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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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Sikerwar S, Yao L, Elfarra Y, Jesudian A. Optimal Management of the Inpatient With Decompensated Cirrhosis. J Clin Gastroenterol 2025; 59:420-432. [PMID: 39889207 DOI: 10.1097/mcg.0000000000002143] [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: 08/21/2024] [Accepted: 01/14/2025] [Indexed: 02/02/2025]
Abstract
Over the past several years, there has been a wealth of new data pertaining to the management of complications of cirrhosis, resulting in several important updates to best practices and consensus guidelines. Despite these advancements and numerous recent targeted quality initiatives, hospitalizations resulting from complications of cirrhosis remain frequent, costly and associated with poor patient outcomes. An emphasis on evidence-based management of hospitalized patients with decompensated cirrhosis has the potential to decrease readmission rates and length of stay while improving overall patient outcomes. Herein, we provide an updated, evidence-based overview of the optimal inpatient management of the most frequently encountered complications associated with cirrhosis.
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Affiliation(s)
- Sandeep Sikerwar
- NewYork-Presbyterian Hospital/Columbia University Medical Center
| | - Leah Yao
- NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY
| | - Yasmine Elfarra
- NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY
| | - Arun Jesudian
- NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY
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Hortelã FR, Kruger RS, de Oliveira VF, Carraro H, Muzzillo DA, Kowalski SC. Hepatorenal Syndrome: direct treatment costs and characteristics of patients admitted to intensive care. EINSTEIN-SAO PAULO 2025; 23:eGS0390. [PMID: 40197881 PMCID: PMC12014156 DOI: 10.31744/einstein_journal/2025gs0390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 10/04/2024] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Hepatorenal Syndrome is a potentially reversible syndrome of endstage cirrhosis. It is a severe complication of cirrhosis that involves a high mortality rate and a significant economic impact on the healthcare system. This study shows the costs of the resources used for disease management and complications to be Int$14,189. Quantifying this figure contributes to an understanding of the economic impact of Hepatorenal Syndrome on patient survival. OBJECTIVE The purpose of this study was to describe the direct medical costs incurred in Brazil for the treatment of Hepatorenal Syndrome in intensive care and intermediate therapy care units, and to investigate the impact of this syndrome on patient survival. METHODS This longitudinal observational retrospective study included patients with Hepatorenal Syndrome admitted to the intensive and intermediate therapy care units of a public tertiary hospital. The cost generated by each patient was the sum of the direct costs and overheads. RESULTS Forty-four patients with 49 episodes of suspected Hepatorenal Syndrome were analyzed, 73% male, with a mean age of 55 years (SD= 11). Diagnosis was presumed in 21 episodes (43%), because not all of the Ascites International Club's criteria were met. Alcoholic cirrhosis was the main etiology (43%); 59% of the patients were Child-Pugh Class C at admission, with a mean (SD) model for end-stage liver disease score of 24.6 (8). Seventy-seven percent of the patients died, 32% from multiple organ failure, 29% of septic shock and 27% of hypovolemic shock. The median (IQR) of the total treatment cost for each patient was Int$14,819 (8,732-23,854). The median (IQR) length of intensive care unit stay in intensive care was 11 days (7-19). Patients with a presumed diagnosis did not have a higher hospitalization cost (p=0.249) than those with true Hepatorenal Syndrome. CONCLUSION The treatment of Hepatorenal Syndrome represents a significant cost, and new resource allocation in strategic areas, such as the treatment and monitoring of patients with cirrhosis, is necessary to improve their outcomes. BACKGROUND ■ The treatment of Hepatorenal Syndrome places a huge economic burden on healthcare systems. BACKGROUND ■ Cost analysis studies of Hepatorenal Syndrome management can help to rationally allocate resources in healthcare. BACKGROUND ■ Timely diagnosis and management of Hepatorenal Syndrome may reduce mortality, resource utilization and costs.
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Affiliation(s)
- Franciele Robes Hortelã
- Postgraduate Program in Internal Medicine and Health SciencesComplexo Hospital de ClínicasUniversidade Federal do ParanáCuritibaPRBrazil Postgraduate Program in Internal Medicine and Health Sciences, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.
| | - Rodrigo Sfredo Kruger
- Semi-Intensive Therapy CenterComplexo Hospital de ClínicasUniversidade Federal do ParanáCuritibaPRBrazil Semi-Intensive Therapy Center, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.
| | - Valéria Filomena de Oliveira
- Cost Accounting UnitComplexo Hospital de ClínicasUniversidade Federal do ParanáCuritibaPRBrazil Cost Accounting Unit, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.
| | - Hipolito Carraro
- Intensive Care UnitComplexo Hospital de ClínicasUniversidade Federal do ParanáCuritibaPRBrazil Intensive Care Unit, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.
| | - Dominique Araújo Muzzillo
- Department of Internal MedicineComplexo Hospital de ClínicasUniversidade Federal do ParanáCuritibaPRBrazil Department of Internal Medicine, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.
| | - Sérgio Candido Kowalski
- Department of Internal MedicineComplexo Hospital de ClínicasUniversidade Federal do ParanáCuritibaPRBrazil Department of Internal Medicine, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.
