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Li W, Dong C, Sun C, Wang K, Zheng W, Wei X, Han C, Yang Y, Wang Z, Cui G, Li L, Gao W. Combining Acute Kidney Injury Grading and Recovery Mode for Screening in Pediatric Liver Transplantation: A Retrospective Observational Study. Pediatr Transplant 2025; 29:e70089. [PMID: 40313057 DOI: 10.1111/petr.70089] [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: 11/20/2024] [Revised: 02/17/2025] [Accepted: 04/17/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND A growing number of studies indicate that acute kidney injury (AKI) and the pattern of recovery after kidney injury are associated with poor outcomes for grafts and long-term renal function after liver transplantation (LT). However, few systematic studies have been conducted on the pediatric liver transplantation (PLT) population. MATERIALS AND METHODS In this single-centered retrospective observational study, according to AKI degree and whether AKI was persistent, patients were divided into three groups: non-AKI/stage 1 AKI, stage 2/3 transient AKI, and stage 2/3 persistent AKI. We compared the survival of patients, graft, and chronic kidney disease (CKD) among the three groups, analyzing the risk factors for the stage 2/3 persistent AKI. RESULTS Among 700 patients, the total incidence of AKI was 39.57%; of children with stage 2/3 AKI, the condition was persistent in 38.06%. In the stage 2/3 persistent-AKI group, the risk of graft loss was 3.264× greater than in the no-AKI/stage 1 AKI group and 4.329× greater than in the stage 2/3 transient AKI group. Pediatric End-stage Liver Disease (PELD) score, preoperative estimated glomerular filtration rate (eGFR), duration of vena cava occlusion, postoperative respiratory support time, and postoperative early allograft dysfunction (EAD) were significantly correlated with the occurrence of stage 2/3 persistent AKI. CONCLUSIONS By combining AKI recovery mode with AKI grading, clinicians can screen out stage 2/3 persistent AKI with a worse prognosis. This method was more accurate in predicting prognosis than applying AKI grading alone.
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Affiliation(s)
- Weihan Li
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Chong Dong
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Chao Sun
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Kai Wang
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Weiping Zheng
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Xinzhe Wei
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Chao Han
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Yang Yang
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Zhen Wang
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Ganlin Cui
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Linxiao Li
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Wei Gao
- Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
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Malakar S, Rungta S, Samanta A, Shamsul Hoda U, Mishra P, Pande G, Roy A, Giri S, Rai P, Mohindra S, Ghoshal UC. Understanding acute kidney injury in cirrhosis: Current perspective. World J Hepatol 2025; 17:104724. [DOI: 10.4254/wjh.v17.i5.104724] [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: 12/29/2024] [Revised: 03/13/2025] [Accepted: 04/15/2025] [Indexed: 05/27/2025] Open
Abstract
Acute kidney injury (AKI) is present in 30%-40% of hospitalized patients with cirrhosis. Its incidence is higher in patients with severe alcoholic hepatitis, spontaneous bacterial peritonitis, and acute-on-chronic-liver failure (ACLF). Kidney injury is an important landmark event in the natural history of cirrhosis as it is associated with higher mortality. Overwhelming systemic vasodilation, cardiac dysfunction, hypoperfusion, endotoxemia, and direct nephrotoxicity predispose patients with cirrhosis to kidney injury. Infection is present in 25% of patients with decompensated cirrhosis and 35%-40% of patients with ACLF. Advanced cirrhosis with portal hypertension leads to a sluggish portal flow, leading to increased gut congestion, altered gut permeability and bacterial translocations. They drive infection and endotoxemia in such patients. Pathogen-associated molecular patterns activate inflammatory cascades, which leads to further deterioration in hemodynamics and reduced glomerular filtration rate. Infections and pro-inflammatory cytokines like interleukin 6 (IL-6), IL-1, and tumor necrosis factor alpha may directly cause kidney parenchymal injury. The combined effect of dysfunctional albumin and systemic and splanchnic vasodilatation leads to low effective blood volume, activating the renin-angiotensin-aldosterone system. This causes renal vasoconstriction, water retention, and ascites, which progresses to hepatorenal physiology and AKI development. Vasoconstriction and volume expansion effectively improve arterial blood volume and systemic hemodynamics, thereby improving renal blood flow. It is of paramount importance to predict, detect, and treat AKI in its early state, as progressive renal dysfunction is invariably associated with higher mortality in patients with decompensated cirrhosis and ACLF. This comprehensive review will focus on the recent evolving concepts of the pathophysiology, diagnosis, and management of AKI in patients with cirrhosis.
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Affiliation(s)
- Sayan Malakar
- Department of Gastroenterology, King George's Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Sumit Rungta
- Department of Medical Gastroenterology, King George's Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Umair Shamsul Hoda
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Piyush Mishra
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Gaurav Pande
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Akash Roy
- Department of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata 700054, West Bengal, India
| | - Suprabhat Giri
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar 751024, Odisha, India
| | - Praveer Rai
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Samir Mohindra
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Ghallab A, Mandorfer M, Stirnimann G, Geyer J, Lindström E, Luedde T, van der Merwe S, Rashidi-Alavijeh J, Schmidt H, Karpen SJ, Fickert P, Trauner M, Hengstler JG, Dawson PA. Enteronephrohepatic Circulation of Bile Acids and Therapeutic Potential of Systemic Bile Acid Transporter Inhibitors. J Hepatol 2025:S0168-8278(25)02207-X. [PMID: 40414504 DOI: 10.1016/j.jhep.2025.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/27/2025]
Abstract
Together with carriers in liver and small intestine, kidney transporters function to conserve and compartmentalize bile acids in the enteronephrohepatic circulation. In patients with liver disease, systemic bile acid levels are elevated, undergo increased renal glomerular filtration, and contribute to the pathogenesis of cholemic nephropathy and acute kidney injury. In this review, we describe mechanisms for renal bile acid transport and highlight very recent discoveries that challenge current paradigms for the pathogenesis of cholemic nephropathy and renal tubule cast formation. We also discuss the therapeutic potential of inhibiting the kidney apical sodium-dependent bile acid transporter (ASBT) to redirect bile acids into urine for elimination, reduce hepatobiliary accumulation and systemic levels of bile acids, and treat cholemic nephropathy. In conclusion, a deeper understanding of the enteronephrohepatic bile acid axis is providing insights into novel strategies to protect both liver and kidney in patients with liver disease.
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Affiliation(s)
- Ahmed Ghallab
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany; Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
| | - Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, Inselspital University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Joachim Geyer
- Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany
| | | | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany
| | | | - Jassin Rashidi-Alavijeh
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Hartmut Schmidt
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Saul J Karpen
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, VA, United States
| | - Peter Fickert
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Jan G Hengstler
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany
| | - Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States.
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Alabdul Razzak I, El Naamani H, Dimitrov D, Morin R, Jaber BL. Bile cast nephropathy: A systematic review of case reports and case series. World J Hepatol 2025; 17:105120. [PMID: 40308820 PMCID: PMC12038420 DOI: 10.4254/wjh.v17.i4.105120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/27/2025] [Accepted: 03/25/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Bile cast nephropathy (BCN) is suspected in the setting of liver disease and hyperbilirubinemia and is characterized by the formation of tubular bile casts and acute tubular injury. While postmortem studies reveal a high prevalence of BCN, little is known about this orphan acute kidney injury syndrome. AIM To address this knowledge gap, we performed a systematic review of case reports and case series of BCN, focusing on risk factors, diagnostic criteria, clinical presentation, kidney biopsy findings, severity, treatment approaches, and outcomes. METHODS Electronic databases were searched to identify eligible studies of patients with possible, probable, or definite BCN, using pre-established criteria. Relevant variables were extracted and analyzed. We explored the impact of serum total bilirubin levels and alcoholic liver disease on BCN severity and outcomes by stratifying cases into total bilirubin tertiles and alcoholic vs non-alcoholic liver disease. Univariate and multivariable logistic regression analyses were used to examine factors associated with the composite outcome of dialysis requirement or death. RESULTS Sixty-seven case reports and six case series (involving 2 patients each) met the inclusion criteria, totaling 79 cases of BCN. The mean age was 48.3 years, and 83.5% were men. The most common cause of liver disease was drug-induced injury (30.4%), followed by infection (18.9%) and alcoholism (12.7%). BCN diagnosis was deemed definite, probable, and possible in 65.8%, 32.9%, and 1.3% of cases, respectively. Levels of serum creatinine, dialysis requirement, and renal recovery did not differ among the total bilirubin tertile groups. However, both initial and peak serum creatinine were significantly higher in the alcoholic liver disease group compared to the non-alcoholic group (P = 0.011 and P = 0.012, respectively). There was also a non-significant trend toward a higher incidence of dialysis requirement or death in the alcoholic liver disease group (80% vs 52%, P = 0.098). Finally, higher initial serum creatinine (per 1 mg/dL increase) was independently associated with dialysis requirement or death (adjusted odds ratio 1.291, 95% confidence interval: 1.032-1.615, P = 0.025). CONCLUSION BCN is a common and potentially serious cause of acute kidney injury in patients with liver disease. The degree of hyperbilirubinemia does not appear to correlate with BCN severity or outcomes. However, in alcoholic liver disease, BCN is associated with a greater rise in serum creatinine and a trend toward worse outcomes compared to non-alcoholic liver disease. Serum creatinine may be a valuable predictor of BCN prognosis. Further studies are needed to develop non-invasive diagnostic tools and establish effective treatments for BCN.
