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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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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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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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Vrettou CS, Issaris V, Kokkoris S, Poupouzas G, Keskinidou C, Lotsios NS, Kotanidou A, Orfanos SE, Dimopoulou I, Vassiliou AG. Exploring Aquaporins in Human Studies: Mechanisms and Therapeutic Potential in Critical Illness. Life (Basel) 2024; 14:1688. [PMID: 39768394 PMCID: PMC11676363 DOI: 10.3390/life14121688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Aquaporins (AQPs) are membrane proteins facilitating water and other small solutes to be transported across cell membranes. They are crucial in maintaining cellular homeostasis by regulating water permeability in various tissues. Moreover, they regulate cell migration, signaling pathways, inflammation, tumor growth, and metastasis. In critically ill patients, such as trauma, sepsis, and patients with acute respiratory distress syndrome (ARDS), which are frequently encountered in intensive care units (ICUs), water transport regulation is crucial for maintaining homeostasis, as dysregulation can lead to edema or dehydration, with the latter also implicating hemodynamic compromise. Indeed, AQPs are involved in fluid transport in various organs, including the lungs, kidneys, and brain, where their dysfunction can exacerbate conditions like ARDS, acute kidney injury (AKI), or cerebral edema. In this review, we discuss the implication of AQPs in the clinical entities frequently encountered in ICUs, such as systemic inflammation and sepsis, ARDS, AKI, and brain edema due to different types of primary brain injury from a clinical perspective. Current and possible future therapeutic implications are also considered.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Alice G. Vassiliou
- First Department of Critical Care Medicine, School of Medicine, National and Kapodistrian University of Athens, Evangelismos Hospital, 106 76 Athens, Greece; (C.S.V.); (V.I.); (S.K.); (G.P.); (C.K.); (N.S.L.); (A.K.); (S.E.O.); (I.D.)
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Qin J, Xie S, Yu Y, Yang J, Zhao Y, Qiu C, Li X, Zhang C, Hu Z, Tong D, Zhu J, Kuehn B, Shen W. Evaluation of Kidney Injury Using Arterial Spin Labeling and Blood Oxygen Level-Dependent MRI: An Experimental Study in Rats With Carbon Tetrachloride-Induced Liver Cirrhosis. J Magn Reson Imaging 2024; 60:2090-2101. [PMID: 38299767 DOI: 10.1002/jmri.29265] [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: 11/27/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Serum creatinine (Scr) may be not suited to timely and accurately reflect kidney injury related to chronic liver disease. Currently, the ability of arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) sequences to evaluate renal blood flow (RBF) and blood oxygen in chronic liver disease remains to be verified. PURPOSE To investigate the value of ASL and BOLD imaging in evaluating hemodynamics and oxygenation changes during kidney injury in an animal model of chronic liver disease. STUDY TYPE Prospective. ANIMAL MODEL Chronic liver disease model was established by subcutaneous injection of carbon tetrachloride. Forty-three male Sprague-Dawley rats (8 weeks) were divided into a pathological group (0, 2, 4, 6, 8, 12 weeks, each group: N = 6) and a continuous-scanning group (N = 7). FIELD STRENGTH/SEQUENCE 3-T, ASL, BOLD, and T2W. ASSESSMENT Regions of interest in the cortex (CO), outer stripe of the outer medulla (OSOM), and inner stripe of the outer medulla (ISOM) are manually delineated. The RBF and T2* values at each time point (0, 2, 4, 6, 8, 12 weeks) are measured and compared. Hematoxylin-eosin score (HE Score, damage area scoring method), alpha-smooth muscle actin (α-SMA), hypoxia-inducible factor-1alpha (HIF-1α), peritubular capillar (PTC) density, Scr, and neutrophil gelatinase-associated lipocalin were harvested. STATISTICAL TESTS Analysis of variance, Spearman correlation analysis, Kruskal-Wallis tests, and receiver operating characteristic analysis with the area under the curve (AUC). A P-value <0.05 was considered statistically significant. RESULTS Renal RBF and T2* values of CO, OSOM, and ISOM were significantly different from baseline. Both RBF and T2* were significantly correlated with HE Score, α-SMA, HIF-1α, and PTC density (|r| = 0.406-0.853). RBF demonstrated superior diagnostic capability in identifying severe kidney injury in this model of chronic liver disease (AUC = 0.964). DATA CONCLUSION Imaging by ASL and BOLD may detect renal hemodynamics and oxygenation changes related to chronic liver disease early. EVIDENCE LEVEL 5 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Jiaming Qin
- The School of Medicine, Nankai University, Tianjin, China
| | - Shuangshuang Xie
- Department of Radiology, Tianjin First Central Hospital, Tianjin Institute of Imaging Medicine, Tianjin, China
| | - Yongquan Yu
- Department of Radiology, Weihai Central Hospital, Weihai, Shandong, China
| | - Jiaqi Yang
- First Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Yumeng Zhao
- The School of Medicine, Nankai University, Tianjin, China
| | - Caixin Qiu
- Department of Radiology, Tianjin First Central Hospital, Tianjin Institute of Imaging Medicine, Tianjin, China
| | - Xiaotian Li
- The School of Medicine, Nankai University, Tianjin, China
| | - Cheng Zhang
- First Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Zhandong Hu
- Department of Pathology, Tianjin First Central Hospital, Tianjin, China
| | - Dan Tong
- Department of Pathology, Tianjin First Central Hospital, Tianjin, China
| | - Jinxia Zhu
- MR Collaboration, Siemens Healthineers, Beijing, China
| | - Bernd Kuehn
- MR Application Predevelopment, Siemens Healthcare GmbH, Erlangen, Germany
| | - Wen Shen
- Department of Radiology, Tianjin First Central Hospital, Tianjin Institute of Imaging Medicine, Tianjin, China
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6
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Xu Z. Editorial for "Evaluation of Kidney Injury Using Arterial Spin Labeling and Blood Oxygen Level-Dependent MRI: An Experimental Study in Rats With Carbon Tetrachloride-Induced Liver Cirrhosis". J Magn Reson Imaging 2024; 60:2102-2103. [PMID: 38438273 DOI: 10.1002/jmri.29336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 02/21/2024] [Indexed: 03/06/2024] Open
Affiliation(s)
- Zhan Xu
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Wang K, Xu X, Shan Q, Ding R, Lyu Q, Huang L, Chen X, Han X, Yang Q, Sang X, Peng M, Hao M, Cao G. Integrated gut microbiota and serum metabolomics reveal the protective effect of oleanolic acid on liver and kidney-injured rats induced by Euphorbia pekinensis. Phytother Res 2024; 38:4877-4892. [PMID: 36426741 DOI: 10.1002/ptr.7673] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 09/16/2022] [Accepted: 10/02/2022] [Indexed: 11/27/2022]
Abstract
