44:2341-2350. [PMID: 38837303 DOI: 10.1111/liv.16005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/10/2024] [Accepted: 05/23/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND AND AIMS Cholemic nephropathy is a cause of acute kidney injury occurring in patients with jaundice. The aim of this study was to evaluate early renal function impairment in patients with mild acute hyperbilirubinemia in the absence of alterations of the common parameters used in clinical practice (serum creatinine or urea) and with normal renal morphology. We studied urinary biomarkers of tubular damage urinary neutrophil gelatinase-associated lipocalin (u-NGAL), urinary beta-2-microglobulin (u-B2M), urinary osteopontin (u-OPN), urinary trefoil factor 3 (u-TFF3) and urinary Cystatin C (u-Cys). METHODS This is a case-control study investigating the following urinary biomarkers of tubular damage: u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys, in patients with mild acute hyperbilirubinemia. Seventy-four patients were included in this study: 36 patients with jaundice and 38 patients without jaundice. RESULTS Subjects with jaundice (total bilirubin 12.4 ± 7.3 mg/dL) showed higher u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys compared with controls. After logistic regression analyses, including the following independent variables: age, estimated Glomerular Filtration Rate (eGFR), haemoglobin, diabetes, hypertension and jaundice, we observed a higher risk of elevated u-NGAL values (OR = 3.8, 95% CI 1.07-13.5, p = .03) and u-B2M (OR = 9.4, 95% CI 2.3-38.9, p = .0018) in jaundiced subjects. Moreover, urinary biomarkers had a direct correlation with serum cholestasis indexes. CONCLUSIONS This study demonstrated increased urinary biomarkers of tubular damage (u-NGAL, u-B2M, u-OPN, u-TFF3, and u-Cys) in patients with mild hyperbilirubinemia in comparison with a control group. These findings suggest early renal tubular damage in the absence of alterations of the normal parameters used in clinical practice (eGFR, serum urea and renal morphology).
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Affiliation(s)
- Sabrina Scilletta
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Stefano Leggio
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Maurizio Di Marco
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Nicoletta Miano
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Marco Musmeci
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Nicola Marrano
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Annalisa Natalicchio
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Giosiana Bosco
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | | | | | - Stefania Di Mauro
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | | | - Luisa Spadaro
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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12
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Dekker SEI, Bierau J, Giera M, Blomberg N, Drenth JPH, Mayboroda OA, de Fijter JW, Soonawala D. Serum bile acids associate with liver volume in polycystic liver disease and decrease upon treatment with lanreotide. Eur J Clin Invest 2024; 54:e14147. [PMID: 38071418 DOI: 10.1111/eci.14147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 03/13/2024]
Abstract
BACKGROUND Polycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a post-hoc exploratory analysis of bile acids in ADPKD patients, who had participated in a trial on the effect of a somatostatin analogue. Our hypothesis was that serum bile acid levels increase in PLD, and that lanreotide, which reduces liver growth, may also reduce bile acid levels. Furthermore, in PLD, urinary excretion of bile acids might contribute to renal disease. METHODS With liquid chromatography-mass spectrometry, 11 bile acids in serum and 6 in urine were quantified in 105 PLD ADPKD patients and 52 age-, sex-, mutation- and eGFR-matched non-PLD ADPKD patients. Sampling was done at baseline and after 120 weeks of either lanreotide or standard care. RESULTS Baseline serum levels of taurine- and glycine-conjugated bile acids were higher in patients with larger livers. In PLD patients, multiple bile acids decreased upon treatment with lanreotide but remained stable in untreated subjects. Changes over time did not correlate with changes in liver volume. Urine bile acid levels did not change and did not correlate with renal disease progression. CONCLUSION In ADPKD patients with PLD, baseline serum bile acids were associated with liver volume. Lanreotide reduced bile acid levels and has previously been shown to reduce liver volume. However, in this study, the decrease in bile acids was not associated with the change in liver volume.
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Affiliation(s)
- Shosha E I Dekker
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Jörgen Bierau
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Niek Blomberg
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Oleg A Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Johan W de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Darius Soonawala
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Internal Medicine, Haga Teaching Hospital, The Hague, the Netherlands
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13
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Zhuang Y, Ortega-Ribera M, Nagesh PT, Joshi R, Huang H, Wang Y, Zivny A, Mehta J, Parikh SM, Szabo G. Bile acid-induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis-induced liver and kidney injury via regulation of ZBP1. Hepatology 2024; 79:752-767. [PMID: 37725754 PMCID: PMC10948324 DOI: 10.1097/hep.0000000000000611] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 08/31/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIMS Cell death and inflammation play critical roles in chronic tissue damage caused by cholestatic liver injury leading to fibrosis and cirrhosis. Liver cirrhosis is often associated with kidney damage, which is a severe complication with poor prognosis. Interferon regulatory factor 3 (IRF3) is known to regulate apoptosis and inflammation, but its role in cholestasis remains obscure. In this study. APPROACH AND RESULTS We discovered increased IRF3 phosphorylation in the liver of patients with primary biliary cholangitis and primary sclerosing cholangitis. In the bile duct ligation model of obstructive cholestasis in mice, we found that tissue damage was associated with increased phosphorylated IRF3 (p-IRF3) in the liver and kidney. IRF3 knockout ( Irf3-/- ) mice showed significantly attenuated liver and kidney damage and fibrosis compared to wide-type mice after bile duct ligation. Cell-death pathways, including apoptosis, necroptosis, and pyroptosis, inflammasome activation, and inflammatory responses were significantly attenuated in Irf3-/- mice. Mechanistically, we show that bile acids induced p-IRF3 in vitro in hepatocytes. In vivo , activated IRF3 positively correlated with increased expression of its target gene, Z-DNA-Binding Protein-1 (ZBP1), in the liver and kidney. Importantly, we also found increased ZBP1 in the liver of patients with primary biliary cholangitis and primary sclerosing cholangitis. We discovered that ZBP1 interacted with receptor interacting protein 1 (RIP1), RIP3, and NLRP3, thereby revealing its potential role in the regulation of cell-death and inflammation pathways. In conclusion. CONCLUSIONS Our data indicate that bile acid-induced p-IRF3 and the IRF3-ZBP1 axis play a central role in the pathogenesis of cholestatic liver and kidney injury.
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Affiliation(s)
- Yuan Zhuang
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Martí Ortega-Ribera
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Prashanth Thevkar Nagesh
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Radhika Joshi
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Huihui Huang
- Division of Nephrology, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Yanbo Wang
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Adam Zivny
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Jeeval Mehta
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Samir M. Parikh
- Division of Nephrology, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern, Dallas, TX, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
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14
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Hajian H, Motallebi M, Akhavan Taheri M, Kheiripour N, Aghadavod E, Shahaboddin ME. The preventive effect of heat-killed Lactobacillus plantarum on male reproductive toxicity induced by cholestasis in rats. Food Chem Toxicol 2024:114571. [PMID: 38452966 DOI: 10.1016/j.fct.2024.114571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/23/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024]
Abstract
This study investigated the preventive effect of heat-killed Lactobacillus plantarum (L. plantarum) on cholestasis-induced male reproductive toxicity in rats. Rats were divided into control normal, sham control, bile duct ligation (BDL) control, and BDL with heat-killed L. plantarum supplementation groups. The effects on sexual hormones, testicular and epididymal histology, sperm parameters, oxidative stress markers, and inflammatory gene expression were evaluated. Compared to the BDL control group, the BDL + heat-killed L. plantarum group showed higher levels of normal sperm, luteinizing hormone, testosterone, total antioxidant capacity, and catalase activity, indicating improved reproductive function. Conversely, markers of oxidative stress, such as total oxidative status, oxidative stress index, and carbonyl protein, were lower in the BDL + heat-killed L. plantarum group. The expression levels of inflammatory genes tumor necrosis factor-alpha and interleukin-6 were reduced, while interleukin-10 gene expression was increased in the BDL + heat-killed L. plantarum group. Histological evaluation confirmed the positive effects of heat-killed L. plantarum intervention on testicular parameters. In conclusion, heat-killed L. plantarum supplementation protects against cholestasis-induced male reproductive dysfunction in rats, as evidenced by improvements in hormonal balance, sperm quality, oxidative stress, and inflammation.