- Department of Health Research Methods, Evidence, and ImpactMcMaster UniversityHamiltonCanada Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
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Liu D, Testro A, Majumdar A, Sinclair M. The current applications and future directions of terlipressin. Hepatol Commun 2025; 9:e0685. [PMID: 40178480 PMCID: PMC11970894 DOI: 10.1097/hc9.0000000000000685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 02/06/2025] [Indexed: 04/05/2025] Open
Abstract
Terlipressin is a vasopressin analog with potent splanchnic vasoconstrictor properties. It has an established role in managing portal hypertensive bleeding and hepatorenal syndrome-acute kidney injury, with a growing body of evidence demonstrating improved safety and efficacy with continuous infusion-based administration compared to bolus dosing. We discuss previously reported adverse effects of terlipressin and evidence-based strategies to maximize the safety of administration. We also review the literature surrounding emerging indications for terlipressin in decompensated cirrhosis, particularly in the management of refractory ascites. Furthermore, we present data on novel ambulatory programs utilizing long-term continuous terlipressin infusion as bridging therapy for liver transplant candidates with recurrent hepatorenal syndrome-acute kidney injury, diuretic-refractory ascites, or hydrothorax.
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Affiliation(s)
- Dorothy Liu
- Victorian Liver Transplant Unit, Austin Health, Melbourne, Victoria, Australia
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Adam Testro
- Victorian Liver Transplant Unit, Austin Health, Melbourne, Victoria, Australia
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Avik Majumdar
- Victorian Liver Transplant Unit, Austin Health, Melbourne, Victoria, Australia
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Marie Sinclair
- Victorian Liver Transplant Unit, Austin Health, Melbourne, Victoria, Australia
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
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Karvellas CJ, Gustot T, Fernandez J. Management of the acute on chronic liver failure in the intensive care unit. Liver Int 2025; 45:e15659. [PMID: 37365997 PMCID: PMC11815614 DOI: 10.1111/liv.15659] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/01/2023] [Accepted: 06/15/2023] [Indexed: 06/28/2023]
Abstract
Acute on chronic liver failure (ACLF) reflects the development of organ failure(s) in a patient with cirrhosis and is associated with high short-term mortality. Given that ACLF has many different 'phenotypes', medical management needs to take into account the relationship between precipitating insult, organ systems involved and underlying physiology of chronic liver disease/cirrhosis. The goals of intensive care management of patients suffering ACLF are to rapidly recognize and treat inciting events (e.g. infection, severe alcoholic hepatitis and bleeding) and to aggressively support failing organ systems to ensure that patients may successfully undergo liver transplantation or recovery. Management of these patients is complex since they are prone to develop new organ failures and infectious or bleeding complications. ICU therapy parallels that applied in the general ICU population in some complications but differs in others. Given that liver transplantation in ACLF is an emerging and evolving field, multidisciplinary teams with expertise in critical care and transplant medicine best accomplish management of the critically ill ACLF patient. The focus of this review is to identify the common complications of ACLF and to describe the proper management in critically ill patients awaiting liver transplantation in our centres, including organ support, prognostic assessment and how to assess when recovery is unlikely.
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Affiliation(s)
- Constantine J. Karvellas
- Department of Critical Care MedicineUniversity of AlbertaEdmontonCanada
- Division of Gastroenterology (Liver Unit)University of AlbertaEdmontonCanada
| | - Thierry Gustot
- Department of Gastroenterology, Hepato‐Pancreatology and Digestive Oncology, H.U.B.CUB Hôpital ErasmeBrusselsBelgium
| | - Javier Fernandez
- Liver ICU, Liver Unit, Hospital ClinicUniversity of Barcelona, IDIBAPS and CIBERehdBarcelonaSpain
- EF CLIF, EASL‐CLIF ConsortiumBarcelonaSpain
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Mattos ÂZD. Cirrhosis in the tropics. TREATMENT AND MANAGEMENT OF TROPICAL LIVER DISEASE 2025:155-166. [DOI: 10.1016/b978-0-323-87031-3.00028-7] [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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Douville NJ, Mathis M, Kheterpal S, Heung M, Schaub J, Naik A, Kretzler M. Perioperative Acute Kidney Injury: Diagnosis, Prediction, Prevention, and Treatment. Anesthesiology 2025; 142:180-201. [PMID: 39527650 PMCID: PMC11620328 DOI: 10.1097/aln.0000000000005215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 08/20/2024] [Indexed: 11/16/2024]
Abstract
In this review, the authors define acute kidney injury in the perioperative setting, describe the epidemiologic burden, discuss procedure-specific risk factors, detail principles of management, and highlight areas of ongoing controversy and research.
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Affiliation(s)
- Nicholas J. Douville
- Department of Anesthesiology, Michigan Medicine, Ann Arbor, Michigan; Institute of Healthcare Policy & Innovation, University of Michigan, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Michael Mathis
- Department of Anesthesiology, Michigan Medicine, Ann Arbor, Michigan; Institute of Healthcare Policy & Innovation, University of Michigan, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan
| | - Sachin Kheterpal
- Department of Anesthesiology, Michigan Medicine, Ann Arbor, Michigan
| | - Michael Heung
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jennifer Schaub
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Abhijit Naik
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Matthias Kretzler
- Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan; Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Pompili E, Iannone G, Carrello D, Zaccherini G, Baldassarre M, Caraceni P. Managing Multiorgan Failure in Acute on Chronic Liver Failure. Semin Liver Dis 2024; 44:492-509. [PMID: 39442531 DOI: 10.1055/a-2448-0664] [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: 10/25/2024]
Abstract
Acute-on-chronic liver failure (ACLF) is defined as a clinical syndrome that develops in patients with chronic liver disease characterized by the presence of organ failure and high short-term mortality, although there is still no worldwide consensus on diagnostic criteria. Management of ACLF is mainly based on treatment of "precipitating factors" (the most common are infections, alcohol-associated hepatitis, hepatitis B flare, and bleeding) and support of organ failure, which often requires admission to the intensive care unit. Liver transplantation should be considered in patients with ACLF grades 2 to 3 as a potentially life-saving treatment. When a transplant is not indicated, palliative care should be considered after 3 to 7 days of full organ support in patients with at least four organ failures or a CLIF-C ACLF score of >70. This review summarizes the current knowledge on the management of organ failure in patients with ACLF, focusing on recent advances.