Euphorbia pekinensis (EP) is a commonly used Chinese medicine treating edema with potential hepatorenal toxicity. However, its toxic mechanism and prevention are remained to be explored. Oleanolic acid (OA) is a triterpene acid with potential hepatorenal protective activities. We investigated the protective effect and potential mechanism of OA on EP-induced hepatorenal toxicity. In this study, rats were given total diterpenes from EP (TDEP, 16 mg/kg) combined with OA (10, 20, 40 mg/kg) by gavage for 4 weeks. The results showed that TDEP administration could lead to a 3-4-fold increasement in hepatorenal biochemical parameters with histopathological injuries, while OA treatment could ameliorate them in a dose-dependent manner. At microbial and metabolic levels, intestinal flora and host metabolism were perturbed after TDEP administration. The disturbance of bile acid metabolism was the most significant metabolic pathway, with secondary bile acids increasing while conjugated bile acids decreased. OA treatment can improve the disorder of intestinal flora and metabolic bile acid spectrum. Further correlation analysis screened out that Escherichia-Shigella, Phascolarctobacterium, Acetatifactor, and Akkermansia were closely related to the bile acid metabolic disorder. In conclusion, oleanolic acid could prevent hepatorenal toxicity induced by EP by regulating bile acids metabolic disorder via intestinal flora improvement.
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Affiliation(s)
- Kuilong Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaofen Xu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiyuan Shan
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rui Ding
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiang Lyu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lichuang Huang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xinyi Chen
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xin Han
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiao Yang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xianan Sang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mengyun Peng
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Min Hao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Gang Cao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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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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Maiwall R, Singh SP, Angeli P, Moreau R, Krag A, Singh V, Singal AK, Tan SS, Puri P, Mahtab M, Lau G, Ning Q, Sharma MK, Rao PN, Kapoor D, Gupta S, Duseja A, Wadhawan M, Jothimani D, Saigal S, Taneja S, Shukla A, Puri P, Govil D, Pandey G, Madan K, Eapen CE, Benjamin J, Chowdhury A, Singh S, Salao V, Yang JM, Hamid S, Shalimar, Jasuja S, Kulkarni AV, Niriella MA, Tevethia HV, Arora V, Mathur RP, Roy A, Jindal A, Saraf N, Verma N, De A, Choudhary NS, Mehtani R, Chand P, Rudra O, Sarin SK. APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure. Hepatol Int 2024; 18:833-869. [PMID: 38578541 DOI: 10.1007/s12072-024-10650-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/20/2024] [Indexed: 04/06/2024]
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Satender Pal Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Paolo Angeli
- Department of Internal Medicine and Hepatology, University of Padova, Padua, Italy
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)-CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Centre de Recherche sur l'Inflammation (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Cité, Paris, France
- Service d'Hépatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Beaujon, Clichy, France
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Virender Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India
| | - Ashwani K Singal
- Department of Medicine, University of Louisville School of Medicine, Trager Transplant Center and Jewish Hospital, Louisville, USA
| | - S S Tan
- Department of Medicine, Hospital Selayang, Bata Caves, Selangor, Malaysia
| | - Puneet Puri
- Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mamun Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - George Lau
- Humanity and Health Medical Group, Humanity and Health Clinical Trial Center, Hong Kong SAR, China
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- State Key Laboratory for Zoonotic Diseases, Wuhan, China
- Department of Pediatrics, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - P N Rao
- Department of Hepatology and Nutrition, Asian Institute of Gastroenterology, Hyderabad, India
| | - Dharmesh Kapoor
- Department of Hepatology, Gleneagles Global Hospitals, Hyderabad, Telangana, India
| | - Subhash Gupta
- Department of Surgery, Center for Liver and Biliary Sciences, Max Healthcare, Saket, New Delhi, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Manav Wadhawan
- Institute of Digestive & Liver Diseases, BLK Superspeciality Hospital Delhi, New Delhi, India
| | - Dinesh Jothimani
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Bharat Institute of Higher Education and Research, Chennai, India
| | - Sanjiv Saigal
- Department of Gastroenterology and Hepatology, Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Akash Shukla
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Pankaj Puri
- Fortis Escorts Liver & Digestive Diseases Institute, New Delhi, India
| | - Deepak Govil
- Department of Critical Care and Anaesthesia, Medanta-The Medicity, Gurugram, Haryana, India
| | - Gaurav Pandey
- Gastroenterology and Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Kaushal Madan
- Department of Gastroenterology and Hepatology, Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - C E Eapen
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Jaya Benjamin
- Department of Clinical Nutrition, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashok Chowdhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Shweta Singh
- Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - Vaishali Salao
- Department of Critical Care, Fortis Hospital, Mulund, Mumbai, India
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Saeed Hamid
- Department of Hepatology, Aga Khan University, Karachi, Pakistan
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Sanjiv Jasuja
- Department of Nephrology, Indraprastha Apollo Hospitals, New Delhi, India
| | | | - Madund A Niriella
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka
| | - Harsh Vardhan Tevethia
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - R P Mathur
- Department of Nephrology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akash Roy
- Department of Gastroenterology, Institute of Gastrosciences and Liver Transplantation, Apollo Hospitals, Kolkata, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Neeraj Saraf
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurgaon, Delhi (NCR), India
| | - Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Narendra S Choudhary
- Department of Hepatology and Liver Transplantation, Medanta-The Medicity Hospital, Gurugram, Haryana, India
| | - Rohit Mehtani
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Phool Chand
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Omkar Rudra
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India.