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Affiliation(s)
- Hajar Hajian
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mitra Motallebi
- Department of Immunology and Microbiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Akhavan Taheri
- Institute for Basic Sciences, Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Nejat Kheiripour
- Institute for Basic Sciences, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavod
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Esmaeil Shahaboddin
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Institute for Basic Sciences, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
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15
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Velez JCQ, Latt N, Rodby RA. Pathophysiology of Hepatorenal Syndrome. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:87-99. [PMID: 38649221 DOI: 10.1053/j.akdh.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 12/17/2023] [Accepted: 01/02/2024] [Indexed: 04/25/2024]
Abstract
Hepatorenal syndrome type 1 (HRS-1) is a unique form of acute kidney injury that affects individuals with decompensated cirrhosis with ascites. The primary mechanism leading to reduction of kidney function in HRS-1 is hemodynamic in nature. Cumulative evidence points to a cascade of events that led to a profound reduction in kidney perfusion. A state of increased intrahepatic vascular resistance characteristic of advanced cirrhosis and portal hypertension is accompanied by maladaptive peripheral arterial vasodilation and reduction in systemic vascular resistance and mean arterial pressure. As a result of a fall in effective arterial blood volume, there is a compensatory activation of the sympathetic nervous system and the renin-angiotensin system, local renal vasoconstriction, loss of renal autoregulation, decrease in renal blood flow, and ultimately a fall in glomerular filtration rate. Systemic release of nitric oxide stimulated by the fibrotic liver, bacterial translocation, and inflammation constitute key components of the pathogenesis. While angiotensin II and noradrenaline remain the critical mediators of renal arterial and arteriolar vasoconstriction, other novel molecules have been recently implicated. Although the above-described mechanistic pathway remains the backbone of the pathogenesis of HRS-1, other noxious elements may be present in advanced cirrhosis and likely contribute to the renal impairment. Direct liver-kidney crosstalk via the hepatorenal sympathetic reflex can further reduce renal blood flow independently of the systemic derangements. Tense ascites may lead to intraabdominal hypertension and abdominal compartment syndrome. Cardio-hemodynamic processes have also been increasingly recognized. Porto-pulmonary hypertension, cirrhotic cardiomyopathy, and abdominal compartment syndrome may lead to renal congestion and complicate the course of HRS-1. In addition, a degree of ischemic or toxic (cholemic) tubular injury may overlap with the underlying circulatory dysfunction and further exacerbate the course of acute kidney injury. Improving our understanding of the pathogenesis of HRS-1 may lead to improvements in therapeutic options for this seriously ill population.
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Affiliation(s)
- Juan Carlos Q Velez
- Department of Nephrology, Ochsner Health, New Orleans, LA; Ochsner Clinical School, The University of Queensland, Brisbane, QLD, Australia.
| | - Nyan Latt
- Virtua Center for Liver Disease, Virtua Health, Toms River, NJ
| | - Roger A Rodby
- Division of Nephrology, Rush University School of Medicine, Chicago, IL
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16
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Pinter K, Rosenkranz A. Cholemic Nephropathy: Role in Acute Kidney Injury in Cholestasis and Cirrhosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:111-126. [PMID: 38649215 DOI: 10.1053/j.akdh.2023.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 06/28/2023] [Accepted: 07/12/2023] [Indexed: 04/25/2024]
Abstract
The concept of structural kidney damage and renal dysfunction as a result of jaundice attracted attention in the medical community in the early and mid-20th century. The postulated doctrine of the time was that the excretion of elevated concentrations of bile results in bile-stained casts occupying collecting and distal convoluted tubules, degeneration of tubular epithelium, and decreased renal function. Compared to the hepatorenal syndrome, the poster child of hepatology and nephrology collaboration, the notion of structural kidney damage and renal dysfunction as a result of cholemia lost its traction and has almost disappeared from modern textbooks. Today, cholemic nephropathy is experiencing a renaissance, with multiple case reports and case series of jaundiced patients with kidney dysfunction and evidence of bile acid casts upon histologic examination. Published cases include acute hepatitis, chronic liver injury, cirrhosis, and obstructive etiologies. Diagnosis of cholemic nephropathy is based on histological examination, typically showing intraluminal bile casts predominantly located in the distal tubules. In common bile duct-ligated mice, the histomorphological and functional alterations of cholemic nephropathy mimic those seen in humans. Some argue against the concept of cholemic nephropathy and postulate that bile casts are a secondary phenomenon. What we need are carefully designed trials to establish diagnostic criteria and subsequently translate this knowledge into evidence-based therapies.
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17
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Yang J, Pontoglio M, Terzi F. Bile Acids and Farnesoid X Receptor in Renal Pathophysiology. Nephron Clin Pract 2024; 148:618-630. [PMID: 38412845 DOI: 10.1159/000538038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/22/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Bile acids (BAs) act not only as lipids and lipid-soluble vitamin detergents but also function as signaling molecules, participating in diverse physiological processes. The identification of BA receptors in organs beyond the enterohepatic system, such as the farnesoid X receptor (FXR), has initiated inquiries into their organ-specific functions. Among these organs, the kidney prominently expresses FXR. SUMMARY This review provides a comprehensive overview of various BA species identified in kidneys and delves into the roles of renal apical and basolateral BA transporters. Furthermore, we explore changes in BAs and their potential implications for various renal diseases, particularly chronic kidney disease. Lastly, we center our discussion on FXR, a key BA receptor in the kidney and a potential therapeutic target for renal diseases, providing current insights into the protective mechanisms associated with FXR agonist treatments. KEY MESSAGES Despite the relatively low concentrations of BAs in the kidney, their presence is noteworthy, with rodents and humans exhibiting distinct renal BA compositions. Renal BA transporters efficiently facilitate either reabsorption into systemic circulation or excretion into the urine. However, adaptive changes in BA transporters are evident during cholestasis. Various renal diseases are accompanied by alterations in BA concentrations and FXR expression. Consequently, the activation of FXR in the kidney could be a promising target for mitigating kidney damage.
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Affiliation(s)
- Jiufang Yang
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR8253, Université Paris Cité, Paris, France,
| | - Marco Pontoglio
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR8253, Université Paris Cité, Paris, France
| | - Fabiola Terzi
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR8253, Université Paris Cité, Paris, France
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18
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Ghallab A, González D, Strängberg E, Hofmann U, Myllys M, Hassan R, Hobloss Z, Brackhagen L, Begher-Tibbe B, Duda JC, Drenda C, Kappenberg F, Reinders J, Friebel A, Vucur M, Turajski M, Seddek AL, Abbas T, Abdelmageed N, Morad SAF, Morad W, Hamdy A, Albrecht W, Kittana N, Assali M, Vartak N, van Thriel C, Sous A, Nell P, Villar-Fernandez M, Cadenas C, Genc E, Marchan R, Luedde T, Åkerblad P, Mattsson J, Marschall HU, Hoehme S, Stirnimann G, Schwab M, Boor P, Amann K, Schmitz J, Bräsen JH, Rahnenführer J, Edlund K, Karpen SJ, Simbrunner B, Reiberger T, Mandorfer M, Trauner M, Dawson PA, Lindström E, Hengstler JG. Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis. J Hepatol 2024; 80:268-281. [PMID: 37939855 PMCID: PMC10849134 DOI: 10.1016/j.jhep.2023.10.035] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 10/06/2023] [Accepted: 10/23/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND & AIMS Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies. METHODS Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia. RESULTS Proximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN. CONCLUSIONS BA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations. IMPACT AND IMPLICATIONS Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN.