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Affiliation(s)
- Enrico Pompili
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giulia Iannone
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Daniele Carrello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Maurizio Baldassarre
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Wan YM, Huang SQ, Wu HM, Li YH, Yin HJ, Xu Y. Terlipressin versus placebo or noradrenalin in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1418826. [PMID: 39295934 PMCID: PMC11408352 DOI: 10.3389/fphar.2024.1418826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024] Open
Abstract
Background Hepatorenal syndrome (HRS) bears a very poor prognosis with unmet need for safe and effective therapies. This systematic review and meta-analysis aimed to re-assess safety and efficacy of terlipressin versus placebo or noradrenaline for HRS, based on previous randomized controlled trials (RCTs). Methods PubMed, EMBASE, MEDLINE (OvidSP) and Cochrane registers were searched for trials reporting HRS treatment by terlipressin or noradrenaline. Search terms included: "hepatorenal syndrome", "terlipressin", "noradrenaline", and corresponding synonyms. Comparisons between terlipressin, noradreanaline, placebo and albumin were included. Meta-analysis was conducted for treatment response (both HRS reversal and complete response), mortality and adverse events. Results 15 RCTs were included, enrolling 1236 HRS patients (type 1: 1166, type 2: 70). Treatment with terlipressin+albumin resulted in significantly higher treatment response than placebo+albumin or albumin alone (risk ratio [RR]:2.75, 95% confidence interval [CI]:1.96 to 3.84; I2 = 28%, p = 0.23; n = 6). Noradrenaline was equally effective in treatment response compared to terlipressin (RR:1.19, 95% CI:0.96 to 1.46; I2 = 16%, p = 0.31; n = 7), but trials were limited by its non-blind design and small size. Sensitivity analysis showed no survival benefit with terlipressin compared to either placebo (RR:1.03, 95% CI:0.83 to 1.28; I2 = 0%, p = 0.72; n = 3) or noradreanline (RR:0.83, 95% CI:0.69 to 1.00; I2 = 4%, p = 0.39; n = 7) at 30 days of follow-up. Terlipressin carried higher risk of treatment-related adverse events compared to either placebo (RR:2.92, 95% CI:1.48 to 5.77; I2 = 0%, p = 0.75; n = 3) or noradrenaline (RR:2.45, 95% CI:1.37 to 4.37; I2 = 0%, p = 0.92; n = 5). Conclusion Terlipressin is superior to placebo, and comparable to noradreanline in treatment response, but survival benefit is lacking. Noradrenaline, with low certainty, may be a better alternative for HRS.
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Affiliation(s)
- Yue-Meng Wan
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Song-Quan Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hua-Mei Wu
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Yu-Hua Li
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Hong-Jing Yin
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Ying Xu
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
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Singh J, Ebaid M, Saab S. Advances in the management of complications from cirrhosis. Gastroenterol Rep (Oxf) 2024; 12:goae072. [PMID: 39104730 PMCID: PMC11299547 DOI: 10.1093/gastro/goae072] [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: 03/21/2024] [Revised: 05/29/2024] [Accepted: 06/15/2024] [Indexed: 08/07/2024] Open
Abstract
Cirrhosis with complications of liver decompensation and hepatocellular carcinoma (HCC) constitute a leading cause of morbidity and mortality worldwide. Portal hypertension is central to the progression of liver disease and decompensation. The most recent Baveno VII guidance included revision of the nomenclature for chronic liver disease, termed compensated advanced chronic liver disease, and leveraged the use of liver stiffness measurement to categorize the degree of portal hypertension. Additionally, non-selective beta blockers, especially carvedilol, can improve portal hypertension and may even have a survival benefit. Procedural techniques with interventional radiology have become more advanced in the management of refractory ascites and variceal bleeding, leading to improved prognosis in patients with decompensated liver disease. While lactulose and rifaximin are the preferred treatments for hepatic encephalopathy, many alternative treatment options may be used in refractory cases and even procedural interventions such as shunt embolization may be of benefit. The approval of terlipressin for the treatment of hepatorenal syndrome (HRS) in the USA has improved the way in which HRS is managed and will be discussed in detail. Malnutrition, frailty, and sarcopenia lead to poorer outcomes in patients with decompensated liver disease and should be addressed in this patient population. Palliative care interventions can lead to improved quality of life and clinical outcomes. Lastly, the investigation of systemic therapies, in particular immunotherapy, has revolutionized the management of HCC. These topics will be discussed in detail in this review.