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10
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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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11
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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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12
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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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13
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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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14
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Calleri A, Alessandria C. Renal damage in Hepatorenal Syndrome: A still unsolved issue. Clin Res Hepatol Gastroenterol 2023; 47:102178. [PMID: 37453679 DOI: 10.1016/j.clinre.2023.102178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 07/02/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023]
Abstract
Acute kidney injury (AKI) is a common complication of cirrhosis, burdened by high morbidity and mortality rates and progression to chronic kidney disease. Hepatorenal syndrome (HRS) is a peculiar type of functional AKI observed in cirrhotic patients with ascites. HRS diagnosis is still clinical, once pre-renal azotemia and intrinsic kidney damage have been excluded by applying well-established and internationally adopted criteria. HRS is considered reversible because of the absence of intrinsic renal damage. However, HRS reversibility has been questioned, due to the lack of response to treatment with vasoconstrictors plus albumin in a relevant percentage of patients and to the persistence of renal dysfunction in HRS patients who underwent liver transplantation (LT). Indeed, LT is the only ultimate treatment, as it solves both liver failure and portal hypertension. Thus, the presence of renal damage in HRS can be hypothesized. In this scenario, neutrophil gelatinase-associated lipocalin (NGAL), one of the most promising biomarkers, may help in characterizing the type of renal injury, distinguishing between HRS and acute tubular necrosis. This review gathers the available evidence in favor and against the presence of structural lesions in HRS in terms of either renal histology and urinary biomarkers with a particular focus on NGAL. The ability to properly characterize which component of renal dysfunction prevails - functional rather than structural - entails a relevant clinical impact for the treatment of these patients, both in terms of medical therapy and liver vs. combined liver-kidney transplantation.
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Affiliation(s)
- Alberto Calleri
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Italy.
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15
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Mohamed A, Peniston M, Mahmood R. Acute Kidney Injury in Patients Admitted to the Intensive Care Unit: A Case Report. Cureus 2023; 15:e40380. [PMID: 37325687 PMCID: PMC10264089 DOI: 10.7759/cureus.40380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2023] [Indexed: 06/17/2023] Open
Abstract
Patients admitted to the intensive care unit are prone to various complications, one of which is acute kidney injury (AKI). The etiology of acute kidney injury can be multifactorial. Among the various causes, sepsis remains the most prevalent. Cholemic nephropathy (CN) is a rare cause of AKI. Patients with CN usually present with elevated total bilirubin levels of greater than 20 mg/dl. However, CN has been reported in patients with total bilirubin levels of less than 20 mg/dL. These patients were found to have chronic elevations of bilirubin due to chronic liver disease rather than an acute rise in bilirubin levels. In this case series, we present two cases of patients with chronic liver disease who were admitted to the intensive care unit and were found to have AKI with elevated total bilirubin levels over 15 mg/dl.
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Affiliation(s)
- Ayman Mohamed
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
| | | | - Rabia Mahmood
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
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16
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Matchett CL, Simonetto DA, Kamath PS. Renal Insufficiency in Patients with Cirrhosis. Clin Liver Dis 2023; 27:57-70. [PMID: 36400467 DOI: 10.1016/j.cld.2022.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Renal failure is one of the most prevalent complications in patients with cirrhosis and is of the utmost prognostic relevance. Acute kidney injury (AKI) in cirrhosis results from a spectrum of etiologies, of which hepatorenal syndrome (HRS) carries the worst prognosis. Correct differentiation of the etiology of AKI in cirrhosis is imperative, as treatment defers substantially. This review summarizes the current diagnostic criteria, pathophysiology, diagnosis, and therapeutic concepts for AKI and HRS-AKI in cirrhosis.
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Affiliation(s)
- Caroline L Matchett
- Internal Medicine Residency Program, Department of Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, 55902 MN, USA
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, 55902 MN, USA
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, 55902 MN, USA.
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17
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Li X, Yuan F, Zhou L. Organ Crosstalk in Acute Kidney Injury: Evidence and Mechanisms. J Clin Med 2022; 11:jcm11226637. [PMID: 36431113 PMCID: PMC9693488 DOI: 10.3390/jcm11226637] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/31/2022] [Accepted: 11/03/2022] [Indexed: 11/11/2022] Open
Abstract
Acute kidney injury (AKI) is becoming a public health problem worldwide. AKI is usually considered a complication of lung, heart, liver, gut, and brain disease, but recent findings have supported that injured kidney can also cause dysfunction of other organs, suggesting organ crosstalk existence in AKI. However, the organ crosstalk in AKI and the underlying mechanisms have not been broadly reviewed or fully investigated. In this review, we summarize recent clinical and laboratory findings of organ crosstalk in AKI and highlight the related molecular mechanisms. Moreover, their crosstalk involves inflammatory and immune responses, hemodynamic change, fluid homeostasis, hormone secretion, nerve reflex regulation, uremic toxin, and oxidative stress. Our review provides important clues for the intervention for AKI and investigates important therapeutic potential from a new perspective.