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Affiliation(s)
- Ahmed Ghallab
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.
| | - Daniela González
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | | | - Ute Hofmann
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376 Stuttgart, Germany
| | - Maiju Myllys
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Reham Hassan
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt
| | - Zaynab Hobloss
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Lisa Brackhagen
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Brigitte Begher-Tibbe
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Julia C Duda
- Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany
| | - Carolin Drenda
- Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany
| | | | - Joerg Reinders
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Adrian Friebel
- Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany
| | - Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany
| | - Monika Turajski
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Abdel-Latief Seddek
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt
| | - Tahany Abbas
- Histology Department, Faculty of Medicine, South Valley University, 83523 Qena, Egypt
| | - Noha Abdelmageed
- Department of Pharmacology, Faculty of Veterinary Medicine, Sohag University, 82524 Sohag, Egypt
| | - Samy A F Morad
- Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt
| | - Walaa Morad
- Histology Department, Faculty of Medicine, South Valley University, 83523 Qena, Egypt
| | - Amira Hamdy
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt
| | - Wiebke Albrecht
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Naim Kittana
- Department of Biomedical Sciences, An-Najah National University, P.O. Box 7 Nablus, Palestine, Israel
| | - Mohyeddin Assali
- Department of Pharmacy, An-Najah National University, P.O. Box 7 Nablus, Palestine, Israel
| | - Nachiket Vartak
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Christoph van Thriel
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Ansam Sous
- Department of Pharmacy, An-Najah National University, P.O. Box 7 Nablus, Palestine, Israel
| | - Patrick Nell
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Maria Villar-Fernandez
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Cristina Cadenas
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Erhan Genc
- MRI Unit, Leibniz Research Centre for Working Environment and Human Factors, Department of Psychology and Neurosciences, Technical University Dortmund, 44139 Dortmund, Germany
| | - Rosemarie Marchan
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany
| | | | | | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Stefan Hoehme
- Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, Inselspital University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376 Stuttgart, Germany; Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University Tuebingen, 72076 Tuebingen, Germany; Cluster of Excellence iFIT (EXC2180), Image-Guided and Functionally Instructed Tumor Therapies, University of Tuebingen, 69120 Tuebingen, Germany
| | - Peter Boor
- Institute of Pathology and Department of Nephrology, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Kerstin Amann
- Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany
| | - Jessica Schmitz
- Institute of Pathology, Nephropathology Unit, Hannover Medical School, 30625 Hannover, Germany
| | - Jan H Bräsen
- Institute of Pathology, Nephropathology Unit, Hannover Medical School, 30625 Hannover, Germany
| | - Jörg Rahnenführer
- Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany
| | - Karolina Edlund
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
| | - Saul J Karpen
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Hans Popper Laboratory of Molecular Hepatology, Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States
| | | | - Jan G Hengstler
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.
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19
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Fickert P. Detour of bile acid routes as therapeutic roadmap for cholemic nephropathy. J Hepatol 2024; 80:188-190. [PMID: 38013144 DOI: 10.1016/j.jhep.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023]
Affiliation(s)
- Peter Fickert
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria.
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20
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Valamparampil J, Gupte GL. Spectrum of renal lesions in infantile cholestasis. Clin Liver Dis (Hoboken) 2024; 23:e0150. [PMID: 38623147 PMCID: PMC11018225 DOI: 10.1097/cld.0000000000000150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 02/05/2024] [Indexed: 04/17/2024] Open
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21
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Badura K, Frąk W, Hajdys J, Majchrowicz G, Młynarska E, Rysz J, Franczyk B. Hepatorenal Syndrome-Novel Insights into Diagnostics and Treatment. Int J Mol Sci 2023; 24:17469. [PMID: 38139297 PMCID: PMC10744165 DOI: 10.3390/ijms242417469] [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: 10/30/2023] [Revised: 12/09/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS.
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Affiliation(s)
- Krzysztof Badura
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Weronika Frąk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Hajdys
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Gabriela Majchrowicz
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
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22
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Arakawa H, Kawanishi T, Shengyu D, Nishiuchi T, Meguro-Horike M, Horike SI, Sugimoto M, Kato Y. Renal Pharmacokinetic Adaptation to Cholestasis Causes Increased Nephrotoxic Drug Accumulation by Mrp6 Downregulation in Mice. J Pharm Sci 2023; 112:3209-3215. [PMID: 37611664 DOI: 10.1016/j.xphs.2023.08.008] [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: 06/23/2023] [Revised: 08/13/2023] [Accepted: 08/13/2023] [Indexed: 08/25/2023]
Abstract
In hepatic dysfunction, renal pharmacokinetic adaptation can be observed, although information on the changes in drug exposure and the interorgan regulation of membrane transporters in kidney in liver diseases is limited. This study aimed to clarify the effects of renal exposure to nephrotoxic drugs during cholestasis induced by bile duct ligation (BDL). Among the 11 nephrotoxic drugs examined, the tissue accumulation of imatinib and cisplatin in kidney slices obtained from mice 2 weeks after BDL operation was higher than that in sham-operated mice. The uptake of imatinib in the kidney slices of BDL mice was slightly higher, whereas its efflux from the slices was largely decreased compared to that in sham-operated mice. Proteomic analysis revealed a reduction in renal expression of the efflux transporter multidrug resistance-associated protein 6 (Mrp6/Abcc6) in BDL mice, and both imatinib and cisplatin were identified as Mrp6 substrates. Survival probability after cisplatin administration was reduced in BDL mice. In conclusion, the present study demonstrated that BDL-induced cholestasis leads to the downregulation of the renal basolateral efflux transporter Mrp6, resulting in drug accumulation in renal cells and promoting drug-induced renal injury.
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Affiliation(s)
- Hiroshi Arakawa
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Takumi Kawanishi
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Dai Shengyu
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Takumi Nishiuchi
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Makiko Meguro-Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Shin-Ichi Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Yamagata, Japan
| | - Yukio Kato
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
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Amer K, Flikshteyn B, Lingiah V, Tafesh Z, Pyrsopoulos NT. Mechanisms of Disease and Multisystemic Involvement. Clin Liver Dis 2023; 27:563-579. [PMID: 37380283 DOI: 10.1016/j.cld.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Affiliation(s)
- Kamal Amer
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Ben Flikshteyn
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Vivek Lingiah
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Zaid Tafesh
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 53, Newark, NJ 07101-1709, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 536, Newark, NJ 07101-1709, USA.
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24
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Liu JJ, Sun YM, Xu Y, Mei HW, Guo W, Li ZL. Pathophysiological consequences and treatment strategy of obstructive jaundice. World J Gastrointest Surg 2023; 15:1262-1276. [PMID: 37555128 PMCID: PMC10405123 DOI: 10.4240/wjgs.v15.i7.1262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/29/2023] [Accepted: 05/31/2023] [Indexed: 07/21/2023] Open
Abstract
Obstructive jaundice (OJ) is a common problem in daily clinical practice. However, completely understanding the pathophysiological changes in OJ remains a challenge for planning current and future management. The effects of OJ are widespread, affecting the biliary tree, hepatic cells, liver function, and causing systemic complications. The lack of bile in the intestine, destruction of the intestinal mucosal barrier, and increased absorption of endotoxins can lead to endotoxemia, production of proinflammatory cytokines, and induce systemic inflammatory response syndrome, ultimately leading to multiple organ dysfunction syndrome. Proper management of OJ includes adequate water supply and electrolyte replacement, nutritional support, preventive antibiotics, pain relief, and itching relief. The surgical treatment of OJ depends on the cause, location, and severity of the obstruction. Biliary drainage, surgery, and endoscopic intervention are potential treatment options depending on the patient's condition. In addition to modern medical treatments, Traditional Chinese medicine may offer therapeutic benefits for OJ. A comprehensive search was conducted on PubMed for relevant articles published up to August 1970. This review discusses in detail the pathophysiological changes associated with OJ and presents effective strategies for managing the condition.
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Affiliation(s)
- Jun-Jian Liu
- Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University Nankai Hospital, Tianjin 300102, China
| | - Yi-Meng Sun
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Yan Xu
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Han-Wei Mei
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Wu Guo
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Zhong-Lian Li
- Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University Nankai Hospital, Tianjin 300102, China
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25
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Annavarajula SK, Tandra VR, Ranga SK, Vennavalli S. Bile Cast Nephropathy, An Often-Missed Diagnosis. Indian J Nephrol 2023; 33:315-316. [PMID: 37781543 PMCID: PMC10503581 DOI: 10.4103/ijn.ijn_149_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/24/2022] [Accepted: 08/30/2022] [Indexed: 10/03/2023] Open
Affiliation(s)
| | | | - Santosh Kumar Ranga
- Department of Internal Medicine, Yashoda Hospital, Malakpet, Hyderabad, Telangana, India
| | - Sarika Vennavalli
- Department of Pathology, Yashoda Hospital, Malakpet, Hyderabad, Telangana, India
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Slc25a39 and Slc25a40 Expression in Mice with Bile Duct Ligation or Lipopolysaccharide Treatment. Int J Mol Sci 2022; 23:ijms23158573. [PMID: 35955707 PMCID: PMC9369313 DOI: 10.3390/ijms23158573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/28/2022] [Accepted: 07/30/2022] [Indexed: 02/01/2023] Open
Abstract
SLC25A39/40, involved in mitochondrial GSH (mGSH) import from the cytoplasm, is essential for protection against oxidative stress and mitochondrial dysfunction. We examined the effects of cholestasis, through bile duct ligation (BDL) and lipopolysaccharide (LPS)-induced inflammation in mice, on Slc25a39/40 expression. Additionally, we used human clear cell renal carcinoma (KMRC-1) cells to elucidate the mechanism of regulation of SLC25A39/40 expression in the kidneys after LPS treatment. BDL resulted in a decrease in Slc25a39 mRNA in the liver and a decrease in Slc25a39/40 mRNA and protein in the kidneys. Consequently, there was a significant decrease in mGSH levels in the kidneys of BDL mice compared with those in sham mice. LPS treatment resulted in increased Slc25a40 expression in the kidneys. In KMRC-1 cells, the combination treatment of LPS-RS or FPS-ZM1 with LPS suppressed the LPS-induced increase in SLC25A40, suggesting that SLC25A40 expression could be regulated by the signaling pathway via toll-like receptor 4 and the receptor for advanced glycation end products, respectively. Our findings contribute to understanding the role of mGSH in the maintenance of the mitochondrial redox state. To the best of our knowledge, this is the first study that demonstrates the changes in Slc25a39/40 expression in mice with cholestasis-associated renal injury and LPS-induced inflammation.