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Affiliation(s)
- Jasleen Singh
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Mark Ebaid
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Sammy Saab
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Olayinka OT, Orelus J, Nisar MR, Kotha R, Saad-Omer SI, Singh S, Yu AK. Comparative Mortality Rates of Vasoconstrictor Agents in the Management of Hepatorenal Syndrome: A Systematic Review and Meta-Analysis. Cureus 2024; 16:e67034. [PMID: 39286706 PMCID: PMC11402629 DOI: 10.7759/cureus.67034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/14/2024] [Indexed: 09/19/2024] Open
Abstract
Hepatorenal syndrome (HRS) is an acute complication of advanced liver disease, which manifests with a rapidly progressive decline in kidney function. Though pharmacological treatment has been recently advanced, there are still high mortality rates. The study compares the mortality rate in patients using different vasoconstrictor agents in the management of HRS. A complete literature search was done in the following databases: PubMed, Cochrane Library, PubMed Central (PMC), and Multidisciplinary Digital Publishing Institute (MDPI). Studies were included according to previously established criteria, in which all studies reporting on adult patients with HRS treated with vasoconstrictor agents were eligible. The data extracted were analyzed with a random-effects model to express variability between studies, and the principal measure was the risk ratio (RR) for mortality. Of the 8,137 studies identified, 29 met the inclusion criteria. In the meta-analysis, vasoconstrictors, mainly terlipressin, significantly improved renal function and decreased the need for renal replacement therapy (RRT) versus placebo. However, a significant impact on mortality was lacking (0.94 (0.84-1.06), p = 0.31). The subgroup analysis found that mortality rates were not significantly different between vasoconstrictors, whether used in combination with or without albumin (0.97 (0.77-1.23), p = 0.79, and 0.98 (0.79-1.21), p = 0.86). Global heterogeneity was low, indicating consistent results in the studies. Vasoconstrictors are helpful in managing HRS, with improvement in renal function and reduction in RRT requirements. However, the effect on mortality was small and nonsignificant. Such findings support the use of terlipressin in HRS management; concomitantly, they emphasize the need for personalized treatment strategies and future research to find alternative therapies that may be more effective for improved survival results with fewer side effects.
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Affiliation(s)
- Oluwatoba T Olayinka
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Jaslin Orelus
- Emergency Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Mah Rukh Nisar
- Neurology and Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Rudrani Kotha
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Sabaa I Saad-Omer
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Shivani Singh
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Ann Kashmer Yu
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
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12
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Juanola A, Ma AT, Gratacós-Ginès J, Soria A, Solé C, Pose E, Ginès P. Renal Complications in Portal Hypertension. Clin Liver Dis 2024; 28:503-523. [PMID: 38945640 DOI: 10.1016/j.cld.2024.03.011] [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: 07/02/2024]
Abstract
Acute kidney injury (AKI) is a common complication among patients with decompensated cirrhosis and its development is associated with worse prognosis in terms of survival. Patients with decompensated cirrhosis may develop a unique type of AKI, known as hepatorenal syndrome (HRS-AKI), characterized by marked impairment of kidney function due to haemodynamic changes that occur in late stages of liver cirrhosis. Besides, patients with cirrhosis also may develop chronic alterations of kidney function (chronic kidney disease, CKD), the incidence of which is increasing markedly and may be associated with clinical complications. The aim of this review is to provide the reader with an update of the most relevant aspects of alterations of kidney function in patients with cirrhossi that may be useful for theri clinical practice.
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Affiliation(s)
- Adrià Juanola
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Ann Thu Ma
- Toronto Centre for Liver Disease Francis Family Liver Clinic, Toronto General Hospital, Toronto, Ontario, Canada
| | - Jordi Gratacós-Ginès
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Anna Soria
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Cristina Solé
- Department of Gastroenterology and Hepatology, Consorci Corporació Sanitària Parc Taulí, Sabadell, Spain
| | - Elisa Pose
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Pere Ginès
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalunya, Spain.
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13
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Malik A, Malik MI, Qureshi S, Nadir A. Efficacy and safety of terlipressin and albumin vs. noradrenaline and albumin in adult patients with hepatorenal syndrome: A systematic review and meta-analysis. Ann Hepatol 2024; 29:101495. [PMID: 38460713 DOI: 10.1016/j.aohep.2024.101495] [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: 08/15/2023] [Revised: 12/10/2023] [Accepted: 01/03/2024] [Indexed: 03/11/2024]
Abstract
INTRODUCTION AND OBJECTIVES Hepatorenal syndrome (HRS) is a serious complication of cirrhosis treated with various medications. We aim to evaluate terlipressin and albumin's effectiveness and safety compared to albumin and noradrenaline in adult hepatorenal disease patients. MATERIALS AND METHODS Clinical trials from four databases were included. Cochrane's approach for calculating bias risk was utilized. We rated the quality evaluation by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). We included the following outcomes: serum creatinine (mg/dl), urine output (ml/24 h), mean arterial pressure (mmHg), reversal rate of HRS, mortality rate, blood plasma renin activity (ng/ml/h), plasma aldosterone concentration (pg/ml), urine sodium (mEq/l), and creatinine clearance (ml/min). RESULTS Our analysis of nine clinical studies revealed that the noradrenaline group was associated with higher creatinine clearance (MD = 4.22 [0.40, 8.05]), (P = 0.03). There were no significant differences in serum creatinine levels (MD = 0.03 [-0.07, 0.13]), urinary sodium (MD = -1.02 [-5.15, 3.11]), urine output (MD = 32.75 [-93.94, 159.44]), mean arterial pressure (MD = 1.40 [-1.17, 3.96]), plasma renin activity (MD = 1.35 [-0.17, 2.87]), plasma aldosterone concentration (MD = 55.35 [-24.59, 135.29]), reversal rate of HRS (RR = 1.15 [0.96, 1.37]), or mortality rate (RR = 0.87 [0.74, 1.01]) between the two groups (p-values > 0.05). CONCLUSIONS Noradrenaline is a safe alternative medical therapy for HRS.