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18
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Wang M, Qin T, Zhang Y, Zhang T, Zhuang Z, Wang Y, Ding Y, Peng Y. Toll-like receptor 4 signaling pathway mediates both liver and kidney injuries in mice with hepatorenal syndrome. Am J Physiol Gastrointest Liver Physiol 2022; 323:G461-G476. [PMID: 36165507 DOI: 10.1152/ajpgi.00048.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatorenal syndrome (HRS) is a complication of cirrhosis with high morbidity and mortality. Nevertheless, the underlying mechanism involving how kidney injury aggravates the progression of cirrhosis remains unclear. This study aims to explore the role of the Toll-like receptor 4 (TLR4) signaling pathway in mediating liver and kidney injuries in HRS mice induced by unilateral ureteral obstruction (UUO) and/or bile duct ligation (BDL). Two weeks after UUO, there were no obvious pathological changes in mouse liver and the unligated side of kidney. Nevertheless, impaired liver and kidney functions, inflammatory response, and fibrosis were examined in mice after 2 wk of BDL. Compared with those of other groups, mice in the BDL + UUO group presented severer liver and kidney injuries, higher levels of inflammatory factors, and faster deposition of collagens, suggesting that kidney injuries accelerated the aggravation of HRS. Correlation analysis identified a positive correlation between expression levels of inflammatory factors and fibrotic levels. Meanwhile, TLR4 and its ligand MyD88 were upregulated during the process of liver and kidney injuries in HRS mice. Further animal experiments in transgenic TLR4-/- mice or in those treated with TAK242, a small molecule inhibitor of TLR4, showed that blocking the TLR4 signaling pathway significantly improved survival quality and survival rate in HRS mice by alleviating liver fibrosis and kidney injury. It is concluded that kidney dysfunction plays an important role in the aggravation of cirrhosis, which may be attributed to the TLR4 signaling pathway. Targeting TLR4 could be a promising therapeutic strategy for protecting both liver and kidneys in patients with HRS.NEW & NOTEWORTHY Our study established BDL, UUO, and BDL + UUO models, providing a novel idea for analyzing liver and kidney diseases. It is highlighted that the kidney injury accelerated the aggravation of HRS via inflammatory response, which could be protected by inhibiting the TLR4 signaling pathway. We believed that targeting TLR4 was a promising therapeutic strategy for protecting both liver and kidney functions in patients with HRS.
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Affiliation(s)
- Mingliang Wang
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Tingting Qin
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Yunyun Zhang
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Ting Zhang
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Zirui Zhuang
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Yingyu Wang
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Yongfang Ding
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Yunru Peng
- Affliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology and Toxicology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
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19
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Aboul-Ezz MA, Rahim AA, El-Mikkawy A, Elkady MA, Elrefaiy MA, El-Shishtawy S, Mosbah O, Mabrouk K, Elshafie M, Sabry OM. Hepatorenal Syndrome: A Way for Early and Accurate Diagnosis. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.9675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Hepatorenal syndrome (HRS) is a devastating consequence of liver cirrhosis that is clinically categorized into two subtypes. Acute malfunction of renal role, as measured by an elevation in blood creatinine, significantly underestimates the loss in renal function in cirrhotic individuals; more accurate biomarkers are desperately required in cirrhotic patients.
AIM: The present study set out to uncover new biomarkers for the early prediction of AKI in cirrhotic cases. A comprehensive panel of biomarkers was investigated to get a clear insight into the pathogenesis of HRS.
PATIENTS AND METHODS: Participants in this study were 70 individuals from the hepatogastroenterology unit of the Theodor Bilharz Research Institute (TBRI). Detailed medical data and a physical examination were recorded. Three groups of patients have been identified; Group 1: 30 cases with compensated liver cirrhosis and normal kidney functions. Group 2: 20 cases with decompensated liver cirrhosis and normal kidney functions. Group 3: 20 cases with decompensated liver cirrhosis proved hepatorenal syndrome Type 2 h. The following biomarkers were detected in serum using the sandwich-ELISA method: Human L-arginine ELISA kit, human neutrophil gelatinase related lipocalin (NGAL), human noradrenaline (NA), human asymmetrical dimethylarginine (ADMA), human symmetric dimethylarginine (SDMA), human nitric oxide (NO), and human renin.
RESULTS: There was a highly significant difference between Groups 1 and 2 in NITRIC and ADMA. Significant differences between Groups 2 and 3 in NGAL, noradrenalin, and SDMA were observed. There was a significant difference (Group 2 vs. Group 3) in renin, NITRIC, ADMA, and L-ARGININE. There was highly significant differentiation (Group 2 vs. Group 3) in NGAL, noradrenalin, and SDMA. There was highly significant variation as per odd ratio and confidence interval between (Group 3 vs. Group 2) in NGAL.
CONCLUSION: Assessment of renal biomarkers in individuals with decompensated cirrhosis gives critical information on the etiology of AKI. Further, it may aid in the diagnosis and prognosis of AKI. Renin, NITRIC, ADMA, and L-ARGININE could be used as biomarkers to indicate HRS in individuals with advanced cirrhosis.