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Affiliation(s)
- Iyiad Alabdul Razzak
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States.
| | - Hind El Naamani
- Department of Medicine, St. Elizabeth's Medical Center, Boston, MA 02135, United States
| | - Dimo Dimitrov
- Department of Medicine, St. Elizabeth's Medical Center, Boston, MA 02135, United States
| | - Rebecca Morin
- Department of Research and Instruction, Tufts University, Boston, MA 02111, United States
| | - Bertrand L Jaber
- Department of Medicine, St. Elizabeth's Medical Center, Boston, MA 02135, United States
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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] [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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Ling S, Diao H, Lu G, Shi L. Associations between serum levels of liver function biomarkers and all-cause and cause-specific mortality: a prospective cohort study. BMC Public Health 2024; 24:3302. [PMID: 39604890 PMCID: PMC11600561 DOI: 10.1186/s12889-024-20773-6] [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: 08/23/2023] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The liver plays critical roles in human health. Circulating level of liver function biomarkers may associate with the long-term and short-term mortality in general population. METHODS We used data from US National Health and Nutrition Examination Survey 1988-94 and 1999-2014. People aged ≥ 20 years with measured serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), total bilirubin (TB), and albumin (ALB) at baseline were included. All-cause and cause-specific mortality was identified from the National Death Index through 31 December 2015. Additive Cox regression models were applied to assess the correlation patterns between the serum level of these analytes and mortality risk. RESULTS A total of 44,508 participants were included; among them, 9,721 deaths occurred during a mean follow-up of 12.5 years. A "J-shaped" correlation was found between serum levels of ALT, AST, and TB and all-cause mortality. The risk of mortality monotonically increased with increasing GGT and ALP levels when their levels exceeded the valley points. A "L-shaped" correlation was found between the serum level of ALB and all-cause mortality. The correlation patterns were comparable among deaths from different causes and were consistent in subgroup and sensitivity analyses. While the integration of all six liver function biomarkers did not yield an optimal predictive performance for mortality (area under ROC curve = 0.706), it demonstrated a significantly better performance compared to any single biomarker.. CONCLUSION Circulating liver function biomarkers showed diverse nonlinear correlations with mortality and may be utilized as part of a screening process to help identify individuals who may be at elevated risk of mortality.
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Affiliation(s)
- Shunhu Ling
- Department of Internal Medicine, Hanshan People's Hospital in Anhui Province, Ma'anshan, 238101, Anhui Province, China
| | - Haiping Diao
- Department of Proctology, Hanshan Hospital of Traditional Chinese Medicine in Anhui Province, Ma'anshan, 238101, Anhui Province, China
| | - Guangbing Lu
- Department of Respiration, Meishan Hospital of Traditional Chinese Medicine in Sichuan Province, Meishan, 620010, Sichuan Province, China
| | - Luhua Shi
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
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Zhang X, Wang S, Xu S, Min R, Ling Y, Sun S, Gong R. Clinical Characteristics, Risk Factors, and Predictors of Nonobese Fatty Liver Disease: A Cross-Sectional Study. Diabetes Metab Syndr Obes 2024; 17:4397-4406. [PMID: 39619223 PMCID: PMC11606184 DOI: 10.2147/dmso.s482638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 11/01/2024] [Indexed: 01/03/2025] Open
Abstract
PURPOSE This study aimed to investigate the risk factors and predictors of non-obese fatty liver disease in the Chinese population. PATIENTS AND METHODS A total of 6,014 adults who underwent physical examinations at Union Hospital of Huazhong University of Science and Technology from March 2019 to March 2023 were included in this study. Fatty liver disease was diagnosed based on at least two of the following criteria: diffuse echo patterns relative to the liver, spleen, and kidney; ultrasonic beam attenuation; and poor intrahepatic visual details. The associations between non-obese fatty liver and gender, age, total bilirubin(TBIL), direct bilirubin(DBIL), alanine aminotransferase(ALT), aspartate aminotransferase(AST), glutamine transferase(GGT), alkaline phosphatase(ALP), triglycerides(TG), total cholesterol(TC), high-density lipoprotein cholesterol(HDLC), low-density lipoprotein cholesterol(LDLC), urea nitrogen(BUN), creatinine(Cr), uric acid(UA), Central nervous system sensitivity PTFQI, TSHI, TT4RI, TFQI, Peripheral sensitivity, free thyroxine(FT4), thyroid-stimulating hormone(TSH), triiodothyronine(FT3), fasting blood glucose(FBG), systolic blood pressure(SBP), diastolic blood pressure(DBP), body mass index(BMI) were analyzed via binary logistic regression. Correlation between non-obese fatty liver and high blood lipids, hypertension, hyperuricemia, diabetes, thyroid dysfunction were analyzed using the Pearson and Spearman methods. ROC curve was used to evaluate the diagnostic effect of the indicator. RESULTS Compared with the normal group, age, proportion of males, ALT, AST, GGT, ALP, TG, TC, BUN, Cr, UA, TSHI, TT4RI, FT3/FT4, TSH, FT3, FBG, SBP, DBP and BMI in the disease group were significantly higher. The prevalence of non-obese fatty liver was associated with hyperlipidemia, hypertension, hyperuricemia and diabetes. Gender, age, DBIL, ALT, ALP, TG, HDL-C, LDL-C, BUN, UA, FBG, DBP, BMI were independent risk factors for non-obese fatty liver.FT3/FT4 may be considered as a predictor of nonobese fatty liver. CONCLUSION Risk factors for non-obese fatty liver may include sex, age, TG, TC, BMI, etc. Hyperlipidemia, hypertension, hyperuricemia and diabetes mellitus are related to non-obese fatty liver. FT3/FT4 may be a predictor of non-obese fatty liver disease.
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Affiliation(s)
- Xiaomei Zhang
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Shi Wang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Sanping Xu
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Rui Min
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Yan Ling
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Shiran Sun
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Rui Gong
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of 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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10
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Riva I, Marino A, Valetti TM, Marchesi G, Fabretti F. Extracorporeal liver support techniques: a comparison. J Artif Organs 2024; 27:261-268. [PMID: 37335451 PMCID: PMC11345327 DOI: 10.1007/s10047-023-01409-9] [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: 03/16/2023] [Accepted: 06/06/2023] [Indexed: 06/21/2023]
Abstract
ExtraCorporeal Liver Support (ECLS) systems were developed with the aim of supporting the liver in its detoxification function by clearing the blood from hepatic toxic molecules. We conducted a retrospective comparative analysis on patients presenting with liver failure who were treated with different extracorporeal techniques in our intensive care unit to evaluate and compare their detoxification abilities. To verify the effectiveness of the techniques, mass balance (MB) and adsorption per hour were calculated for total bilirubin (TB), direct bilirubin (DB), and bile acids (BA) from the concentrations measured. MB represents the total amount (mg or mcMol) of a molecule removed from a solution and is the only representative parameter to verify the purification effectiveness of one system as it is not affected by the continuous production of the molecules, released in the circulation from the tissues, as it is the case for the reduction rate (RR). The total adsorption per hour is calculated by the ratio between MB and the time duration and shows the adsorption ability in an hour. Our comparative study shows the superior adsorption capability of CytoSorb system regarding TB, DB, and BA, evaluated through the MB and adsorption per hour, in comparison with CPFA, MARS, Prometheus, and PAP. In conclusion, as extracorporeal purification in liver failure could be considered useful for therapeutic purposes, Cytosorb, being more performing than other systems considered, could represent the device of first choice.