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27
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Ponzo P, Campion D, Rizzo M, Roma M, Caviglia GP, Giovo I, Rizzi F, Bonetto S, Saracco GM, Alessandria C. Transjugular intrahepatic porto-systemic shunt in cirrhotic patients with hepatorenal syndrome - chronic kidney disease: Impact on renal function. Dig Liver Dis 2022; 54:1101-1108. [PMID: 34625366 DOI: 10.1016/j.dld.2021.09.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 09/10/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Transjugular intrahepatic porto-systemic shunt (TIPS) ameliorates renal function in type-2 hepatorenal syndrome (HRS). Available evidence is based on 'old' HRS diagnostic criteria, and not on the current definition of HRS - chronic kidney disease (HRS-CKD). Among patients who underwent TIPS for refractory ascites over the last 12 years, we investigated clinical and renal function evolution of those with HRS-CKD. METHODS among 212 patients, 41 with HRS-CKD were included. Renal function was evaluated for 12 months after TIPS, along with management of ascites and transplant-free survival (TFS). RESULTS renal function significantly improved already one week after TIPS [serum creatinine (sCr): 1.37 ± 0.23 vs 1.94 ± 0.54 mg/dl, p< 0.001]; the amelioration was maintained during the whole follow-up and was observed in every CKD stage, defined according to baseline estimated Glomerular Filtration Rate (eGFR). sCr and eGFR became comparable between different CKD stages after only one week, whilst significantly different at baseline. TIPS led to a remarkable improvement in the control of ascites in all CKD stages and no significant differences in TFS were recorded. CONCLUSIONS TIPS led to an early, substantial and persistent improvement in renal function in patients with HRS-CKD, irrespective of their baseline CKD stage.
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Affiliation(s)
- Paola Ponzo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Daniela Campion
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Martina Rizzo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Michele Roma
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - Ilaria Giovo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Felice Rizzi
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Silvia Bonetto
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Giorgio Maria Saracco
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy.
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28
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Mahmoud Kh N, Refaat She M, Saber Moha A, Mohamed El M. Ovothiol-A Ameliorates Renal Injury Induced by Bile Duct Ligation in Rats (Biological, Quantum-Chemical and Molecular Docking Study). INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.1210.1218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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29
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Yang B, Huang S, Li S, Feng Z, Zhao G, Ma Q. Safety Evaluation of Porcine Bile Acids in Laying Hens: Effects on Laying Performance, Egg Quality, Blood Parameters, Organ Indexes, and Intestinal Development. Front Vet Sci 2022; 9:895831. [PMID: 35685343 PMCID: PMC9171047 DOI: 10.3389/fvets.2022.895831] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/06/2022] [Indexed: 01/14/2023] Open
Abstract
Bile acids (BAs) have long been known to facilitate digestion, transport, and absorption of lipids in the small intestine as well as regulate host lipid metabolic homeostasis. However, excessive BAs may lead to long-term damage to tissue. Also, it is unknown whether different levels of porcine BAs supplementation could improve performance, host metabolism, intestinal functions in laying hens. Hence, this study was aimed to investigate the potential effects of BAs addition on laying performance, egg quality, blood parameters, organ indexes, and intestinal histopathology of hens in the late phase. A total of 300 58-week-old Hy-line Gray hens were randomly divided into five groups which fed a basal diet (control) or basal diets supplemented with 60, 300, 600, and 3,000 mg/kg BAs for 56 days. Compared with the control group, no significant differences (P > 0.05) were observed in egg production, egg weight, ADFI, and FCR of hens in 60, 300, 600, and 3,000 mg/kg BAs groups. Dietary 60 mg/kg BAs supplementation resulted in a significant increase (P < 0.05) in egg mass. Meanwhile, no significant differences were observed in egg quality, including eggshell strength, eggshell thickness, albumen height, and Haugh unit among any treatment groups (P > 0.05). Dramatically, dietary 3,000 mg/kg BAs supplement decreased yolk color (P < 0.05). There was no significant difference in the blood parameters such as WBC, RBC, HGB, HCT, and PLT among any treatments. However, in 3,000 mg/kg BAs group, ovary coefficient was lower than the control (P < 0.05), and serum urea and creatinine were higher than the control (P < 0.05). Also, kidney and oviduct injury appeared in 3,000 mg/kg BAs group. These results indicated that a porcine BAs concentration of 3,000 mg/kg may cause harmful effects while 600 mg/kg was non-deleterious to laying hens after a daily administration for 56 days, namely that dietary supplement of up to 10 times the recommended dose of BAs was safely tolerated by laying hens.
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Affiliation(s)
- Bowen Yang
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, China
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shimeng Huang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shupeng Li
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, China
| | - Zhihua Feng
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, China
| | - Guoxian Zhao
- College of Animal Science and Technology, Hebei Agricultural University, Baoding, China
- *Correspondence: Guoxian Zhao
| | - Qiugang Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
- Qiugang Ma
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30
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Huang Y, Cai J, Ha F, Guo B, Xin S, Duan Z, Han T. Characteristics of acute kidney injury and its impact on outcome in patients with acute-on-chronic liver failure. BMC Gastroenterol 2022; 22:231. [PMID: 35545763 PMCID: PMC9092688 DOI: 10.1186/s12876-022-02316-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/03/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Acute kidney injury (AKI) is a common and life-threatening complication of liver failure. The purpose of this study is to construct a nomogram and online calculator to predict the development of hospital-acquired acute kidney injury (HA-AKI) in patients with acute-on-chronic liver failure (ACLF), which may contribute to the prognosis of ACLF. METHODS 574 ACLF patients were evaluated retrospectively. AKI was defined by criteria proposed by International Club of Ascites (ICA) and divided into community-acquired and hospital-acquired AKI (CA-AKI and HA-AKI). The difference between CA-AKI and HA-AKI, factors associated with development into and recovered from AKI periods. The risk factors were identified and nomograms were developed to predict the morbidity of HA-AKI in patients with ACLF. RESULTS Among 574 patients, 217(37.8%) patients had AKI, CA-AKI and HA-AKI were 56 (25.8%) and 161 (74.2%) respectively. The multivariate logistic regression model (KP-AKI) for predicting the occurrence of HA-AKI were age, gastrointestinal bleeding, bacterial infections, albumin, total bilirubin, blood urea nitrogen and prothrombin time. The AUROC of the KP-AKI in internal and external validations were 0.747 and 0.759, respectively. Among 217 AKI patients, 81(37.3%), 96(44.2%) and 40(18.4%) patients were with ICA-AKI stage progression, regression and fluctuated in-situ, respectively. The 90-day mortality of patients with AKI was 55.3% higher than non-AKI patients 21.6%. The 90-day mortality of patients with progression of AKI was 88.9%, followed by patients with fluctuated in-situ 40% and regression of AKI 33.3%. CONCLUSIONS The nomogram constructed by KP-AKI can be conveniently and accurately in predicting the development of HA-AKI, and AKI can increase the 90-day mortality significantly in ACLF patients. Trial registration Chinese clinical trials registry: ChiCTR1900021539.