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20
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Shulpekova Y, Zharkova M, Tkachenko P, Tikhonov I, Stepanov A, Synitsyna A, Izotov A, Butkova T, Shulpekova N, Lapina N, Nechaev V, Kardasheva S, Okhlobystin A, Ivashkin V. The Role of Bile Acids in the Human Body and in the Development of Diseases. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113401. [PMID: 35684337 PMCID: PMC9182388 DOI: 10.3390/molecules27113401] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/13/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022]
Abstract
Bile acids are specific and quantitatively important organic components of bile, which are synthesized by hepatocytes from cholesterol and are involved in the osmotic process that ensures the outflow of bile. Bile acids include many varieties of amphipathic acid steroids. These are molecules that play a major role in the digestion of fats and the intestinal absorption of hydrophobic compounds and are also involved in the regulation of many functions of the liver, cholangiocytes, and extrahepatic tissues, acting essentially as hormones. The biological effects are realized through variable membrane or nuclear receptors. Hepatic synthesis, intestinal modifications, intestinal peristalsis and permeability, and receptor activity can affect the quantitative and qualitative bile acids composition significantly leading to extrahepatic pathologies. The complexity of bile acids receptors and the effects of cross-activations makes interpretation of the results of the studies rather difficult. In spite, this is a very perspective direction for pharmacology.
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Affiliation(s)
- Yulia Shulpekova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Maria Zharkova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Pyotr Tkachenko
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Igor Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexander Stepanov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Alexandra Synitsyna
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
- Correspondence: ; Tel.: +7-499-764-98-78
| | - Alexander Izotov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Tatyana Butkova
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | | | - Natalia Lapina
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Nechaev
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Svetlana Kardasheva
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexey Okhlobystin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
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21
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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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22
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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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23
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Tien Tai T, Adachi Y, Taketani S. A Fluorescence-Based Quantitative Analysis for Total Bilirubin in Blood and Urine. Lab Med 2022; 53:6-11. [PMID: 34350959 DOI: 10.1093/labmed/lmab043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Bilirubin is a catabolic product of heme metabolism that circulates in the bloodstream in its unconjugated or glucuronide-conjugated form. Because the accumulation of bilirubin in the blood is a common symptom of liver diseases, its measurement in plasma (serum) is important for the diagnosis of these diseases. METHOD We developed a method to assess total bilirubin levels in serum and urine, using the fluorescent protein UnaG and β-glucuronidase. RESULTS Our results indicate good correlation in serum total bilirubin levels between UnaG and the conventional bilirubin oxidase (BOD) methods. We found low levels of conjugated and unconjugated bilirubin in the urine of healthy subject individuals. Urinary bilirubin levels were elevated in patients with liver or bile duct diseases. A simple spot test of bilirubin using serum and urine showed a strong signal in patients with liver diseases. CONCLUSION The proposed method to assess bilirubin levels in serum and urine will contribute to the accurate diagnosis of health conditions such as jaundice, anemia, and liver disease.
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Affiliation(s)
- Tran Tien Tai
- Department of Biotechnology, Kyoto Institute of Technology, Kyoto 606-8585, Japan
- Department of Physiology-Pathophysiology-Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh, Vietnam
| | - Yasushi Adachi
- Division of Diagnostic Pathology, Toyooka Hospital, Hyogo 668-8501, Japan
- Department of Pediatrics, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan
| | - Shigeru Taketani
- Department of Biotechnology, Kyoto Institute of Technology, Kyoto 606-8585, Japan
- Research Complex, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan
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Liu S, Meng Q, Xu Y, Zhou J. Hepatorenal syndrome in acute-on-chronic liver failure with acute kidney injury: more questions requiring discussion. Gastroenterol Rep (Oxf) 2021; 9:505-520. [PMID: 34925848 PMCID: PMC8677535 DOI: 10.1093/gastro/goab040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 07/04/2021] [Accepted: 07/29/2021] [Indexed: 12/13/2022] Open
Abstract
In cirrhosis with ascites, hepatorenal syndrome (HRS) is a specific prerenal dysfunction unresponsive to fluid volume expansion. Acute-on-chronic liver failure (ACLF) comprises a group of clinical syndromes with multiple organ failure and early high mortality. There are differences in the characterization of ACLF between the Eastern and Western medical communities. Patients with ACLF and acute kidney injury (AKI) have more structural injuries, contributing to confusion in diagnosing HRS-AKI. In this review, we discuss progress in the pathogenesis, diagnosis, and management of HRS-AKI, especially in patients with ACLF. Controversy regarding HRS-AKI in ACLF and acute liver failure, hepatic carcinoma, shock, sepsis, and chronic kidney disease is also discussed. Research on the treatment of HRS-AKI with ACLF needs to be more actively pursued to improve disease prognosis.