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Affiliation(s)
- Ivano Riva
- General Intensive Care Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Piazza OMS, 1, 24127, Bergamo, Italy.
| | - Antonella Marino
- General Intensive Care Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Piazza OMS, 1, 24127, Bergamo, Italy.
| | - Tino Martino Valetti
- General Intensive Care Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Piazza OMS, 1, 24127, Bergamo, Italy
| | - Gianmariano Marchesi
- General Intensive Care Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Piazza OMS, 1, 24127, Bergamo, Italy
| | - Fabrizio Fabretti
- General Intensive Care Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Piazza OMS, 1, 24127, Bergamo, Italy
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11
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Lyu L, Miao Y, Liu X, Dong H, Chu H, Wang X. Effect of Serum Bilirubin Levels on Contrast-induced Acute Kidney Injury: A Systematic Evaluation and Meta-analysis. Angiology 2024; 75:605-624. [PMID: 37379462 DOI: 10.1177/00033197231186493] [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] [Indexed: 06/30/2023]
Abstract
Contrast-induced acute kidney injury (CI-AKI) is an important complication following the use of iodinated contrast media. Bilirubin has a protective effect but may also aggravate CI-AKI. The purpose of this systematic review was to assess whether bilirubin is a risk factor for CI-AKI. We searched the databases PubMed, Embase, Web of Science, Cochrane Library, Scopus, Ovid Medline, CNKI (China National Knowledge Infrastructure), VPCS (Vip Paper Check System), Wanfang, and CBM (Chinese BioMedical Literature Database) from the initial date to May 6, 2023. We summarized the results by directly combining the effect-size odds ratio (OR) and 95% confidence interval (CI) and identified sources of heterogeneity through subgroup analysis, sensitivity analysis, and meta-regression analysis. A total of 10 studies (14 data sets) were included: 7 retrospective studies (10 data sets) and 3 prospective studies (4 data sets), involving 12776 participants. The incidence of CI-AKI of 16% (95% CI: 14-19%). Total bilirubin was positively associated with the occurrence of CI-AKI (OR = 1.80; 95% CI: 1.36-2.38). Both low and high bilirubin concentrations were risk factors for CI-AKI. The incidence of CI-AKI was higher in the low bilirubin group than in the high bilirubin group.
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Affiliation(s)
- Lin Lyu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuxin Miao
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xuequan Liu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - He Dong
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haichen Chu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoyu Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
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12
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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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13
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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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14
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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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15
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Yang J, Pontoglio M, Terzi F. Bile Acids and Farnesoid X Receptor in Renal Pathophysiology. Nephron Clin Pract 2024; 148:618-630. [PMID: 38412845 DOI: 10.1159/000538038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/22/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Bile acids (BAs) act not only as lipids and lipid-soluble vitamin detergents but also function as signaling molecules, participating in diverse physiological processes. The identification of BA receptors in organs beyond the enterohepatic system, such as the farnesoid X receptor (FXR), has initiated inquiries into their organ-specific functions. Among these organs, the kidney prominently expresses FXR. SUMMARY This review provides a comprehensive overview of various BA species identified in kidneys and delves into the roles of renal apical and basolateral BA transporters. Furthermore, we explore changes in BAs and their potential implications for various renal diseases, particularly chronic kidney disease. Lastly, we center our discussion on FXR, a key BA receptor in the kidney and a potential therapeutic target for renal diseases, providing current insights into the protective mechanisms associated with FXR agonist treatments. KEY MESSAGES Despite the relatively low concentrations of BAs in the kidney, their presence is noteworthy, with rodents and humans exhibiting distinct renal BA compositions. Renal BA transporters efficiently facilitate either reabsorption into systemic circulation or excretion into the urine. However, adaptive changes in BA transporters are evident during cholestasis. Various renal diseases are accompanied by alterations in BA concentrations and FXR expression. Consequently, the activation of FXR in the kidney could be a promising target for mitigating kidney damage.
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Affiliation(s)
- Jiufang Yang
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR8253, Université Paris Cité, Paris, France,
| | - Marco Pontoglio
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR8253, Université Paris Cité, Paris, France
| | - Fabiola Terzi
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR8253, Université Paris Cité, Paris, France
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16
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Fickert P. Detour of bile acid routes as therapeutic roadmap for cholemic nephropathy. J Hepatol 2024; 80:188-190. [PMID: 38013144 DOI: 10.1016/j.jhep.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023]
Affiliation(s)
- Peter Fickert
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria.
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17
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Sharan K, Sharma A, Rana S, Patnaik I, Gupta R. Neutrophil Gelatinase-associated Lipocalin Predicts Short-term Outcomes in Decompensated Cirrhosis With Acute Kidney Injury. J Clin Exp Hepatol 2024; 14:101274. [PMID: 38076377 PMCID: PMC10709204 DOI: 10.1016/j.jceh.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 08/24/2023] [Indexed: 01/05/2025] Open
Abstract
Background and aims Acute kidney injury (AKI) increases mortality in cirrhosis. Early identification of the cause of AKI helps in planning appropriate management. We aimed to find whether neutrophil gelatinase-associated lipocalin (NGAL) can be used to differentiate between different types of AKI in cirrhosis and predict short-term outcomes in patients with decompensated cirrhosis and AKI. Method This was a time-bound study in which consecutive hospitalized patients with cirrhosis and AKI were prospectively recruited and managed as per standard care. Acute on chronic liver failure (ACLF) was diagnosed as per the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) criteria. Urine NGAL was measured by enzyme-linked immunosorbent assay (ELISA) by Epitope Diagnostics Inc. kit (San Diego, USA.) in all patients on admission, and patients were followed up until hospital discharge or death. Results A total of 110 consecutive patients (median [range] age: 44 [28-81] years;87.3%were male; ACLF: 71.8%; acute decompensation 28.2%; Model for end-stage liver disease (MELD) 27 [13-46]; Child-Turcotte-Pugh (CTP) 11 [7-15]) with cirrhosis and AKI were recruited. Alcohol was the most common etiology of cirrhosis(64.5%)). Pre-renal azotemia (PRA) was the most common cause of AKI (n = 56). Urine NGAL was significantly elevated in acute tubular necrosis (ATN) (1747 [6-6141] ng/ml than in hepatorenal syndrome (HRS) (379 [33.5-2320] ng/ml; P < 0.0001) and PRA (167 ng/ml [3.34-660]; P < 0.0001). Sixty-four percent patients with ATN, 27.6% patients with HRS, and none with PRA required dialysis. A total of 79.31% patients with HRS and 76% with ATN died. Urine NGAL was significantly higher in patients who required hemodialysis than in those who did not (1733 [243-6141] ng/ml vs 235 [3.34-2320] ng/ml; P < 0.0001). Both urine NGAL (n = 110) and plasma NGAL (n = 90) were significantly higher in patients who died (urine NGAL: -475 [6-6141] ng/ml vs 247 [3.34-2320] ng/ml; P = 0.002;plasma NGAL-950 [94-4859] ng/ml vs 608 [18-3300)]g/ml; P < 0.001). On multivariate analysis, urine NGAL and INR could predict mortality. Conclusion NGAL can differentiate between different types of AKI in cirrhosis and predict the need for hemodialysis and mortality in decompensated cirrhosis with AKI.