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Affiliation(s)
- Yue Huang
- Department of Hepatology and Gastroenterology, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China.,Department of Hepatology and Gastroenterology, Tianjin Union Medical Center affiliated to Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, China
| | - Junjun Cai
- Department of Hepatology and Gastroenterology, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China.,Artificial Cell Engineering Technology Research Center, Tianjin, China.,Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
| | - Fushuang Ha
- Department of Hepatology and Gastroenterology, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China.,Department of Hepatology and Gastroenterology, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China.,Artificial Cell Engineering Technology Research Center, Tianjin, China.,Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
| | - Beichen Guo
- Department of Hepatology and Gastroenterology, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China.,Department of Hepatology and Gastroenterology, Tianjin Union Medical Center affiliated to Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, China
| | - Shaojie Xin
- Liver Failure Treatment and Research Center, The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Zhongping Duan
- Liver Disease Center (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Tao Han
- Department of Hepatology and Gastroenterology, The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China. .,Department of Hepatology and Gastroenterology, Tianjin Union Medical Center affiliated to Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, China.
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Abstract
Hepatorenal syndrome (HRS) is defined as a functional renal failure without major histologic changes in individuals with severe liver disease and it is associated with a high mortality rate. Renal hypoperfusion due to marked vasoconstriction as a result of complex circulatory dysfunction has been suggested to be the cornerstone of HRS. Splanchnic and peripheral arterial vasodilation and cirrhotic cardiomyopathy result in effective arterial hypovolemia and compensatory activation of vasoconstrictor mechanisms. The efficacy of current therapeutic strategies targeting this circulatory dysfunction is limited. Increasing evidence suggests a substantial role of systemic inflammation in HRS via either vascular or direct renal effects. Here we summarize the current understanding of HRS pathophysiology.
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Affiliation(s)
- Timea Csak
- Sandra Atlas Bass Center for Liver Diseases, Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
| | - David Bernstein
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 400 Community Drive, Manhasset, NY 11030, USA
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32
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Habas E, Ibrahim AR, Moursi MO, Shraim BA, Elgamal ME, Elzouki AN. Update on hepatorenal Syndrome: Definition, Pathogenesis, and management. Arab J Gastroenterol 2022; 23:125-133. [PMID: 35473682 DOI: 10.1016/j.ajg.2022.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 12/25/2021] [Accepted: 01/27/2022] [Indexed: 12/18/2022]
Abstract
Hepatorenal syndrome (HRS) is acute kidney injury (AKI) that occurs without evidence of structural abnormalities in the kidneys in patients with liver disease. It is thought to be due to splanchnic vasculature dilatation that is associated with intense increase of renal arteries' tone, leading to renal cortex ischemia and AKI. Nitric oxide, endotoxins, neurohormonal changes, bacterial infection, high serum bilirubin and bile acids are examples for factors contributing to HRS development. Nevertheless, other unknown factors may have role in HRS pathophysiology. Hence, further discussion and research are needed to clearly understand HRS. Plasma volume restoration and vasoconstrictors are the cornerstone of HRS treatment. Others such as octreotide, noradrenaline, infection control, systemic inflammatory response prevention, shunting, and renal replacement therapy are currently used to manage HRS. Liver or combined liver and kidney transplantation is currently the ultimate cure for HRS. This review was written to help in better understanding the pathogenesis, diagnosis, and treatment options for HRS.
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Affiliation(s)
- Elmukhtar Habas
- Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
| | - Ayman R Ibrahim
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Moaz O Moursi
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Bara A Shraim
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | | | - Abdel-Naser Elzouki
- Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar; College of Medicine, QU Health, Qatar University, Doha, Qatar; Weill Cornell Medical College, Qatar.
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33
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Salas-Silva S, López-Ramirez J, Barrera-Chimal J, Lazzarini-Lechuga R, Simoni-Nieves A, Souza V, Miranda-Labra RU, Masso F, Roma MG, Gutiérrez-Ruiz MC, Bucio-Ortiz L, Gomez-Quiroz LE. Hepatocyte growth factor reverses cholemic nephropathy associated with α-naphthylisothiocyanate-induced cholestasis in mice. Life Sci 2022; 295:120423. [DOI: 10.1016/j.lfs.2022.120423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/15/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023]
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34
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Somagutta MR, Jain MS, Pormento MKL, Pendyala SK, Bathula NR, Jarapala N, Mahadevaiah A, Sasidharan N, Gad MA, Mahmutaj G, Hange N. Bile Cast Nephropathy: A Comprehensive Review. Cureus 2022; 14:e23606. [PMID: 35505725 PMCID: PMC9053373 DOI: 10.7759/cureus.23606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 03/29/2022] [Indexed: 11/14/2022] Open
Abstract
Bile cast nephropathy (BCN) or cholemic nephropathy (CN) is an acute renal dysfunction, including acute kidney injury (AKI) in the setting of liver injury. It is a common phenomenon in patients with liver disease and is associated with significant morbidity and mortality. CN is characterized by hemodynamic changes in the liver, kidney, systemic circulation, intratubular cast formation, and tubular epithelial cell injury. CN has been overlooked as a differential diagnosis in chronic liver disease patients due to more importance to hepatic injury. However, frequent and considerable reporting of case reports recently has further investigated this topic in the last two decades. This review determines the evidence behind the potential role of bile acids and bilirubin in acute renal dysfunction in liver injury, summarizing the implied pathophysiology risk factors, and incorporating the therapeutic mechanisms and outcomes.
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35
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Tinti F, Umbro I, D’Alessandro M, Lai S, Merli M, Noce A, Di Daniele N, Mazzaferro S, Mitterhofer AP. Cholemic Nephropathy as Cause of Acute and Chronic Kidney Disease. Update on an Under-Diagnosed Disease. Life (Basel) 2021; 11:1200. [PMID: 34833076 PMCID: PMC8620937 DOI: 10.3390/life11111200] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/14/2022] Open
Abstract
Cholemic nephropathy (CN) is a recognized cause of acute kidney injury (AKI) in patients with severe hyperbilirubinemia (sHyb) and jaundice. Pathophysiological mechanisms of CN are not completely understood, but it seems caused both by direct toxicity of cholephiles and bile casts formation in nephrons enhanced by prolonged exposure to sHyb, particularly in the presence of promoting factors, as highlighted by a literature reviewed and by personal experience. The aim of our update is to retrace CN in its pathophysiology, risk factors, diagnosis and treatment, underlining the role of sHyb, promoting factors, and CN-AKI diagnostic criteria in the different clinical settings associated with this often-concealed disease. Our purpose is to focus on clinical manifestation of CN, exploring the possible transition to CKD. Cholemic nephropathy is an overlooked clinical entity that enters differential diagnosis with other causes of AKI. Early diagnosis and treatment are essential because renal injury could be fully reversible as rapidly as bilirubin levels are reduced. In conclusion, our proposal is to introduce an alert for considering CN in diagnostic and prognostic scores that include bilirubin and/or creatinine with acute renal involvement, with the aim of early diagnosis and treatment of sHyb to reduce the burden on renal outcome.
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Affiliation(s)
- Francesca Tinti
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (I.U.); (S.L.); (S.M.)
| | - Ilaria Umbro
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (I.U.); (S.L.); (S.M.)
| | - Mariadomenica D’Alessandro
- Clinical Pathology Unit, Department of General Surgery “P.Stefanini”, Sapienza University of Rome, 00161 Rome, Italy;
| | - Silvia Lai
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (I.U.); (S.L.); (S.M.)
| | - Manuela Merli
- Gastroenterology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy;
| | - Annalisa Noce
- UOC of Internal Medicine—Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (A.N.); (N.D.D.)
| | - Nicola Di Daniele
- UOC of Internal Medicine—Center of Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (A.N.); (N.D.D.)
| | - Sandro Mazzaferro
- Nephrology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (I.U.); (S.L.); (S.M.)
| | - Anna Paola Mitterhofer
- Nephrology and Dialysis Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
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36
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Liu SY, Huang CC, Huang SF, Liao TL, Kuo NR, Yang YY, Li TH, Liu CW, Hou MC, Lin HC. Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats. Cells 2021; 10:3044. [PMID: 34831270 PMCID: PMC8616474 DOI: 10.3390/cells10113044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 01/23/2023] Open
Abstract
Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.