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Affiliation(s)
- Songtao Liu
- Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, P. R. China
- Department of Severe Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, P. R. China
| | - Qinghua Meng
- Department of Severe Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, P. R. China
| | - Yuan Xu
- Department of Critical Care Medicine, Beijing Tsinghua Chang Gung Hospital, Beijing, P. R. China
| | - Jianxin Zhou
- Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, P. R. China
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25
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Predictors of Development of Hepatorenal Syndrome in Hospitalized Cirrhotic Patients with Acute Kidney Injury. J Clin Med 2021; 10:jcm10235621. [PMID: 34884323 PMCID: PMC8658275 DOI: 10.3390/jcm10235621] [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] [Received: 11/02/2021] [Revised: 11/23/2021] [Accepted: 11/27/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatorenal syndrome (HRS) is a type of acute kidney injury (AKI), occurring in patients with decompensated liver cirrhosis and is associated with high mortality. We aim to describe the predictors associated with the development of HRS in cirrhotic patients with AKI. We retrospectively analyzed 529 cirrhotic patient encounters with AKI across all Northwell Health institutions between 1 January 2015 and 31 December 2018. We performed multivariate analyses to determine independent predictors of development of HRS. Alcoholic cirrhosis was the most common identified etiology of cirrhosis. The mean Model for End-Stage Liver Disease Scorewas18 (±7). Ascites was the most commonly identified clinical feature of portal hypertension. Infection was identified in 38.4% of patients with urinary tract infection/pyelonephritis being the most common. Spontaneous bacterial peritonitis occurred in 5.9% of patients. The most common cause of AKI was pre-renal. Hepatorenal syndrome was identified in 9.8% of patient encounters. Predictors of HRS were history of ascites, serum creatinine >2.5 mg/dL, albumin <3 g/dL, bilirubin >2 mg/dL and spontaneous bacterial peritonitis. We demonstrate strong predictors for the development of HRS which can aid clinicians to attain an early diagnosis of HRS, leading to prompt and targeted management and improving outcomes.
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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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27
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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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28
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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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29
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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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30
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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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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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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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Guo JY, Lin J, Huang YQ, Talukder M, Yu L, Li JL. AQP2 as a target of lycopene protects against atrazine-induced renal ionic homeostasis disturbance. Food Funct 2021; 12:4855-4863. [PMID: 33960999 DOI: 10.1039/d0fo03214j] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Atrazine (ATR), a ubiquitous environmental contaminant in water and soil, causes environmental nephrosis. To reveal the toxic effect of ATR on the kidney and the potential chemical nephroprotective effect of lycopene (LYC), Kun-Ming mice of specific pathogen-free (SPF) grade were treated with LYC (5 mg kg-1) and/or ATR (50 mg kg-1 or 200 mg kg-1) for 21 days. The degree of renal injury was evaluated by measuring the ion concentration, ATPase activities and the mRNA expressions/levels of associated ATPase subunits. In addition, the expression of renal aquaporins (AQPs) was analyzed. The results showed that the renal tubular epithelial cells of ATR-exposed mice were swollen, the glomeruli were significantly atrophied, and the ion concentrations were obviously changed. The activity of Na+-K+-ATPase and the transcription of its subunits were downregulated. The activity of Ca2+-Mg2+-ATPase and the transcription of its subunits were upregulated. The expression of AQPs, especially the critical AQP2, was affected. Notably, ATR-induced nephrotoxicity was significantly improved by LYC supplementation. Therefore, LYC could protect the kidney against ATR-induced nephrotoxicity via maintaining ionic homeostasis, reversing the changes in ATPase activity and controlling the expression of AQPs on the cell membrane. These results suggested that AQP2 was a target of LYC and protected against ATR-induced renal ionic homeostasis disturbance.
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Affiliation(s)
- Jian-Ying Guo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Jia Lin
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. and Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, P.R. China
| | - Yue-Qiang Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. and Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Lei Yu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. and Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, P. R. China and Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China
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Farshad O, Ommati MM, Yüzügülen J, Jamshidzadeh A, Mousavi K, Ahmadi Z, Azarpira N, Ghaffari H, Najibi A, Shafaghat M, Niknahad H, Heidari R. Carnosine Mitigates Biomarkers of Oxidative Stress, Improves Mitochondrial Function, and Alleviates Histopathological Alterations in the Renal Tissue of Cholestatic Rats. PHARMACEUTICAL SCIENCES 2020. [DOI: 10.34172/ps.2020.60] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: Cholestatic liver disease primarily affects hepatic tissue. Cholestasis could also influence the function of other organs rather than the liver. Cholestasis-induced kidney injury is a severe clinical complication known as "cholemic nephropathy" (CN). Bile duct ligation (BDL) is a trustworthy experimental model for inducing CN. Although the precise mechanism of renal injury in cholestasis is not fully recognized, several studies revealed the role of oxidative stress in CN. There is no promising pharmacological intervention against CN. Carnosine (CAR) is a peptide extensively investigated for its pharmacological effects. Radical scavenging and antioxidative stress are major features of CAR. The current study aimed to evaluate the role of CAR supplementation on the CN. Methods: CAR was administered (250 and 500 mg/kg, i.p) to BDL rats for 14 consecutive days. Urine and serum markers of renal injury, biomarkers of oxidative stress in the kidney tissue, and renal histopathological alterations were monitored. Results: Significant elevation in oxidative stress biomarkers, including ROS formation, lipid peroxidation, oxidized glutathione (GSSG) levels, and protein carbonylation were found in the kidney of BDL rats. Moreover, renal tissue antioxidant capacity and reduced glutathione (GSH) levels were significantly decreased in the organ of cholestatic animals. Renal histopathological changes, including tubular atrophy, interstitial inflammation, tissue fibrosis, and cast formation, were detected in the kidney of BDL rats. It was found that CAR administration significantly protected the kidney of cholestatic animals. Conclusion: The antioxidative properties of this peptide might play a fundamental role in its protective properties during cholestasis.