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Affiliation(s)
- Kshitiz Sharan
- Department of Medical Gastroenterology, All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Anand Sharma
- Department of Medical Gastroenterology, All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Satyavati Rana
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Itish Patnaik
- Department of Medical Gastroenterology, All India Institute of Medical Sciences (AIIMS), Rishikesh, India
| | - Rohit Gupta
- Department of Medical Gastroenterology, All India Institute of Medical Sciences (AIIMS), Rishikesh, India
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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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Arakawa H, Kawanishi T, Shengyu D, Nishiuchi T, Meguro-Horike M, Horike SI, Sugimoto M, Kato Y. Renal Pharmacokinetic Adaptation to Cholestasis Causes Increased Nephrotoxic Drug Accumulation by Mrp6 Downregulation in Mice. J Pharm Sci 2023; 112:3209-3215. [PMID: 37611664 DOI: 10.1016/j.xphs.2023.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/13/2023] [Accepted: 08/13/2023] [Indexed: 08/25/2023]
Abstract
In hepatic dysfunction, renal pharmacokinetic adaptation can be observed, although information on the changes in drug exposure and the interorgan regulation of membrane transporters in kidney in liver diseases is limited. This study aimed to clarify the effects of renal exposure to nephrotoxic drugs during cholestasis induced by bile duct ligation (BDL). Among the 11 nephrotoxic drugs examined, the tissue accumulation of imatinib and cisplatin in kidney slices obtained from mice 2 weeks after BDL operation was higher than that in sham-operated mice. The uptake of imatinib in the kidney slices of BDL mice was slightly higher, whereas its efflux from the slices was largely decreased compared to that in sham-operated mice. Proteomic analysis revealed a reduction in renal expression of the efflux transporter multidrug resistance-associated protein 6 (Mrp6/Abcc6) in BDL mice, and both imatinib and cisplatin were identified as Mrp6 substrates. Survival probability after cisplatin administration was reduced in BDL mice. In conclusion, the present study demonstrated that BDL-induced cholestasis leads to the downregulation of the renal basolateral efflux transporter Mrp6, resulting in drug accumulation in renal cells and promoting drug-induced renal injury.
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Affiliation(s)
- Hiroshi Arakawa
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Takumi Kawanishi
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Dai Shengyu
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Takumi Nishiuchi
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Makiko Meguro-Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Shin-Ichi Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Yamagata, Japan
| | - Yukio Kato
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
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Ramteke V, Patil S, Nandurkar D. AKI in Patient with Acute Viral Hepatitis. KIDNEY360 2023; 4:1659-1660. [PMID: 38032769 PMCID: PMC10697477 DOI: 10.34067/kid.0000000000000215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Affiliation(s)
- Vishal Ramteke
- Department of Nephrology, Alexis Hospital, Nagpur, Maharashtra, India
| | - Sagar Patil
- Department of Gastroenterology, Alexis Hospital, Nagpur, Maharashtra, India
| | - Dipak Nandurkar
- Department of Internal Medicine, Alexis Hospital, Nagpur, Maharashtra, India
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21
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Issac AG, Yu MA, Rogers DM, Subramanian RM. Case Report: Efficacy of albumin dialysis for the reversal of bile cast nephropathy-induced acute kidney injury. FRONTIERS IN NEPHROLOGY 2023; 3:1256672. [PMID: 37885924 PMCID: PMC10598339 DOI: 10.3389/fneph.2023.1256672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 09/07/2023] [Indexed: 10/28/2023]
Abstract
Background Bile cast nephropathy (BCN) is an underdiagnosed renal complication associated with severe hyperbilirubinemia and is seen in patients with liver failure who have cholestatic complications. BCN-induced acute kidney injury (AKI) can require hemodialysis (HD), and the molecular adsorbent recirculating system (MARS) is a potentially useful therapeutic option. Case summary A 57-year-old male presented with jaundice persisting for 1 month, with laboratory test results indicative of hyperbilirubinemia and AKI. Abdominal imaging and a biopsy confirmed biliary ductal dilation secondary to a pancreatic head mass. The patient had rapidly progressive renal failure and refractory hyperbilirubinemia, despite biliary decompression, and was started on HD. Subsequent therapy with albumin dialysis therapy using MARS was successful in reversing the AKI, the cessation of HD, and the restoration of native renal function. Conclusion In the setting of BCN-induced AKI, timely initiation of MARS can provide a useful therapeutic strategy to reverse renal dysfunction and facilitate intrinsic renal recovery.
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Affiliation(s)
- Aaron G. Issac
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Michael A. Yu
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, United States
| | - Desiree M. Rogers
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Division of Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Ram M. Subramanian
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, United States
- Division of Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, United States
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22
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Trautman CL, Khan M, Baker LW, Aslam N, Fitzpatrick P, Porter I, Mao M, Wadei H, Ball CT, Hickson LJ. Kidney Outcomes Following Utilization of Molecular Adsorbent Recirculating System. Kidney Int Rep 2023; 8:2100-2106. [PMID: 37850016 PMCID: PMC10577361 DOI: 10.1016/j.ekir.2023.07.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/24/2023] [Accepted: 07/31/2023] [Indexed: 10/19/2023] Open
Abstract
Introduction Molecular adsorbent recirculating system (MARS) is an extracorporeal system combining conventional veno-venous hemodiafiltration and adsorption to provide rescue support in fulminant hepatic failure. Acute kidney injury (AKI) is common in patients with hepatic failure warranting continuous kidney replacement therapy (CKRT). Our primary aim was to characterize a cohort of patients who received MARS therapy and examine kidney events given the current paucity of available data. Methods Patients initiating MARS in a tertiary care setting from January 2014 through December 2020 were assessed for treatment indications, transplantation, CKRT, kidney recovery, and death. Data was collected using the REDCAP software. Results A total of 49 patients (67% female; 75% White) received MARS therapy with 29 patients (59%) requiring concomitant CKRT. Hepatic encephalopathy (HE) was the most common indication for MARS initiation (55%). In-hospital mortality was 41% (12/29) among patients who received CKRT versus 10% (2/20) among those not requiring CKRT (relative risk [RR] 4.15, 95% confidence interval [CI] 1.04 to 16.52, P = 0.044); this persisted following adjustment for prespecified patient characteristics (all RR ≥ 3.76, all P ≤ 0.060). One-year mortality post-MARS initiation was high overall but highest among the CKRT group (59% [17/29] vs. 25% [5/20] unadjusted RR 2.92, 95% CI 1.08 to 7.94, P = 0.035). Liver transplant after MARS occurred in 41% of patients (20/49). After CKRT, 39% of patients (9/29) recovered kidney function prior to hospital discharge. Conclusions Patients requiring MARS frequently have AKI warranting the use of concomitant CKRT, which is associated with a high rate of in-hospital and 1-year mortality.
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Affiliation(s)
- Christopher L. Trautman
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
| | - Mahnoor Khan
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
| | - Lyle W. Baker
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
| | - Nabeel Aslam
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
| | - Peter Fitzpatrick
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
| | - Ivan Porter
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
| | - Michael Mao
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
| | - Hani Wadei
- Department of Transplantation; Mayo Clinic Jacksonville, Florida, USA
| | - Colleen T. Ball
- Division of Biomedical Statistics and Informatics, Mayo Clinic Jacksonville, Florida, USA
| | - LaTonya J. Hickson
- Division of Nephrology and Hypertension, Department of Medicine; Mayo Clinic Jacksonville, Florida, USA
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23
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Shintani T, Imamura C, Ueyama-Toba Y, Inui J, Watanabe A, Mizuguchi H. Establishment of UGT1A1-knockout human iPS-derived hepatic organoids for UGT1A1-specific kinetics and toxicity evaluation. Mol Ther Methods Clin Dev 2023; 30:429-442. [PMID: 37663646 PMCID: PMC10471830 DOI: 10.1016/j.omtm.2023.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 08/08/2023] [Indexed: 09/05/2023]
Abstract
Uridine diphosphate glucuronosyltransferases (UGTs) are highly expressed in the liver and are involved in the metabolism of many drugs. In particular, UGT1A1 has a genetic polymorphism that causes decreased activity, leading to drug-induced hepatotoxicity. Therefore, an in vitro evaluation system that accurately predicts the kinetics of drugs involving UGT1A1 is required. However, there is no such evaluation system because of the absence of the UGT1A1-selective inhibitor. Here, using human induced pluripotent stem (iPS) cells, genome editing technology, and organoid technology, we generated UGT1A1-knockout human iPS hepatocyte-derived liver organoids (UGT1A1-KO i-HOs) as a model for UGT1A1-specific kinetics and toxicity evaluation. i-HOs showed higher gene expression of many drug-metabolizing enzymes including UGT1A1 than human iPS cell-derived hepatocyte-like cells (iPS-HLCs), suggesting that hepatic organoid technology improves liver functions. Wild-type (WT) i-HOs showed similar levels of UGT1A1 activity to primary human (cryopreserved) hepatocytes, while UGT1A1-KO i-HOs completely lost the activity. Additionally, to evaluate whether this model can be used to predict drug-induced hepatotoxicity, UGT1A1-KO i-HOs were exposed to SN-38, the active metabolite of irinotecan, an anticancer drug, and acetaminophen and confirmed that these cells could predict UGT1A1-mediated toxicity. Thus, we succeeded in generating model cells that enable evaluation of UGT1A1-specific kinetics and toxicity.