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Affiliation(s)
- Szu-Yu Liu
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Chia-Chang Huang
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Shiang-Fen Huang
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Tsai-Ling Liao
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 11217, Taiwan
| | - Nai-Rong Kuo
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Ying-Ying Yang
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Tzu-Hao Li
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Foundation, Taipei 11217, Taiwan
| | - Chih-Wei Liu
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Ming-Chih Hou
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Han-Chieh Lin
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
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Zhao J, Setchell KDR, Gong Y, Sun Y, Zhang P, Heubi JE, Fang L, Lu Y, Xie X, Gong J, Wang JS. Genetic spectrum and clinical characteristics of 3β-hydroxy-Δ 5-C 27-steroid oxidoreductase (HSD3B7) deficiency in China. Orphanet J Rare Dis 2021; 16:417. [PMID: 34627351 PMCID: PMC8501698 DOI: 10.1186/s13023-021-02041-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/19/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Biallelic variants in HSD3B7 cause 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a life-threatening but treatable liver disease. The goal of this study was to obtain detailed information on the correlation between the genotype and phenotype of HSD3B7 deficiency and to report on responses to primary bile acid therapy. METHODS The medical records of a cohort of 39 unrelated patients with genetically and biochemically confirmed HSD3B7 deficiency were examined to determine whether there exist genotype-phenotype relationships in this bile acid synthesis disorder. RESULTS In all, 34 of the 44 variants identified in HSD3B7 were novel. A total of 32 patients presented early with neonatal cholestasis, and 7 presented after 1-year of age with liver failure (n = 1), liver cirrhosis (n = 3), cholestasis (n = 1), renal cysts and abnormal liver biochemistries (n = 1), and coagulopathy from vitamin K1 deficiency and abnormal liver biochemistries (n = 1). Renal lesions, including renal cysts, renal stones, calcium deposition and renal enlargement were observed in 10 of 35 patients. Thirty-three patients were treated with oral chenodeoxycholic acid (CDCA) resulting in normalization of liver biochemistries in 24, while 2 showed a significant clinical improvement, and 7 underwent liver transplantation or died. Remarkably, renal lesions in 6 patients resolved after CDCA treatment, or liver transplantation. There were no significant correlations between genotype and clinical outcomes. CONCLUSIONS In what is the largest cohort of patients with HSD3B7 deficiency thus far studied, renal lesions were a notable clinical feature of HSD3B7 deficiency and these were resolved with suppression of atypical bile acids by oral CDCA administration.
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Affiliation(s)
- Jing Zhao
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Kenneth D R Setchell
- Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Ying Gong
- Department of Radiology, Children's Hospital of Fudan University, Shanghai, China
| | - Yinghua Sun
- Department of Ultrasonography, Children's Hospital of Fudan University, Shanghai, China
| | - Ping Zhang
- Center for Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China
| | - James E Heubi
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Lingjuan Fang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Yi Lu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Xinbao Xie
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Jingyu Gong
- Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China.
- Shanghai Key Laboratory of Birth Defect, Shanghai, China.
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38
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Desai MS. Mechanistic insights into the pathophysiology of cirrhotic cardiomyopathy. Anal Biochem 2021; 636:114388. [PMID: 34587512 DOI: 10.1016/j.ab.2021.114388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/22/2021] [Accepted: 09/15/2021] [Indexed: 02/08/2023]
Abstract
Myocardial dysfunction in end stage cirrhotic liver disease, termed cirrhotic cardiomyopathy, is a long known, but little understood comorbidity seen in ∼50% of adults and children who present for liver transplantation. Structural, functional, hemodynamic and electrocardiographic aberrations that occur in the heart as a direct consequence of a damaged liver, is associated with multi-organ failure and increased mortality and morbidity in patients undergoing surgical procedures such as porto-systemic shunt placement and liver transplantation. Despite its clinical significance and rapid advances in science and pharmacotherapy, there is yet no specific treatment for this disease. This may be due to a lack of understanding of the pathogenesis and mechanisms behind how a cirrhotic liver causes cardiac pathology. This review will focus specifically on insights into the molecular mechanisms that drive this liver-heart interaction. Deeper understanding of the etio-pathogenesis of cirrhotic cardiomyopathy will allow us to design and test treatments that can be targeted to prevent and/or reverse this co-morbid consequence of liver failure and improve health care delivery and outcomes in patients with cirrhosis.
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Affiliation(s)
- Moreshwar S Desai
- Department of Pediatrics, Section of Pediatric Critical Care Medicine and Liver ICU. Baylor College of Medicine, Houston, TX, 77030, USA.
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39
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Reiter S, Dunkel A, Dawid C, Hofmann T. Targeted LC-MS/MS Profiling of Bile Acids in Various Animal Tissues. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:10572-10580. [PMID: 34490775 DOI: 10.1021/acs.jafc.1c03433] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Bile acids are being increasingly investigated in humans and laboratory animals as markers for various diseases in addition to their important functions, such as promoting the emulsification in fat digestion and preventing gallstone formation. In humans and animals, primary bile acids are formed from cholesterol in the liver, converted in the intestine into various secondary bile acids by the intestinal microbiota and reabsorbed in the terminal ileum, and partially returned to the liver. A universal high-throughput workflow, including a simple workup, was applied as a tool for bile acid analysis in animal studies. The complex bile acid profiles in various tissues, organs, and body fluids from different animals were mapped using a newly developed comprehensive liquid chromatography-tandem mass spectrometry method. The method can also be used in screening food to obtain information about the nutritional content of bile acids. This could be relevant to investigations on various animal diseases and on the bioavailability of bile acids that pass through the gastric tract.
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Affiliation(s)
- Sinah Reiter
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
- ZIEL-Institute for Food and Health, Technical University of Munich, Weihenstephaner Berg 1, 85354 Freising, Germany
| | - Andreas Dunkel
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Straße 34, 85354 Freising, Germany
| | - Corinna Dawid
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
| | - Thomas Hofmann
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
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40
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Ommati MM, Attari H, Siavashpour A, Shafaghat M, Azarpira N, Ghaffari H, Moezi L, Heidari R. Mitigation of cholestasis-associated hepatic and renal injury by edaravone treatment: Evaluation of its effects on oxidative stress and mitochondrial function. LIVER RESEARCH 2021; 5:181-193. [PMID: 39957848 PMCID: PMC11791843 DOI: 10.1016/j.livres.2020.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/20/2020] [Accepted: 10/25/2020] [Indexed: 02/07/2023]
Abstract
Background and aim The liver is the primary organ affected by cholestasis, and complications such as renal injury, renal failure, and the need for renal transplantation are associated with cholestatic liver disease. There is substantial evidence indicating that reactive oxygen species (ROS) and mitochondrial impairment are fundamental mechanisms underlying cholestasis-induced hepatic and renal injury. Edaravone (EDV) is a potent radical scavenger and antioxidant that may prevent oxidative stress and improve impaired mitochondrial function in various diseases. This study was performed to evaluate the effects and mechanisms of action of EDV on hepatic and renal injury in an animal model of cholestasis. Methods Rats subjected to bile duct ligation (BDL) were treated with EDV 1 or 10 mg/kg/day intraperitoneally for 14 consecutive days. Biomarkers of oxidative stress and mitochondrial impairment in the liver and kidney were assessed in EDV-treated and untreated rats with cholestasis. Results Significant increases in tissue ROS level, lipid peroxidation, protein carbonylation, and oxidized glutathione level were detected in rats subjected to BDL. Additionally, significant decreases in tissue glutathione level and antioxidant capacity were observed in the hepatic and renal tissues of rats with cholestasis. Markers of mitochondrial impairment, including mitochondrial depolarization, lipid peroxidation, mitochondrial permeabilization, depleted adenosine triphosphate content, and decreased dehydrogenase activity, were also detected in rats subjected to BDL. Furthermore, portal inflammation, necrosis, and tissue fibrosis were detected in the liver and significant tubular atrophy and interstitial inflammation, as well as fibrotic lesions, were detected in the kidneys of rats with cholestasis. EDV treatment significantly mitigated cholestasis-associated hepatic and renal injury. Conclusions The antioxidative properties of EDV and its positive effects on the indices of mitochondrial function may be critical factors contributing to protection against cholestasis-associated hepatic and renal injury.