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Affiliation(s)
- Adnan Malik
- Division of Gastroenterology, Mountain Vista Medical Center, Mesa, AZ, United States.
| | | | - Shahbaz Qureshi
- Division of Gastroenterology, Mountain Vista Medical Center, Mesa, AZ, United States
| | - Abdul Nadir
- Division of Gastroenterology, Mountain Vista Medical Center, Mesa, AZ, United States
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14
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Peluso L, Savi M, Coppalini G, Veliaj D, Villari N, Albano G, Petrou S, Pace MC, Fiore M. Management of hepatorenal syndrome and treatment-related adverse events. Curr Med Res Opin 2024; 40:1155-1162. [PMID: 38773739 DOI: 10.1080/03007995.2024.2358242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 05/05/2024] [Accepted: 05/17/2024] [Indexed: 05/24/2024]
Abstract
Hepatorenal Syndrome is a critical complication of liver failure, mainly in cirrhotic patients and rarely in patients with acute liver disease. It is a complex spectrum of conditions that leads to renal dysfunction in the liver cirrhosis population; the pathophysiology is characterized by a specific triad: circulatory dysfunction, nitric oxide (NO) dysfunction and systemic inflammation but a specific kidney damage has never been demonstrated, in a clinicopathological study, kidney biopsies of patients with cirrhosis showed a wide spectrum of kidney damage. In addition, the absence of significant hematuria or proteinuria does not exclude renal damage. It is estimated that 40% of cirrhotic patients will develop hepatorenal syndrome with in-hospital mortality of about one-third of these patients. The burden of the problem is dramatic considering the worldwide prevalence of more than 10 million decompensated cirrhotic patients, and the age-standardized prevalence rate of decompensated cirrhosis has gone through a significant rise between 1990 and 2017. Given the syndrome's poor prognosis, the clinician must know how to manage early treatment and any complications. The widespread adoption of albumin and vasopressors has increased Hepatorenal syndrome-acute kidney injury reversal and may increase overall survival, as previously shown. Further research is needed to define whether the subclassification of patients may allow to find a personalized strategy to treat Hepatorenal Syndrome and to define the role of new molecules and extracorporeal treatment may allow better outcomes with a reduction in treatment-related adverse effects. This review aims to examine both pharmacological and non-pharmacological treatment of hepatorenal syndrome, with a particular focus on managing adverse events caused by treatment.
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Affiliation(s)
- Lorenzo Peluso
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Marzia Savi
- Department of Anesthesia and Intensive Care, Humanitas Gavazzeni, Bergamo, Italy
| | - Giacomo Coppalini
- Department of Anesthesia and Intensive Care, Humanitas Gavazzeni, Bergamo, Italy
| | - Deliana Veliaj
- Department of Anesthesia and Intensive Care, Humanitas Gavazzeni, Bergamo, Italy
| | - Nicola Villari
- Department of Anesthesia and Intensive Care, Humanitas Gavazzeni, Bergamo, Italy
| | - Giovanni Albano
- Department of Anesthesia and Intensive Care, Humanitas Gavazzeni, Bergamo, Italy
| | - Stephen Petrou
- Department of Emergency Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Maria C Pace
- Department of Women, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marco Fiore
- Department of Women, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
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15
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Bielawski AM, Frishman WH. A Review of Terlipressin in Hepatorenal Syndrome: Targeting Endothelial Dysfunction and Subsequent Cardiovascular Adverse Events. Cardiol Rev 2024:00045415-990000000-00249. [PMID: 38832784 DOI: 10.1097/crd.0000000000000697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Hepatorenal syndrome (HRS) is a serious complication of decompensated liver cirrhosis that results in acute kidney injury (AKI). The mortality rate is high. Endothelial dysfunction secondary to liver cirrhosis is a key driver of the development of portal hypertension, which is eventually complicated by ascites and HRS. Ultimately, splanchnic vasodilation and excess gut lymph production result in ascites, low effective arterial blood volume, and maladaptive compensatory mechanisms that contribute to renal hypoperfusion and injury. While the only curative treatment is liver transplantation, vasoconstrictors and albumin have been the mainstay of treatment for candidates who are ineligible or waiting for transplantation. On September 14, 2022, terlipressin, a V1 vasopressin receptor agonist, was approved by the Food and Drug Administration for the treatment of HRS-AKI. In clinical trials, terlipressin plus albumin have been superior to albumin alone and equivocal to noradrenaline plus albumin in renal function improvement. Terlipressin, however, does not improve survival, is costly, and is associated with severe adverse events-including severe cardiac and vascular complications. The aim of this review is to provide an overview of terlipressin pharmacology, adverse events-with a focus on cardiovascular complications-and comparative randomized controlled trials that resulted in the Food and Drug Administration's approval of terlipressin. New literature since its approval and ongoing clinical trials will also be highlighted.