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Affiliation(s)
- Tomohiro Shintani
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Chiharu Imamura
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Yukiko Ueyama-Toba
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Functional Organoid for Drug Discovery, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan
| | - Jumpei Inui
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Akira Watanabe
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Hiroyuki Mizuguchi
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Functional Organoid for Drug Discovery, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan
- Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan
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24
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Adebayo D, Wong F. Pathophysiology of Hepatorenal Syndrome - Acute Kidney Injury. Clin Gastroenterol Hepatol 2023; 21:S1-S10. [PMID: 37625861 DOI: 10.1016/j.cgh.2023.04.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/14/2023] [Accepted: 04/06/2023] [Indexed: 08/27/2023]
Abstract
Hepatorenal syndrome is a complication of liver cirrhosis with ascites that results from the complex interplay of many pathogenetic mechanisms. Advanced cirrhosis is characterized by the development of hemodynamic changes of splanchnic and systemic arterial vasodilatation, with paradoxical renal vasoconstriction and renal hypoperfusion. Cirrhosis is also an inflammatory state. The inflammatory cascade is initiated by a portal hypertension-induced increased translocation of bacteria, bacterial products, and endotoxins from the gut to the splanchnic and then to the systemic circulation. The inflammation, whether sterile or related to infection, is responsible for renal microcirculatory dysfunction, microthrombi formation, renal tubular oxidative stress, and tubular damage. Of course, many of the bacterial products also have vasodilatory properties, potentially exaggerating the state of vasodilatation and worsening the hemodynamic instability in these patients. The presence of cardiac dysfunction, related to cirrhotic cardiomyopathy, with its associated systolic incompetence, can aggravate the mismatch between the circulatory capacitance and the circulation volume, worsening the extent of the effective arterial underfilling, with lower renal perfusion pressure, contributing to renal hypoperfusion and increasing the risk for development of acute kidney injury. The presence of tense ascites can exert an intra-abdominal compartmental syndrome effect on the renal circulation, causing renal congestion and hampering glomerular filtration. Other contributing factors to renal dysfunction include the tubular damaging effects of cholestasis and adrenal dysfunction. Future developments include the use of metabolomics to identify metabolic pathways that can lead to the development of renal dysfunction, with the potential of identifying biomarkers for early diagnosis of renal dysfunction and the development of treatment strategies.
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Affiliation(s)
- Danielle Adebayo
- Department of Gastroenterology, Royal Berkshire National Health Service Foundation Trust, Reading, United Kingdom
| | - Florence Wong
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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25
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Surace M, Andria I, Valentini G. Renal dysfunctions and liver disease: a brief update on management with particular attention to hepatorenal syndrome. Minerva Gastroenterol (Torino) 2023; 69:412-422. [PMID: 33829727 DOI: 10.23736/s2724-5985.21.02816-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In 2015 the International Club of Ascites gave an accurate, exact and new definition of acute renal injury in cirrhotic patient, identifying objective criteria of severity and recoding hepatorenal syndrome as a particular form of renal dysfunction for which excessive renal vasoconstriction is one of the main, but not the only, pathophysiological mechanisms. In this review we tried to outline new pathophysiological and therapeutic insights, and to summarize the most recent recommendations. Vasopressor such as terlipressin and norepinephrine, in combination with albumin, still represent the first line therapy. However, the new discoveries in the pathophysiology of the disease have led the search for new pharmacological approaches, although, to date, the only definitive remedy is represented by liver (or simultaneous liver-kidney) transplantation.
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Affiliation(s)
- Monica Surace
- Unit of Gastroenterology, Hospital of Rivoli, Rivoli, Turin, Italy -
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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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Amer K, Flikshteyn B, Lingiah V, Tafesh Z, Pyrsopoulos NT. Mechanisms of Disease and Multisystemic Involvement. Clin Liver Dis 2023; 27:563-579. [PMID: 37380283 DOI: 10.1016/j.cld.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Affiliation(s)
- Kamal Amer
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Ben Flikshteyn
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Vivek Lingiah
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Zaid Tafesh
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 53, Newark, NJ 07101-1709, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 536, Newark, NJ 07101-1709, USA.
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Colletta A, Cooper KM, Devuni D. The progression of hepatorenal syndrome-acute kidney injury in acute alcohol-associated hepatitis: renal outcomes after liver transplant. Therap Adv Gastroenterol 2023; 16:17562848231188813. [PMID: 37533707 PMCID: PMC10392193 DOI: 10.1177/17562848231188813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 06/20/2023] [Indexed: 08/04/2023] Open
Abstract
Background Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a complication of advanced liver disease in patients with ascites and circulatory dysfunction. Little data remain on the relationship between HRS-AKI outcomes and different etiologies of liver disease post-liver transplant (LT). Objectives The primary aim was to evaluate the effect of HRS-AKI on renal outcomes in patients with acute alcohol-associated hepatitis (AAH) compared to chronic liver disease (CLD) after LT. The secondary aim was to evaluate the impact of acuity and chronicity of alcohol-associated liver disease in patients with HRS-AKI post-LT renal outcomes. Design A retrospective observational study of patients undergoing urgent inpatient liver transplant evaluation (LTE) for cirrhosis and AAH at single academic LT center between October 2017 and July 2021 was conducted. Methods Patients with HRS-AKI were selected based on indication for LTE: acute AAHHRS or CLDHRS. CLDHRS was categorized by disease etiology: cirrhosis due to alcohol (A-CLDHRS) versus cirrhosis from other causes (O-CLDHRS). CLD patients without HRS-AKI were labeled CLDno HRS. Results A total of 210 subjects underwent LTE; 25% were evaluated for AAH and 75% were evaluated for CLD. Hepatorenal syndrome was more common in subjects evaluated for AAH (37/47) than CLD (104/163) (78.7 versus 63.8%, p = 0.04). For the primary outcome, AAHHRS subjects required ⩾30 days post-LT renal replacement therapy (RRT) more often than subjects with CLDHRS (p = 0.02) and CLDno HRS (p < 0.01). There was no significant difference in other forms of long-term renal outcomes including kidney transplant referral and kidney transplant among cohorts. In subgroup analysis, 30-days post-LT RRT was more common in AAHHRS than in A-CLDHRS (p = 0.08). Logistic regression showed that AAHHRS conferred a 20× and 3.3× odds of requiring ⩾30 days post-LT RRT compared to CLDno HRS and CLDHRS, respectively. Postoperative complications were similar across cohorts, but had a significant effect on 30-day renal outcome post-LT. Conclusions Patients with AAH were more likely to develop HRS and require RRT pre- and post-LT at our center. The etiology of hepatic decompensation and postoperative complications affect renal recovery post-LT. The systemic inflammation of AAH in addition to conditions favoring renal hypoperfusion may contribute to the unfavorable outcomes of HRS-AKI after LT in this patient population.