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Affiliation(s)
- Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz Iran
| | - Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi 030801, Peoples’ Republic of China
| | - Jale Yüzügülen
- Eastern Mediterranean University, Faculty of Pharmacy, Famagusta, North Cyprus, Turkey
| | - Akram Jamshidzadeh
- 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
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Ahmadi
- Eastern Mediterranean University, Faculty of Pharmacy, Famagusta, North Cyprus, Turkey
| | - 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
| | - Asma Najibi
- 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
| | - 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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Abstract
Hepatorenal syndrome (HRS), the extreme manifestation of renal impairment in patients with cirrhosis, is characterized by reduction in renal blood flow and glomerular filtration rate. Hepatorenal syndrome is diagnosed when kidney function is reduced but evidence of intrinsic kidney disease, such as hematuria, proteinuria, or abnormal kidney ultrasonography, is absent. Unlike other causes of acute kidney injury (AKI), hepatorenal syndrome results from functional changes in the renal circulation and is potentially reversible with liver transplantation or vasoconstrictor drugs. Two forms of hepatorenal syndrome are recognized depending on the acuity and progression of kidney injury. The first represents an acute impairment of kidney function, HRS-AKI, whereas the second represents a more chronic kidney dysfunction, HRS-CKD (chronic kidney disease). In this review, we provide critical insight into the definition, pathophysiology, diagnosis, and management of hepatorenal syndrome.
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Affiliation(s)
- Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Pere Gines
- Liver Unit, Hospital Clinic, University of Barcelona IDIBAPS - CIBEReHD, Barcelona, Spain
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
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Chango Azanza JJ, Lopetegui Lia N, Calle Sarmiento PM. Bile Cast Nephropathy Secondary to Hemophagocytic Lymphohistiocytosis With Liver Failure. Cureus 2020; 12:e10226. [PMID: 33042669 PMCID: PMC7535873 DOI: 10.7759/cureus.10226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Acute kidney injury (AKI) is a common complication seen in patients with hemophagocytic lymphohistiocytosis (HLH). More than half of patients with HLH require renal replacement therapy (RRT). There are four main causes of kidney dysfunction in HLH, which include acute tubular necrosis (ATN), hypoperfusion, tumor lysis syndrome (TLS), and HLH-related glomerulopathies. Bile cast nephropathy (BCN) is a known cause of kidney injury in patients with liver failure and hyperbilirubinemia. We present the case of a 58-year-old man who presented to the hospital with painless jaundice, choluria, acholia, and generalized malaise and was found to have hyperbilirubinemia and kidney injury in the setting of HLH, who underwent a renal biopsy showing bile salt casts with degenerating tubular lining cells consistent with BCN. This case highlights the importance of considering BCN as a cause of kidney injury when a patient with HLH presents with liver failure and elevated bilirubin levels.
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Affiliation(s)
| | - Nerea Lopetegui Lia
- Internal Medicine, University of Connecticut School of Medicine, Farmington, USA
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Fuhrmann V, Weber T, Roedl K, Motaabbed J, Tariparast A, Jarczak D, de Garibay APR, Kluwe J, Boenisch O, Herkner H, Kellum JA, Kluge S. Advanced organ support (ADVOS) in the critically ill: first clinical experience in patients with multiple organ failure. Ann Intensive Care 2020; 10:96. [PMID: 32676849 PMCID: PMC7364697 DOI: 10.1186/s13613-020-00714-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 07/08/2020] [Indexed: 02/07/2023] Open
Abstract
Background Prevalence of multiple organ failure (MOF) in critically ill patients is increasing and associated mortality remains high. Extracorporeal organ support is a cornerstone in the management of MOF. We report data of an advanced hemodialysis system based on albumin dialysis (ADVOS multi device) that can regulate acid–base balance in addition to the established properties of renal replacement therapy and albumin dialysis systems in critically ill patients with MOF. Methods 34 critically ill patients with MOF received 102 ADVOS treatment sessions in the Department of Intensive Care Medicine of the University Medical Center Hamburg-Eppendorf. Markers of metabolic detoxification and acid–base regulation were collected and blood gas analyses were performed. A subgroup analyses were performed in patients with severe acidemia (pH < 7.2). Results Median number of treatment sessions was 2 (range 1–9) per patient. Median duration of treatment was 17.5 (IQR 11–23) hours per session. Treatment with the ADVOS multi-albumin dialysis device caused a significant decrease in bilirubin levels, serum creatinine, BUN and ammonia levels. The relative elimination rate of bilirubin was concentration dependent. Furthermore, a significant improvement in blood pH, HCO3− and PaCO2, was achieved during ADVOS treatment including six patients that suffered from severe metabolic acidosis refractory to continuous renal replacement therapy. Delta pH, HCO3− and PaCO2 were significantly affected by the ADVOS blood flow rate and pH settings. This improvement in the clinical course during ADVOS treatments allowed a reduction in norepinephrine during ADVOS therapy. Treatments were well tolerated. Mortality rates were 50% and 62% for 28 and 90 days, respectively. Conclusions In this case series in patients with MOF, ADVOS was able to eliminate water-soluble and albumin-bound substances. Furthermore, the device corrected severe metabolic and respiratory acid–base disequilibrium. No major adverse events associated with the ADVOS treatments were observed.