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Affiliation(s)
- Adrienne M Bielawski
- From the Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY
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16
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Karvellas CJ, Bajaj JS, Kamath PS, Napolitano L, O'Leary JG, Solà E, Subramanian R, Wong F, Asrani SK. AASLD Practice Guidance on Acute-on-chronic liver failure and the management of critically ill patients with cirrhosis. Hepatology 2024; 79:1463-1502. [PMID: 37939273 DOI: 10.1097/hep.0000000000000671] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 11/10/2023]
Affiliation(s)
- Constantine J Karvellas
- Division of Gastroenterology (Liver Unit), Department of Critical Care Medicine, University of Alberta, Edmonton, Canada
| | - Jasmohan S Bajaj
- Virginia Commonwealth University, Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
| | - Patrick S Kamath
- Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | | | - Jacqueline G O'Leary
- Department of Medicine, Dallas Veterans Medical Center, University of Texas Southwestern Medical Center Dallas, Texas, USA
| | - Elsa Solà
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA
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17
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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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18
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Roozbeh J, Ezzatzadegan Jahromi S, Rezazadeh MH, Hamidianjahromi A, Malekmakan L. Management of hepatorenal syndrome and associated outcomes: a systematic reviews. BMJ Open Gastroenterol 2024; 11:e001319. [PMID: 38631807 PMCID: PMC11033346 DOI: 10.1136/bmjgast-2023-001319] [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: 12/02/2023] [Accepted: 03/11/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Hepatorenal syndrome (HRS), a multiorgan condition of acute kidney injury, is seen in advanced liver disease. This study aims to evaluate the current treatment for HRS. METHODS The authors searched PubMed, Scopus and Google Scholar literature. After quality assessment, 31 studies were included in this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology and the population, intervention, comparison and outcome scheme were used. We included human-controlled trials that evaluate the current treatment for HRS. Two authors independently screened articles for inclusion, extracted data and assessed the quality of included studies. RESULTS This study investigated the studies conducted on the effects of different treatments on follow-up of HRS patients. We gathered 440 articles, so 31 articles remained in our study. Of which 24 articles were conducted on terlipressin versus placebo or other treatments (midodrine/octreotide, norepinephrine, etc) that showed the higher rate of HRS reversal was detected for terlipressin in 17 studies (10 of them were significant), 2 studies achieved an insignificant lower rate of the model for end-stage liver disease score for terlipressin, 15 studies showed a decreased mortality rate in the terlipressin group (4 of them were significant). CONCLUSION This review showed that terlipressin has a significantly higher reversal rate of HRS than the other treatments. Even the results showed that terlipressin is more efficient than midodrine/octreotide and norepinephrine as a previous medication, in reverse HRS, increasing patient survival.
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Affiliation(s)
- Jamshid Roozbeh
- Shiraz University of Medical Sciences, shiraz, Iran (the Islamic Republic of)
- Shiraz Nephro-Urology Research Center, Shiraz, Iran
| | - Shahrokh Ezzatzadegan Jahromi
- Shiraz University of Medical Sciences, shiraz, Iran (the Islamic Republic of)
- Shiraz Nephro-Urology Research Center, Shiraz, Iran
| | - Mohamad Hossein Rezazadeh
- Shiraz University of Medical Sciences, shiraz, Iran (the Islamic Republic of)
- Shiraz Nephro-Urology Research Center, Shiraz, Iran
| | - Anahid Hamidianjahromi
- Shiraz University of Medical Sciences, shiraz, Iran (the Islamic Republic of)
- Shiraz Nephro-Urology Research Center, Shiraz, Iran
| | - Leila Malekmakan
- Shiraz University of Medical Sciences, shiraz, Iran (the Islamic Republic of)
- Shiraz Nephro-Urology Research Center, Shiraz, Iran
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19
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Pose E, Piano S, Juanola A, Ginès P. Hepatorenal Syndrome in Cirrhosis. Gastroenterology 2024; 166:588-604.e1. [PMID: 38246506 DOI: 10.1053/j.gastro.2023.11.306] [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: 06/16/2023] [Revised: 11/10/2023] [Accepted: 11/19/2023] [Indexed: 01/23/2024]
Abstract
Hepatorenal syndrome (HRS) is a form of kidney dysfunction that characteristically occurs in liver cirrhosis. It is characterized by a marked impairment of kidney function in response to circulatory and hemodynamic alterations that occur in advanced stages of liver cirrhosis, aggravated by systemic inflammation and bacterial translocation. The classical definitions of the types of HRS have been recently revisited and 2 forms of HRS have been redefined: the acute form, referred to as acute kidney injury (HRS-AKI), and the chronic form, referred to as chronic kidney disease. HRS-AKI is one of the most severe forms of AKI in patients with cirrhosis and it consists of an abrupt impairment of kidney function, frequently triggered by an infection, appearing in the setting of advanced decompensated cirrhosis. Differential diagnosis with other causes of AKI is crucial because HRS-AKI requires a specific treatment. Differential diagnosis with AKI-acute tubular necrosis may be challenging and kidney biomarkers may be useful in this setting. Treatment of HRS-AKI is based on the administration of vasoconstrictor drugs in combination with volume expansion with albumin. Prognosis of HRS-AKI is poor, and the ideal definitive treatment consists of liver transplantation or simultaneous liver-kidney transplantation. HRS-AKI has a big impact on patients' quality of life. Management of HRS-AKI remains challenging in specific situations such as alcohol-associated hepatitis or metabolic-associated steatotic liver disease cirrhosis. Developing preventive measures for HRS-AKI, improving its early identification, discovering new biomarkers for differential diagnosis, and improving the response to therapy are some of the unmet needs in the field of HRS-AKI.