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Affiliation(s)
| | | | - Deepika Devuni
- UMass Chan Medical School, Division of Gastroenterology, Worcester, MA, USA
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Annavarajula SK, Tandra VR, Ranga SK, Vennavalli S. Bile Cast Nephropathy, An Often-Missed Diagnosis. Indian J Nephrol 2023; 33:315-316. [PMID: 37781543 PMCID: PMC10503581 DOI: 10.4103/ijn.ijn_149_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/24/2022] [Accepted: 08/30/2022] [Indexed: 10/03/2023] Open
Affiliation(s)
| | | | - Santosh Kumar Ranga
- Department of Internal Medicine, Yashoda Hospital, Malakpet, Hyderabad, Telangana, India
| | - Sarika Vennavalli
- Department of Pathology, Yashoda Hospital, Malakpet, Hyderabad, Telangana, India
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Arayangkool C, Gozun M, Tanariyakul M, Techasatian W, Leesutipornchai T, Nishimura Y. Bile Cast Nephropathy Because of Acute Liver Injury Associated With Selective Androgen Receptor Modulators. ACG Case Rep J 2023; 10:e01105. [PMID: 37501938 PMCID: PMC10371315 DOI: 10.14309/crj.0000000000001105] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/22/2023] [Indexed: 07/29/2023] Open
Abstract
Selective androgen receptor modulators (SARMs) are novel nonsteroidal agents abused for performance enhancement such as anabolic steroids. We report a case of a 27-year-old man who used 3 different SARMs and presented with progressive weakness. Initial laboratory testing showed kidney and liver injury with creatinine 4.8 mg/dL and total bilirubin 43.3 mg/dL. An extensive workup was negative for other causes, and the results of liver and kidney biopsies were consistent with bile cast nephropathy because of SARM-associated drug-induced liver injury. His organ functions improved with the cessation of SARMs and plasmapheresis. Providers need to recognize the extreme consequences of SARM use.
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Affiliation(s)
- Chinnawat Arayangkool
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | - Maan Gozun
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | - Manasawee Tanariyakul
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | - Witina Techasatian
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | | | - Yoshito Nishimura
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
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Kiani C, Zori AG. Recent advances in pathophysiology, diagnosis and management of hepatorenal syndrome: A review. World J Hepatol 2023; 15:741-754. [PMID: 37397940 PMCID: PMC10308288 DOI: 10.4254/wjh.v15.i6.741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/18/2023] [Accepted: 05/06/2023] [Indexed: 06/25/2023] Open
Abstract
Hepatorenal syndrome with acute kidney injury (HRS-AKI) is a form of rapidly progressive kidney dysfunction in patients with decompensated cirrhosis and/or acute severe liver injury such as acute liver failure. Current data suggest that HRS-AKI occurs secondary to circulatory dysfunction characterized by marked splanchnic vasodilation, leading to reduction of effective arterial blood volume and glomerular filtration rate. Thus, volume expansion and splanchnic vasoconstriction constitute the mainstay of medical therapy. However, a significant proportion of patients do not respond to medical management. These patients often require renal replacement therapy and may be eligible for liver or combined liver-kidney transplantation. Although there have been advances in the management of patients with HRS-AKI including novel biomarkers and medications, better-calibrated studies, more widely available biomarkers, and improved prognostic models are sorely needed to further improve diagnosis and treatment of HRS-AKI.
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Affiliation(s)
- Calvin Kiani
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Florida, Gainesville, FL 32610, United States
| | - Andreas G Zori
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Florida, Gainesville, FL 32610, United States
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Mandorfer M, Aigner E, Cejna M, Ferlitsch A, Datz C, Gräter T, Graziadei I, Gschwantler M, Hametner-Schreil S, Hofer H, Jachs M, Loizides A, Maieron A, Peck-Radosavljevic M, Rainer F, Scheiner B, Semmler G, Reider L, Reiter S, Schoder M, Schöfl R, Schwabl P, Stadlbauer V, Stauber R, Tatscher E, Trauner M, Ziachehabi A, Zoller H, Fickert P, Reiberger T. Austrian consensus on the diagnosis and management of portal hypertension in advanced chronic liver disease (Billroth IV). Wien Klin Wochenschr 2023:10.1007/s00508-023-02229-w. [PMID: 37358642 DOI: 10.1007/s00508-023-02229-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 05/15/2023] [Indexed: 06/27/2023]
Abstract
The Billroth IV consensus was developed during a consensus meeting of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) and the Austrian Society of Interventional Radiology (ÖGIR) held on the 26th of November 2022 in Vienna.Based on international recommendations and considering recent landmark studies, the Billroth IV consensus provides guidance regarding the diagnosis and management of portal hypertension in advanced chronic liver disease.
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Affiliation(s)
- Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Manfred Cejna
- Department of Radiology, LKH Feldkirch, Feldkirch, Austria
| | - Arnulf Ferlitsch
- Department of Internal Medicine I, KH Barmherzige Brüder Wien, Vienna, Austria
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Tilmann Gräter
- Department of Radiology, Medical University of Graz, Graz, Austria
| | - Ivo Graziadei
- Department of Internal Medicine, KH Hall in Tirol, Hall, Austria
| | - Michael Gschwantler
- Division of Gastroenterology and Hepatology, Department of Medicine IV, Klinik Ottakring, Vienna, Austria
| | - Stephanie Hametner-Schreil
- Department of Gastroenterology and Hepatology, Ordensklinikum Linz Barmherzige Schwestern, Linz, Austria
| | - Harald Hofer
- Department of Internal Medicine I, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alexander Loizides
- Department of Radiology, Medical University of Innbsruck, Innsbruck, Austria
| | - Andreas Maieron
- Department of Internal Medicine II, University Hospital St. Pölten, St. Pölten, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine and Gastroenterology, Hepatology, Endocrinology, Rheumatology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Florian Rainer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Reider
- Department of Interventional Radiology, Medical University of Vienna, Vienna, Austria
| | - Silvia Reiter
- Department of Internal Medicine and Gastroenterology and Hepatology, Kepler Universitätsklinikum, Linz, Austria
| | - Maria Schoder
- Department of Interventional Radiology, Medical University of Vienna, Vienna, Austria
| | - Rainer Schöfl
- Department of Gastroenterology and Hepatology, Ordensklinikum Linz Barmherzige Schwestern, Linz, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Vanessa Stadlbauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Rudolf Stauber
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Elisabeth Tatscher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Alexander Ziachehabi
- Department of Internal Medicine and Gastroenterology and Hepatology, Kepler Universitätsklinikum, Linz, Austria
| | - Heinz Zoller
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Hong S, Li S, Meng X, Li P, Wang X, Su M, Liu X, Liu L. Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin. Acta Pharm Sin B 2023; 13:227-245. [PMID: 36815051 PMCID: PMC9939304 DOI: 10.1016/j.apsb.2022.06.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/17/2022] [Accepted: 06/01/2022] [Indexed: 11/26/2022] Open
Abstract
Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.
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Affiliation(s)
- Shijin Hong
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Shuai Li
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Xiaoyan Meng
- Tianjin Institutes of Pharmaceutical Research, Tianjin 300301, China
| | - Ping Li
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Xun Wang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Mengxiang Su
- Departments of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China
| | - Xiaodong Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China,Corresponding author. Tel./fax: +86 25 83271060.
| | - Li Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210098, China,Corresponding author. Tel./fax: +86 25 83271060.