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Affiliation(s)
| | - Hanie Attari
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Siavashpour
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Marzieh Shafaghat
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hasti Ghaffari
- Department of Veterinary Sciences, Islamic Azad University, Urmia Branch, Urmia, Iran
| | - Leila Moezi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Ommati MM, Mohammadi H, Mousavi K, Azarpira N, Farshad O, Dehghani R, Najibi A, Kamran S, Niknahad H, Heidari R. Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function. LIVER RESEARCH 2021; 5:171-180. [PMID: 39957842 PMCID: PMC11791814 DOI: 10.1016/j.livres.2020.12.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/01/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022]
Abstract
Background and aim Cholestasis-associated renal injury or cholemic nephropathy (CN) is a serious clinical problem. Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN. There is no specific pharmacological intervention for CN. Metformin is an anti-diabetic drug administered for decades. On the other hand, novel pharmacological properties have emerged for this drug. The effect of metformin on oxidative stress parameters has been well-recognized in different experimental models. It has also been found that metformin positively affected mitochondrial function. The current study aimed to evaluate the effects of metformin in an animal model of CN. Methods Rats underwent bile duct ligation (BDL) and were treated with metformin (250 and 500 mg/kg) for 14 consecutive days. Two weeks after the BDL operations, urine, serum, and kidney samples were collected and analyzed. Results Markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, depleted antioxidant capacity, and decreased glutathione (GSH) levels were detected in BDL animals. Moreover, mitochondrial indices, including adenosine triphosphate (ATP) level, dehydrogenase activity, mitochondrial membrane potential, and mitochondrial permeability, were impaired in the kidney of cholestatic rats. Renal histopathological alterations in cholestatic animals included tubular degeneration and interstitial inflammation, cast formation, and fibrosis. It was found that metformin significantly alleviated oxidative stress and improved mitochondrial indices in the kidney of cholestatic rats. Tissue histopathological alterations were also mitigated in metformin-treated groups. Conclusions Metformin could be a candidate for managing CN. The nephroprotective role of metformin is primarily associated with its effects on oxidative stress parameters and mitochondrial function.
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Affiliation(s)
| | - Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Khadijeh Mousavi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reyhaneh Dehghani
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Najibi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Chemistry, Payame Noor University, Tehran, Iran
| | - Sedigheh Kamran
- Department of Chemistry, Payame Noor University, Tehran, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Zhao X, Huang R, Wong P, Fiset PO, Deschênes M. Renal tubular injury in hyperbilirubinemia: Bile cast nephropathy. CANADIAN LIVER JOURNAL 2021; 4:332-337. [PMID: 35992254 PMCID: PMC9202769 DOI: 10.3138/canlivj-2020-0031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/26/2020] [Indexed: 04/25/2025]
Abstract
The toxic renal accumulation of bile pigment sparked clinical intrigue almost a century ago. More recently, however, the identification of bile casts within renal tubules in patients with liver dysfunction has been largely overlooked. We have reviewed the literature, including natural history, pathophysiology, and potential treatment of bile cast nephropathy (BCN). We report two cases of acute kidney injury (AKI) associated with acute-on-chronic liver failure in which prolonged hyperbilirubinemia and bile cast identification on renal biopsy evoked the diagnosis of BCN.
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Affiliation(s)
- Xun Zhao
- Department of Hepatology, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada
| | - Ruiyao Huang
- Department of Hepatology, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada
| | - Philip Wong
- Department of Hepatology, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada
| | - Pierre-Oliver Fiset
- Department of Pathology, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada
| | - Marc Deschênes
- Department of Hepatology, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada
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Mousavi K, Niknahad H, Li H, Jia Z, Manthari RK, Zhao Y, Shi X, Chen Y, Ahmadi A, Azarpira N, Khalvati B, Ommati MM, Heidari R. The activation of nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling blunts cholestasis-induced liver and kidney injury. Toxicol Res (Camb) 2021; 10:911-927. [PMID: 34484683 PMCID: PMC8403611 DOI: 10.1093/toxres/tfab073] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/29/2021] [Accepted: 07/08/2021] [Indexed: 12/26/2022] Open
Abstract
Cholestasis is a severe clinical complication that severely damages the liver. Kidneys are also the most affected extrahepatic organs in cholestasis. The pivotal role of oxidative stress has been mentioned in the pathogenesis of cholestasis-induced organ injury. The activation of the nuclear factor-E2-related factor 2 (Nrf2) pathway is involved in response to oxidative stress. The current study was designed to evaluate the potential role of Nrf2 signaling activation in preventing bile acids-induced toxicity in the liver and kidney. Dimethyl fumarate was used as a robust activator of Nrf2 signaling. Rats underwent bile duct ligation surgery and were treated with dimethyl fumarate (10 and 40 mg/kg). Severe oxidative stress was evident in the liver and kidney of cholestatic animals (P < 0.05). On the other hand, the expression and activity of Nrf2 and downstream genes were time-dependently decreased (P < 0.05). Moreover, significant mitochondrial depolarization, decreased ATP levels, and mitochondrial permeabilization were detected in bile duct-ligated rats (P < 0.05). Histopathological alterations included liver necrosis, fibrosis, inflammation and kidney interstitial inflammation, and cast formation. It was found that dimethyl fumarate significantly decreased hepatic and renal injury in cholestatic animals (P < 0.05). Based on these data, the activation of the cellular antioxidant response could serve as an efficient therapeutic option for managing cholestasis-induced organ injury.
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Affiliation(s)
- Khadijeh Mousavi
- Department of Bio-informatics, College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi 030801, China
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran
| | - Hossein Niknahad
- Department of Bio-informatics, College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi 030801, China
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran
| | - Huifeng Li
- Shanxi Key Laboratory of Environmental Veterinary Medicine, College of Animal Sciences and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Zhipeng Jia
- Shanxi Key Laboratory of Environmental Veterinary Medicine, College of Animal Sciences and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Ram Kumar Manthari
- Department of Biotechnology, GITAM Institute of Science, Visakhapatnam, Gandhi Institute of Technology and Management, Andhra Pradesh 530045, India
| | - Yangfei Zhao
- Shanxi Key Laboratory of Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Xiong Shi
- Shanxi Key Laboratory of Environmental Veterinary Medicine, College of Animal Sciences and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Yuanyu Chen
- Shanxi Key Laboratory of Environmental Veterinary Medicine, College of Animal Sciences and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China
| | - Asrin Ahmadi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran
| | - Bahman Khalvati
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj 75919-51176, Iran
| | - Mohammad Mehdi Ommati
- Department of Bio-informatics, College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi 030801, China
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran
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Simbrunner B, Trauner M, Reiberger T, Mandorfer M. Recent advances in the understanding and management of hepatorenal syndrome. Fac Rev 2021; 10:48. [PMID: 34131658 PMCID: PMC8170686 DOI: 10.12703/r/10-48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Renal dysfunction occurs frequently in hospitalized patients with advanced chronic liver disease (ACLD)/cirrhosis and has profound prognostic implications. In ACLD patients with ascites, hepatorenal syndrome (HRS) may result from circulatory dysfunction that leads to reduced kidney perfusion and glomerular filtration rate (in the absence of structural kidney damage). The traditional subclassification of HRS has recently been replaced by acute kidney injury (AKI) type of HRS (HRS-AKI) and non-AKI type of HRS (HRS-NAKI), replacing the terms “HRS type 1” and “HRS type 2”, respectively. Importantly, the concept of absolute serum creatinine (sCr) cutoffs for diagnosing HRS was partly abandoned and short term sCr dynamics now may suffice for AKI diagnosis, which facilitates early treatment initiation that may prevent the progression to HRS-AKI or increase the chances of AKI/HRS-AKI reversal. Recent randomized controlled trials have established (a) the efficacy of (long-term) albumin in the prevention of complications of ascites (including HRS-AKI), (b) the benefits of transjugular intrahepatic portosystemic shunt placement in patients with recurrent ascites, and (c) the superiority of terlipressin over noradrenaline for the treatment of HRS-AKI in the context of acute-on-chronic liver failure. This review article aims to summarize recent advances in the understanding and management of HRS.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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Weng J, Han X, Zeng F, Zhang Y, Feng L, Cai L, Liang K, Liu S, Li S, Fu G, Zeng M, Gao Y. Fiber scaffold bioartificial liver therapy relieves acute liver failure and extrahepatic organ injury in pigs. Theranostics 2021; 11:7620-7639. [PMID: 34335954 PMCID: PMC8315066 DOI: 10.7150/thno.58515] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 04/15/2021] [Indexed: 02/06/2023] Open
Abstract
Rationale: Acute liver failure (ALF) causes severe liver injury and a systemic inflammatory response, leading to multiorgan failure with a high short-term mortality. Bioartificial liver (BAL) therapy is a promising approach that is hampered by the lack of appropriate bioreactors and carriers to retain hepatic cell function and poor understanding of BAL treatment mechanisms in ALF and extrahepatic organ injury. Recently, we used a fiber scaffold bioreactor (FSB) for the high-density, three-dimensional (3D) culture of primary porcine hepatocytes (PPHs) combined with an absorption component to construct a BAL and verified its function in a D-galactosamine (D-gal)-induced ALF porcine model to evaluate its protective effects on the liver and extrahepatic organs. Methods: Male pigs were randomized into standard/supportive therapy (ST), ST+no-cell BAL (ST+Sham BAL) and ST+BAL groups and received treatment 48 h after receiving a D-gal injection. Changes in blood chemistry and clinical symptoms were monitored for 120 h. Tissues and plasma were collected for analysis by pathological examination, immunoblotting, quantitative PCR and immunoassays. Results: PPHs cultured in the FSB obtained sufficient aeration and nutrition for high-density, 3D culture and maintained superior viability and functionality (biosynthesis and detoxification) compared with those cultured in flasks. All the animals developed ALF, acute kidney injury (AKI) and hepatic encephalopathy (HE) 48 h after D-gal infusion and received corresponding therapies. Animals in the BAL group showed markedly improved survival (4/5; 80%) compared with those in the ST+Sham BAL (0/5; p < 0.001) and ST (0/5; p < 0.001) groups. The levels of blood ammonia and biochemical and inflammatory indices were alleviated after BAL treatment. Increased liver regeneration and attenuations in the occurrence and severity of ALF, AKI and HE were observed in the ST+BAL group compared with the ST (p = 0.0009; p = 0.038) and ST+Sham BAL (p = 0.011; p = 0.031) groups. Gut leakage, the plasma endotoxin level, bacterial translocation, and peripheral and neuroinflammation were alleviated in the ST+BAL group compared with those in the other groups. Conclusions: BAL treatment enhanced liver regeneration and alleviated the systemic inflammatory response and extrahepatic organ injury to prolong survival in the ALF model and has potential as a therapeutic approach for ALF patients.