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Affiliation(s)
- Valentin Fuhrmann
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. .,Department of Medicine B, University Münster, Münster, Germany.
| | - Theresa Weber
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Kevin Roedl
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | | | - Adel Tariparast
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Dominik Jarczak
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Aritz Perez Ruiz de Garibay
- University of Strasbourg, CNRS, Immunopathology and Therapeutic Chemistry, UPR 3572, 67000, Strasbourg, France
| | - Johannes Kluwe
- Department of Internal Medicine 1, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Olaf Boenisch
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Harald Herkner
- Department of Emergency Medicine, Medical University Vienna, Vienna, Austria
| | - John A Kellum
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh Medical Center, Pittsburgh, USA
| | - Stefan Kluge
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
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Siavashpour A, Khalvati B, Azarpira N, Mohammadi H, Niknahad H, Heidari R. Poly (ADP-Ribose) polymerase-1 (PARP-1) overactivity plays a pathogenic role in bile acids-induced nephrotoxicity in cholestatic rats. Toxicol Lett 2020; 330:144-158. [PMID: 32422328 DOI: 10.1016/j.toxlet.2020.05.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023]
Abstract
Cholestatic liver disease is a clinical complication with a wide range of etiologies. The liver is the primary organ influenced by cholestasis. Other organs, rather than the liver (e.g., kidneys), could also be affected by cholestatic liver disease. Cholestasis-induced renal injury is known as cholemic nephropathy (CN). Although the structural and functional alterations of the kidney in cholestasis have been well described, the cellular and molecular mechanisms of CN are not well understood. Some studies mentioned the role of oxidative stress and mitochondrial impairment in CN. Several cellular targets, including proteins, lipids, and DNA, could be affected by oxidative stress. Poly (ADP-Ribose) polymerase-1 (PARP-1) is an enzyme that its physiological activity plays a fundamental role in DNA repair. However, PARP-1 overexpression is associated with enhanced oxidative stress and cell death. The current study was designed to evaluate the role of PARP-1 activity in the pathogenesis of CN. Bile duct ligated (BDL) rats were treated with nicotinamide (NA) as a PARP-1 inhibitor. Kidney, urine, and plasma samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Serum and urine biomarkers of kidney injury, markers of oxidative stress and DNA damage, PARP-1 expression and activity in the kidney tissue, inflammatory response, renal fibrosis markers, and kidney histopathological alterations were assessed. Significant changes in the serum and urine biomarkers of kidney injury were evident in the BDL rats. Markers of oxidative stress were increased, and tissue ATP levels and antioxidant capacity were decreased in the kidney of cholestatic animals. A significant increase in PARP-1 expression and activity was evident in BDL rats (3, 7, 14, and 28 days after BDL). Moreover, inflammatory response (IL-1β and TNF-α expression; and myeloperoxidase activity), renal tissue histopathological alterations, and kidney fibrosis (α-SMA and TGF-β expression, as well as collagen deposition) were detected in cholestatic animals. It was found that the PARP-1 inhibitor, NA (50 and 100 mg/kg, i.p), significantly mitigated cholestasis-induced renal injury. The positive effects of NA were more significant at a lower dose and the early stage of CN. These data indicate a pathogenic role for PARP-1 overexpression in CN.
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Affiliation(s)
- Asma Siavashpour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bahman Khalvati
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamidreza Mohammadi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmacology and Toxicology, Faculty 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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Huber W, Ruiz de Garibay AP. Options in extracorporeal support of multiple organ failure. Med Klin Intensivmed Notfmed 2020; 115:28-36. [PMID: 32095838 PMCID: PMC7220977 DOI: 10.1007/s00063-020-00658-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 01/14/2020] [Indexed: 12/29/2022]
Abstract
Multiorgan failure is among the most frequent reasons of death in critically ill patients. Based on extensive and long-term use of renal replacement therapy, extracorporeal organ support became available for other organ failures. Initially, most of these techniques (e.g. extracorporeal membrane oxygenation, extracorporeal CO2 removal [ECCO2R] and extracorporeal liver support) were used as stand-alone single organ support systems. Considering multiple interactions between native organs (“crosstalk”), combined or integrated extracorporeal organ support (ECOS) devices are intriguing. The concept of multiple organ support therapy (MOST) providing simultaneous and combined support for different failing organs was described more than 15 years ago by Ronco and Bellomo. This concept also implicates overcoming the “compartmentalized” approach provided by different single organ specialized professionals by a multidisciplinary and multiprofessional strategy. The idea of MOST is supported by the failure of several recent studies on single organ support including liver and lung support. Improvement of outcome by ECOS necessarily depends on optimized patient selection, integrated organ support and limitation of its side effects. This implicates challenges for engineers, industry and healthcare professionals. From a technical viewpoint, modular combination of pre-existing technologies such as renal replacement, albumin-dialysis, ECCO2R and potentially cytokine elimination can be considered as a first step. While this allows for stepwise and individual combination of standard organ support facilities, it carries the disadvantage of large extracorporeal blood volume and surfaces as well as additive costs. The more intriguing next step is an integrated platform providing the capacity of multiple organ support within one device. (This article is freely available.)
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Affiliation(s)
- W Huber
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, München, Germany.
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Abstract
Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.
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Affiliation(s)
| | - Hartmut Jaeschke
- †Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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42
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Abstract
Emerging evidence has shown that bile acids play important roles in renal physiology and diseases by activating two major receptors, the nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled bile acid receptor-1 (Gpbar1; also known as TGR5). Both FXR and TGR5 have been identified in human and rodent kidneys, where they are deeply involved in renal water handling. In mice, FXR- or TGR5-related gene deficiency has been associated with reduced aquaporin-2 expression accompanied with impaired urinary concentration ability. In this mini-review, we briefly discuss the current understanding of FXR/TGR5 signaling in the kidneys, with a special focus on the regulation of aquaporin-2 expression by bile acids in the collecting ducts and its potential significance in disease conditions.
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Affiliation(s)
- Suchun Li
- Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Chunling Li
- Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Weidong Wang
- Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
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Mandorfer M, Hecking M. The Renaissance of Cholemic Nephropathy: A Likely Underestimated Cause of Renal Dysfunction in Liver Disease. Hepatology 2019; 69:1858-1860. [PMID: 30746731 DOI: 10.1002/hep.30558] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 02/08/2019] [Indexed: 12/19/2022]
Affiliation(s)
- Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Manfred Hecking
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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