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Maiwall R, Rastogi A, Pasupuleti SSR, Hidam AK, Singh M, Kadyan S, Jain P, Kumar G, Sarin SK. Natural history, spectrum and outcome of stage 3 AKI in patients with acute-on-chronic liver failure. Liver Int 2022; 42:2800-2814. [PMID: 36017749 DOI: 10.1111/liv.15413] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 07/30/2022] [Accepted: 08/24/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM There is limited data on natural course and interventions in stage-3 acute kidney injury (AKI-3) in patients with acute-on-chronic liver failure (ACLF). We studied the factors of AKI-3 reversal and outcomes of dialysis in ACLF patients. METHODS Consecutive patients with ACLF were prospectively enrolled (n = 1022) and variables determining AKI and its outcomes were analysed. RESULTS At 1 month, 337 (33%) patients had AKI-3, of which, 131 had AKI-3 at enrolment and 206 developed AKI-3 during hospital stay. Of patients with AKI-3 at enrolment, 18% showed terlipressin response, 21% had AKI resolution and 59% required dialysis. High MELD (≥35) (model 1), serum bilirubin (≥23 mg/dL) (model 2) and AARC score (≥11) (model 3) were independent risk factors for dialysis. Dialysis was associated with worse survival in all AKI patients but improved outcomes in patients with AKI-3 (p = .022, HR 0.69 [0.50-0.95]). Post-mortem kidney biopsies (n = 61) revealed cholemic nephropathy (CN) in 54%, acute tubular necrosis (ATN) in 31%, and a combination (CN and ATN) in 15%. Serum bilirubin was significantly higher in patients with CN, CN and ATN compared with ATN respectively ([30.8 ± 12.2] vs. [26.7 ± 12.0] vs. [18.5 ± 9.8]; p = .002). CONCLUSION AKI-3 rapidly increases from 13% to 33% within 30 days in ACLF patients. Histopathological data suggested cholemic nephropathy as the predominant cause which correlated with high bilirubin levels. AKI-3 resolves in only one in five patients. Patients with AARC grade 3 and MELD >35 demand need for early dialysis in AKI-3 for improved outcomes.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Samba Siva R Pasupuleti
- Department of Statistics, Mizoram University (A Central University), Pachhunga University College Campus, Aizawl, India
| | - Ashini K Hidam
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Mansi Singh
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sonia Kadyan
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Priyanka Jain
- Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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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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Abstract
AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal syndrome type 1, also referred to as hepatorenal syndrome-AKI, is the most salient and unique etiology. Patients with cirrhosis are vulnerable to traditional causes of AKI, such as prerenal azotemia, acute tubular injury, and acute interstitial nephritis. In addition, other less common etiologies of AKI specifically related to chronic liver disease should be considered, including abdominal compartment syndrome, cardiorenal processes linked to cirrhotic cardiomyopathy and portopulmonary hypertension, and cholemic nephropathy. Furthermore, certain types of GN can cause AKI in cirrhosis, such as IgA nephropathy or viral hepatitis related. Therefore, a comprehensive diagnostic approach is needed to evaluate patients with cirrhosis presenting with AKI. Management should be tailored to the specific underlying etiology. Albumin-based volume resuscitation is recommended in prerenal AKI. Acute tubular injury and acute interstitial nephritis are managed with supportive care, withdrawal of the offending agent, and, potentially, corticosteroids in acute interstitial nephritis. Short of liver transplantation, vasoconstrictor therapy is the primary treatment for hepatorenal syndrome type 1. Timing of initiation of vasoconstrictors, the rise in mean arterial pressure, and the degree of cholestasis are among the factors that determine vasoconstrictor responsiveness. Large-volume paracentesis and diuretics are indicated to relieve intra-abdominal hypertension and renal vein congestion. Direct-acting antivirals with or without immunosuppression are used to treat hepatitis B/C-associated GN. In summary, AKI in cirrhosis requires careful consideration of multiple potentially pathogenic factors and the implementation of targeted therapeutic interventions.
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Affiliation(s)
- Giuseppe Cullaro
- Department of Medicine, University of California, San Francisco, California
| | - Swetha Rani Kanduri
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | - Juan Carlos Q. Velez
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
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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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Wang S, Yang L, Zhou J, Yang J, Wang X, Chen X, Ji L. A prediction model for acute kidney injury in adult patients with hemophagocytic lymphohistiocytosis. Front Immunol 2022; 13:987916. [PMID: 36203572 PMCID: PMC9531274 DOI: 10.3389/fimmu.2022.987916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background and aims Hemophagocytic lymphohistiocytosis is a clinical syndrome resulting from abnormally active immune cells and a cytokine storm, with the accompanying phagocytosis of blood cells. Patients with hemophagocytic lymphohistiocytosis often suffer acute kidney injury during hospitalization, which usually signifies poor prognosis. We would like to establish a prediction model for the occurrence of acute kidney injury in adult patients with hemophagocytic lymphohistiocytosis for risk stratification. Method We extracted the electronic medical records of patients diagnosed with hemophagocytic lymphohistiocytosis during hospitalization from January 2009 to July 2019. The observation indicator is the occurrence of acute kidney injury within 28 days of hospitalization. LASSO regression was used to screen variables and modeling was performed by COX regression. Results In the present study, 136 (22.7%) patients suffered from acute kidney injury within 28 days of hospitalization. The prediction model consisted of 11 variables, including vasopressor, mechanical ventilation, disseminated intravascular coagulation, admission heart rate, hemoglobin, baseline cystatin C, phosphorus, total bilirubin, lactic dehydrogenase, prothrombin time, and procalcitonin. The risk of acute kidney injury can be assessed by the sum of the scores of each parameter on the nomogram. For the development and validation groups, the area under the receiver operating characteristic curve was 0.760 and 0.820, and the C-index was 0.743 and 0.810, respectively. Conclusion We performed a risk prediction model for the development of acute kidney injury in patients with hemophagocytic lymphohistiocytosis, which may help physicians to evaluate the risk of acute kidney injury and prevent its occurrence.
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Affiliation(s)
- Siwen Wang
- Department of Nephrology, West China Hospital Sichuan University, Chengdu, China
- Department of Occupational Disease and Toxicosis/Nephrology, West China Fourth Hospital Sichuan University, Chengdu, China
| | - Lichuan Yang
- Department of Nephrology, West China Hospital Sichuan University, Chengdu, China
| | - Jiaojiao Zhou
- Department of Ultrasound, West China Hospital Sichuan University, Chengdu, China
- *Correspondence: Jiaojiao Zhou,
| | - Jia Yang
- Department of Nephrology, West China Hospital Sichuan University, Chengdu, China
| | - Xin Wang
- Department of Pediatric Nephrology, West China Second Hospital Sichuan University, Chengdu, China
| | - Xuelian Chen
- Department of Nephrology, West China Hospital Sichuan University, Chengdu, China
| | - Ling Ji
- Department of Nephrology, West China Hospital Sichuan University, Chengdu, China
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Ponzo P, Campion D, Rizzo M, Roma M, Caviglia GP, Giovo I, Rizzi F, Bonetto S, Saracco GM, Alessandria C. Transjugular intrahepatic porto-systemic shunt in cirrhotic patients with hepatorenal syndrome - chronic kidney disease: Impact on renal function. Dig Liver Dis 2022; 54:1101-1108. [PMID: 34625366 DOI: 10.1016/j.dld.2021.09.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 09/10/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Transjugular intrahepatic porto-systemic shunt (TIPS) ameliorates renal function in type-2 hepatorenal syndrome (HRS). Available evidence is based on 'old' HRS diagnostic criteria, and not on the current definition of HRS - chronic kidney disease (HRS-CKD). Among patients who underwent TIPS for refractory ascites over the last 12 years, we investigated clinical and renal function evolution of those with HRS-CKD. METHODS among 212 patients, 41 with HRS-CKD were included. Renal function was evaluated for 12 months after TIPS, along with management of ascites and transplant-free survival (TFS). RESULTS renal function significantly improved already one week after TIPS [serum creatinine (sCr): 1.37 ± 0.23 vs 1.94 ± 0.54 mg/dl, p< 0.001]; the amelioration was maintained during the whole follow-up and was observed in every CKD stage, defined according to baseline estimated Glomerular Filtration Rate (eGFR). sCr and eGFR became comparable between different CKD stages after only one week, whilst significantly different at baseline. TIPS led to a remarkable improvement in the control of ascites in all CKD stages and no significant differences in TFS were recorded. CONCLUSIONS TIPS led to an early, substantial and persistent improvement in renal function in patients with HRS-CKD, irrespective of their baseline CKD stage.
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Affiliation(s)
- Paola Ponzo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Daniela Campion
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Martina Rizzo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Michele Roma
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
| | - Ilaria Giovo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Felice Rizzi
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Silvia Bonetto
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Giorgio Maria Saracco
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Corso Bramante 88, 10126, Turin, Italy.