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Affiliation(s)
- Jun Weng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Xu Han
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Fanhong Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Yue Zhang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Lei Feng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Lei Cai
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Kangyan Liang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Shusong Liu
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Shao Li
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Gongbo Fu
- Department of Medical Oncology, Jinling Hospital, First School of Clinical Medicine, Southern Medical University, Nanjing 210000, China
| | - Min Zeng
- Guangdong Qianhui Biotechnology Co., Ltd., Guangzhou 510285, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
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Ommati MM, Farshad O, Azarpira N, Ghazanfari E, Niknahad H, Heidari R. Silymarin mitigates bile duct obstruction-induced cholemic nephropathy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:1301-1314. [PMID: 33538845 DOI: 10.1007/s00210-020-02040-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/09/2020] [Indexed: 12/14/2022]
Abstract
Bile duct obstruction or cholestasis can occur by several diseases or xenobiotics. Cholestasis and the accumulation of the bile constituents in the liver primarily damage this organ. On the other hand, extrahepatic organs are also affected by cholestasis. The kidney is the most affected tissue during cholestatic liver injury. Cholestasis-associated renal injury is known as cholemic nephropathy (CN). Several lines of evidence specify the involvement of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to assess the role of silymarin as a potent antioxidant on CN-induced oxidative stress and mitochondrial dysfunction in the kidney. Bile duct ligated (BDL) rats were treated with silymarin (10 and 100 mg/kg, oral) for seven consecutive days. A significant increase in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and oxidized glutathione (GSSG) levels were evident in the kidney of BDL animals. Moreover, reduced glutathione (GSH) content and total antioxidant capacity were significantly decreased in the kidney of cholestatic rats. Mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depleted ATP stores were detected in the kidney mitochondria isolated from BDL animals. Kidney histopathological alterations, as well as serum and urine levels of renal injury biomarkers, were also significantly different in the BDL group. It was found that silymarin treatment significantly ameliorated CN-induced renal injury. The antioxidant effects of silymarin and its positive impact on mitochondrial indices seem to play a significant role in its renoprotective effects during cholestasis.
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Affiliation(s)
- Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St., Shiraz, Fars, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elmira Ghazanfari
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St., Shiraz, Fars, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St., Shiraz, Fars, Iran.
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Ghanbarinejad V, Jamshidzadeh A, Khalvati B, Farshad O, Li H, Shi X, Chen Y, Ommati MM, Heidari R. Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:1191-1203. [PMID: 33527194 DOI: 10.1007/s00210-020-02041-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/13/2020] [Indexed: 02/07/2023]
Abstract
Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues' AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease. Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.
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Affiliation(s)
- Vahid Ghanbarinejad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran
- Department of Pharmacology and Toxicology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran
- Department of Pharmacology and Toxicology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bahman Khalvati
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran
| | - Huifeng Li
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Xiong Shi
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Yuanyu Chen
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China.
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran.
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Maiwall R, Pasupuleti SSR, Chandel SS, Narayan A, Jain P, Mitra LG, Kumar G, Moreau R, Sarin SK. Co-orchestration of acute kidney injury and non-kidney organ failures in critically ill patients with cirrhosis. Liver Int 2021; 41:1358-1369. [PMID: 33534915 DOI: 10.1111/liv.14809] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 12/21/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Little is known on the course of acute kidney injury (AKI) and its relation to non-kidney organ failures and mortality in critically ill patients with cirrhosis (CICs). METHODS We conducted a large prospective, single-centre, observational study in which CICs were followed up daily, during the first 7 days of intensive care, collecting prespecified criteria for AKI, extrarenal extrahepatic organ failures (ERH-OFs) and systemic inflammatory response syndrome (SIRS). RESULTS A total of 291 patients admitted to ICU were enrolled; 231 (79.4%) had at least one ERH-OFs, 168 (58%) had AKI at presentation, and 145 (49.8%) died by 28 days. At day seven relative to baseline, 151 (51.8%) patients had progressive or persistent AKI, while the rest remained free of AKI or had AKI improvement. The 28-day mortality rate was higher among patients with progressive/persistent AKI (74.2% vs 23.5%; P < .001) or maximum stage 3 of AKI in the first week. Two-level mixed logistic regression modelling identified independent baseline risk factors for progressive/persistent AKI, including 3 to 4 SIRS criteria, infections due to multidrug-resistant bacteria (MDR), elevated serum bilirubin, and number of ERH-OFs. Follow-up risk factors included increases in bilirubin and chloride levels, and new development of 2 or 3 ERH-OFs. CONCLUSIONS Our results show that among CICs admitted to the ICU, the stage and course of AKI in the first week determines outcomes. Strategies combating MDR infections, multiorgan failure, liver failure and intense systemic inflammation could prevent AKI progression or persistence in CICs.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Science, New Delhi, India
| | - Samba Siva R Pasupuleti
- Department of Biostatistics, Institute of Liver and Biliary Science, New Delhi, India.,Department of Statistics, Pachhunga University College, Mizoram University, Aizawl, India
| | - Shivendra S Chandel
- Department of Hepatology, Institute of Liver and Biliary Science, New Delhi, India
| | - Ashad Narayan
- Department of Hepatology, Institute of Liver and Biliary Science, New Delhi, India
| | - Priyanka Jain
- Department of Biostatistics, Institute of Liver and Biliary Science, New Delhi, India
| | - Lalita Gouri Mitra
- Department of Anaesthesia and Critical Care, Institute of Liver and Biliary Science, New Delhi, India
| | - Guresh Kumar
- Department of Biostatistics, Institute of Liver and Biliary Science, New Delhi, India
| | - Richard Moreau
- Inserm, Université de Paris, Centre de Recherche sur l'Inflammation (CRI), Paris, France.,Assistance Publique-Hôpitaux de Paris, Service d'Hépatologie, Hôpital Beaujon, Clichy, France
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Science, New Delhi, India
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Allegretti AS, Belcher JM. Bile Acids Are Important Contributors to AKI Associated with Liver Disease: CON. KIDNEY360 2021; 3:21-24. [PMID: 35378020 PMCID: PMC8967622 DOI: 10.34067/kid.0006512020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/11/2020] [Indexed: 01/10/2023]
Affiliation(s)
- Andrew S. Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Justin M. Belcher
- Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut,Divison of Nephrology, Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
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Fickert P, Rosenkranz AR. Bile Acids Are Important Contributors to AKI Associated with Liver Disease: PRO. KIDNEY360 2021; 3:17-20. [PMID: 35378026 PMCID: PMC8967615 DOI: 10.34067/kid.0005932020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 05/03/2021] [Indexed: 01/10/2023]
Affiliation(s)
- Peter Fickert
- Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
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