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Affiliation(s)
- Elisa Pose
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Adrià Juanola
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Pere Ginès
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Catalunya, Spain; School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalunya, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
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20
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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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21
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Allegretti AS, Patidar KR, Ma AT, Cullaro G. From past to present to future: Terlipressin and hepatorenal syndrome-acute kidney injury. Hepatology 2024:01515467-990000000-00741. [PMID: 38353565 PMCID: PMC11322426 DOI: 10.1097/hep.0000000000000790] [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: 09/11/2023] [Accepted: 10/11/2023] [Indexed: 03/01/2024]
Abstract
Hepatorenal syndrome (HRS) is a rare and highly morbid form of kidney injury unique to patients with decompensated cirrhosis. HRS is a physiologic consequence of portal hypertension, leading to a functional kidney injury that can be reversed by restoring effective circulating volume and renal perfusion. While liver transplantation is the only definitive "cure" for HRS, medical management with vasoconstrictors and i.v. albumin is a cornerstone of supportive care. Terlipressin, a V1a receptor agonist that acts on the splanchnic circulation, has been used for many years outside the United States for the treatment of HRS. However, its recent Food and Drug Administration approval has generated new interest in this population, as a new base of prescribers now work to incorporate the drug into clinical practice. In this article, we review HRS pathophysiology and diagnostic criteria, the clinical use of terlipressin and alternative therapies, and identify areas of future research in the space of HRS and kidney injury in cirrhosis.
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Affiliation(s)
- Andrew S. Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Kavish R. Patidar
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston TX, USA
| | - Ann T. Ma
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada
| | - Giuseppe Cullaro
- Division of Gastroenterology, Department of Medicine, University of California-San Francisco, San Francisco CA, USA
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22
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Erstad BL. Hepatorenal Syndrome With Acute Kidney Injury: Diagnosis and Medical Management. Ann Pharmacother 2024; 58:156-164. [PMID: 37271967 DOI: 10.1177/10600280231177698] [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: 06/06/2023] Open
Abstract
OBJECTIVES To review the current definitions and diagnostic criteria for acute kidney injury (AKI) and type 1 hepatorenal syndrome (HRS) now termed HRS-AKI and discuss the challenges in deciding the most appropriate medication regimens to treat patients with HRS-AKI. DATA SOURCES PubMed (inception to April 2023) with bibliographies of retrieved articles searched for additional articles; organizational websites for clinical practice guidelines (CPGs). STUDY SELECTION AND DATA EXTRACTION Randomized controlled trials (RCTs) evaluating albumin and vasoconstrictors for HRS-AKI. DATA SYNTHESIS A major change in the most recent revision of definitions and diagnostic criteria for HRS-AKI is the elimination of the set cutoff serum creatinine values for AKI. This change should be considered when comparing studies of HRS-AKI over time. Albumin has been administered to both vasoconstrictor treatment and placebo groups in all recent RCTs; however, there has never been a large RCT evaluating a no-albumin group. Most prospective trials comparing a midodrine/octreotide combination or norepinephrine to placebo or terlipressin have enrolled less than 100 patients limiting any conclusions regarding clinically important outcomes. Terlipressin with albumin has shown mixed results for complete HRS-AKI reversal with no reductions in crude mortality but adverse effect concerns involving ischemic and pulmonary events. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Type 1 hepatorenal syndrome with acute kidney injury is a potentially life-threatening syndrome with diagnostic and treatment challenges. Albumin plus a vasoconstrictor has become the routine HRS-AKI treatment even though there has not been a large RCT evaluating a no-albumin group. Terlipressin is the vasoconstrictor of choice for HRS-AKI in current CPGs, but it has adverse effect concerns and, until recently, was not available in the United States. CONCLUSIONS In conjunction with changes in the definitions and diagnostic criteria for HRS-AKI, debate continues regarding the optimal therapy for HRS-AKI, particularly considering recent trials demonstrating ischemic and pulmonary adverse events with terlipressin used in combination with albumin.