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Abdul-Hamid M, Abdel-Reheim ES, Hegazy W, Allam A, Othman SI, Alwaele MA, Abdel-Kawi SH. Effect of gervital in attenuating hepatotoxicity caused by methotrexate or azathioprine in adult albino rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:46788-46801. [PMID: 35169948 DOI: 10.1007/s11356-022-18903-x] [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: 07/13/2021] [Accepted: 01/23/2022] [Indexed: 06/14/2023]
Abstract
Methotrexate (MTX) and azathioprine (AZA) are chemotherapeutic, antimetabolic, and immunosuppressive agents with substantial risks such as oxidative lesions to the liver. This study examined the effect of grape seed extract (GSE; gervital) in attenuating hepatotoxicity caused by MTX or AZA treatment. Rats were divided into six groups (six rats per group): Group I, normal control group; Group II, GSE (150 mg/kg/day); Group III, MTX (8 mg/kg/week); Group IV, AZA (15 mg/kg/day); Group V, GSE (150 mg/kg/day) + MTX (8 mg/kg/week); and Group VI, GSE (150 mg/kg/day) + AZA (15 mg/kg/day). After 35-day experimental period, all rats were sacrificed and blood was collected for biochemical study and hemoglobin (Hb) assessment. The liver was weighed and triaged for histological, ultrastructural, and biochemical studies. MTX and AZA treatment decreased Hb levels, increased relative liver weight, increased the activity of glutamate pyruvate transaminase (ALT) and glutamate oxaloacetate transaminase (AST) aminotransferase (ALT) and aspartate aminotransferase (AST) values, and displayed histopathological and ultrastructural alterations. These changes included the disorganization of hepatocytes, pyknosis, karyolysis of some nuclei, and mononuclear leukocytic infiltration. The liver with significant oxidative stress (OS) showed decreased reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) and increased malondialdehyde (MDA) levels. In contrast, GSE administration ameliorated ALT, AST, and all histopathological and ultrastructural changes. GSE treatment also reduced MDA levels but increased the antioxidant parameters. In conclusion, it was concluded that GSE supplementation could be considered as a promising antioxidant in reducing OS, histopathological and ultrastructural alterations induced by MTX and AZA.
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Affiliation(s)
- Manal Abdul-Hamid
- Histology and Cell Biology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni Suef, Egypt.
| | - Eman Salah Abdel-Reheim
- Molecular Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
| | - Walaa Hegazy
- Basic Science Department, Faculty of Physical Therapy, Nahda University, Beni Suef, Egypt
| | - Ahmed Allam
- Developmental Biology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
| | - Sarah I Othman
- Biology Department, Faculty of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Maha Abdulla Alwaele
- Biology Department, Faculty of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Samraa Hussein Abdel-Kawi
- Medical Histology & Cell Biology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt
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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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Buccheri S, Da BL. Hepatorenal Syndrome: Definitions, Diagnosis, and Management. Clin Liver Dis 2022; 26:181-201. [PMID: 35487604 DOI: 10.1016/j.cld.2022.01.002] [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
Hepatorenal syndrome (HRS) is a hemodynamically driven process mediated by renal dysregulation and inflammatory response. Albumin, antibiotics, and β-blockers are among therapies that have been studied in HRS prevention. There are no Food and Drug Administration-approved treatments for HRS although multiple liver societies have recommended terlipressin as first-line pharmacotherapy. Renal replacement therapy is the primary modality used to bridge to definitive therapy with orthotopic liver transplant or simultaneous liver-kidney transplant. Advances in our understanding of HRS pathophysiology and emerging therapeutic modalities are needed to change outcomes for this vulnerable population.
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Affiliation(s)
- Sebastiano Buccheri
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA
| | - Ben L Da
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases & Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
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Dolan V. Low Serum Creatinine as a Marker for Undisclosed Alcohol Abuse. J Insur Med 2022; 49:114-116. [PMID: 35192710 DOI: 10.17849/insm-49-2-1-3.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 01/27/2021] [Indexed: 11/20/2022]
Abstract
Detecting undisclosed alcohol abuse in life insurance applicants has always been a challenge to life underwriters and medical directors. This case report describes a 38-year-old woman with classic signs, symptoms, behavior and biochemical markers of undisclosed alcohol abuse. Review of 10 years of medical records revealed chronic abnormally low serum creatinine results associated with abnormally elevated liver function tests, and repeated denials to attending physicians of ever consuming alcohol. Kidney function throughout the 10-year history was not impaired. Low serum creatinine may be a good marker for detecting undisclosed alcohol abuse, but only when there is no kidney injury, dysfunction or impairment obscuring it.
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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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45
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Donadei C, Angeletti A, Cappuccilli M, Conti M, Conte D, Zappulo F, De Giovanni A, Malvi D, Aldini R, Roda A, La Manna G. Adaptive Mechanisms of Renal Bile Acid Transporters in a Rat Model of Carbon Tetrachloride-Induced Liver Cirrhosis. J Clin Med 2022; 11:jcm11030636. [PMID: 35160088 PMCID: PMC8836491 DOI: 10.3390/jcm11030636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Acute kidney injury (AKI) is common in advanced liver cirrhosis, a consequence of reduced kidney perfusion due to splanchnic arterial vasodilation and intrarenal vasoconstriction. It clinically manifests as hepatorenal syndrome type 1, type 2, or as acute tubular necrosis. Beyond hemodynamic factors, an additional mechanism may be hypothesized to explain the renal dysfunction during liver cirrhosis. Recent evidence suggest that such mechanisms may be closely related to obstructive jaundice. Methods: Given the not completely elucidated role of bile acids in kidney tissue damage, this study developed a rat model of AKI with liver cirrhosis induction by carbon tetrachloride (CCl4) inhalation for 12 weeks. Histological analyses of renal and liver biopsies were performed at sacrifice. Organic anion tubular transporter distribution and apoptosis in kidney cells were analyzed by immunohistochemistry. Circulating and urinary markers of inflammation and tubular injury were assayed in 21 treated rats over time (1, 2, 4, 8, and 12 weeks of CCl4 administration) and 5 controls. Results: No renal histopathological alterations were found at sacrifice. Comparing treated rats with controls, organic anion transporters were differentially expressed and localized. High serum bile acid values were detected in cirrhotic animals, while caspase-3 staining was negative in both groups. Increased levels of serum inflammatory and urinary tubular injury biomarkers were observed during cirrhosis progression, with a peak after 4 and 8 weeks of treatment. Conclusions: These findings suggest possible adaptive tubular mechanisms for bile acid transporters in response to cirrhosis-induced AKI.
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Affiliation(s)
- Chiara Donadei
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Andrea Angeletti
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
- Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa Largo Gaslini, 16148 Genoa, Italy
| | - Maria Cappuccilli
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Massimiliano Conti
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy;
| | - Diletta Conte
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Fulvia Zappulo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Alessio De Giovanni
- Department of Experimental, Diagnostic and Specialty Medicine—DIMES, “F. Addarii” Institute of Oncology and Transplant Pathology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (A.D.G.); (D.M.)
| | - Deborah Malvi
- Department of Experimental, Diagnostic and Specialty Medicine—DIMES, “F. Addarii” Institute of Oncology and Transplant Pathology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (A.D.G.); (D.M.)
| | - Rita Aldini
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy; (R.A.); (A.R.)
| | - Aldo Roda
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy; (R.A.); (A.R.)
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
- Correspondence: ; Tel.: +39-051-214-4577
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Gupta MM, Deng X. Hepatorenal Syndrome. APPROACHES TO CHRONIC KIDNEY DISEASE 2022:151-168. [DOI: 10.1007/978-3-030-83082-3_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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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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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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Bile acid nephropathy induced by anabolic steroids: A case report and review of the literature. Clin Nephrol Case Stud 2021; 9:123-129. [PMID: 34790517 PMCID: PMC8594315 DOI: 10.5414/cncs110711] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/24/2021] [Indexed: 01/13/2023] Open
Abstract
Bile acid nephropathy also known as cholemic nephropathy is a rare and overlooked form of acute kidney injury that occurs in the setting of severe hyperbilirubinemia. The exact etiology remains unknown, and there is a lack of treatment guidelines for this clinical condition. Anabolic steroids are known to cause hepatoxicity occasionally leading to acute kidney injury. We report the case of a 27-year-old male patient who developed bile acid nephropathy as a result of severe hyperbilirubinemia secondary to anabolic steroids-induced liver injury. He was conservatively managed. We review the current literature touching on the etiology, pathophysiology, diagnosis, and management of bile acid nephropathy in an attempt to shed light on this clinical condition, which may present as a diagnostic and therapeutic challenge.
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50
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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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