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Affiliation(s)
- Brian L Erstad
- Department of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA
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23
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Olson JC, Subramanian RM. Comparative efficacy of terlipressin and norepinephrine for treatment of hepatorenal syndrome-acute kidney injury: A systematic review and meta-analysis. PLoS One 2024; 19:e0296690. [PMID: 38285703 PMCID: PMC10824429 DOI: 10.1371/journal.pone.0296690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 12/15/2023] [Indexed: 01/31/2024] Open
Abstract
The treatment of choice for hepatorenal syndrome-acute kidney injury (HRS-AKI) is vasoconstrictor therapy in combination with albumin, preferably norepinephrine or terlipressin as recommended by recent guidelines. In the absence of larger head-to-head trials comparing the efficacy of terlipressin and norepinephrine, meta-analysis of smaller studies can provide insights needed to understand the comparative effects of these medications. Additionally, recent changes in the HRS diagnosis and treatment guidelines underscore the need for newer analyses comparing terlipressin and norepinephrine. In this systematic review, we aimed to assess reversal of hepatorenal syndrome (HRS) and 1-month mortality in subjects receiving terlipressin or norepinephrine for the management of HRS-AKI. We searched literature databases, including PubMed, Cochrane, Clinicaltrials.gov, International Clinical Trials Registry Platform, Embase, and ResearchGate, for randomized controlled trials (RCTs) published from January 2007 to June 2023 on June 26, 2023. Only trials comparing norepinephrine and albumin with terlipressin and albumin for the treatment of HRS-AKI in adults were included, and trials without HRS reversal as an endpoint or nonresponders were excluded. Pairwise meta-analyses with the random effects model were conducted to estimate odds ratios (ORs) for HRS reversal and 1-month mortality as primary outcomes. Additional outcomes assessed, included HRS recurrence, predictors of response, and incidence of adverse events (AEs). We used the Cochrane risk of bias assessment tool for quality assessment. We included 7 RCTs with a total of 376 subjects with HRS-AKI or HRS type 1. This meta-analysis showed numerically higher rates of HRS reversal (OR 1.33, 95% confidence interval [CI] [0.80-2.22]; P = 0.22) and short-term survival (OR 1.50, 95% CI [0.64-3.53]; P = 0.26) with terlipressin, though these results did not reach statistical significance. Terlipressin was associated with AEs such as abdominal pain and diarrhea, whereas norepinephrine was associated with cardiovascular AEs such as chest pain and ischemia. Most of the AEs were reversible with a reduction in dose or discontinuation of therapy across both arms. Of the terlipressin-treated subjects, 5.3% discontinued therapy due to serious AEs compared to 2.7% of the norepinephrine-treated subjects. Limitations of this analysis included small sample size and study differences in HRS-AKI diagnostic criteria. As more studies using the new HRS-AKI criteria comparing terlipressin and norepinephrine are completed, a clearer understanding of the comparability of these 2 therapies will emerge.
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Affiliation(s)
- Jody C. Olson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Ram M. Subramanian
- Department of Medicine, Divisions of Gastroenterology and Hepatology and Pulmonary and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
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Ozturk NB, Dinc EJ, Swami A, Gurakar A. Acute Kidney Injury and Hepatorenal Syndrome in Patients with Cirrhosis. J Clin Med 2023; 13:199. [PMID: 38202206 PMCID: PMC10779857 DOI: 10.3390/jcm13010199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/25/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Acute kidney injury (AKI) is common in hospitalized patients with cirrhosis. Hepatorenal syndrome (HRS) is a type of AKI known as HRS-AKI. It is a severe complication of cirrhosis with high morbidity and mortality. While certain vasoconstrictor medications have been shown to improve HRS-AKI, no clear transplant-free survival benefit has been reported with medical therapies. Patients with HRS-AKI should be considered for urgent liver transplantation evaluation. In this review, we discuss the most recent updates on the definition, diagnosis, and management of AKI in cirrhosis, with special a emphasis on HRS.
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Affiliation(s)
- Nazli Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, MI 48073, USA
| | - Ece Janet Dinc
- School of Medicine, Baskent University, 06790 Ankara, Turkey
| | - Abhishek Swami
- Division of Nephrology, Beaumont Hospital, Royal Oak, MI 48073, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins University Hospital, Baltimore, MD 21287, USA
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Huang X, Bindra J, Chopra I, Niewoehner J, Wan GJ. Treatment-Related Cost Analysis of Terlipressin for Adults with Hepatorenal Syndrome with Rapid Reduction in Kidney Function. Adv Ther 2023; 40:5432-5446. [PMID: 37812332 PMCID: PMC10611877 DOI: 10.1007/s12325-023-02674-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 08/31/2023] [Indexed: 10/10/2023]
Abstract
INTRODUCTION Hepatorenal syndrome (HRS), a special form of acute kidney failure, is a rare, acute, life-threatening complication of cirrhosis and has a very poor prognosis. Terlipressin (TERLIVAZ®) is the first and only pharmacological treatment approved by Food and Drug Administration (September 2022) to improve kidney function for adults with HRS with rapid reduction in kidney function. We constructed a decision analytic economic model to estimate the cost per complete response/HRS reversal of terlipressin + albumin from a United States hospital perspective. METHODS A decision analytic model was developed to estimate the HRS treatment-related cost per response over an HRS hospitalization (assuming 14 days). Patients can experience either HRS reversal (complete response) or no HRS reversal (partial/no response) upon receipt of treatment. The efficacy, safety, and treatment duration data were from published head-to-head randomized international trials. Total treatment cost comprised drug acquisition and treatment-related costs (intensive care unit [ICU], dialysis [intermittent or continuous], pulse oximetry monitoring for terlipressin, and adverse events) sourced from the published literature. Cost per response, defined as the total treatment cost per HRS reversal was estimated for each treatment. The number needed to treat (NNT), defined as the number of patients treated to achieve HRS reversal in 1 additional patient, was estimated. RESULTS Cost per response of terlipressin + albumin was lower than midodrine and octreotide + albumin (M&O) (US$85,315 vs. $467,794) and norepinephrine + albumin ($81,614 vs. $139,324). NNT for HRS reversal was 2 patients with terlipressin + albumin vs. M&O + albumin and 4 patients with terlipressin + albumin vs. norepinephrine + albumin, respectively. CONCLUSIONS The analysis shows that terlipressin is a cost-effective treatment due to its higher efficacy and administration in the non-ICU setting. Terlipressin is a value-based treatment option for appropriate adults with HRS with rapid reduction in kidney function.
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Affiliation(s)
- Xingyue Huang
- Mallinckrodt Pharmaceuticals, 440 Route 22 East, Bridgewater, NJ, USA.
| | - Jas Bindra
- Falcon Research Group, North Potomac, MD, USA
| | | | - John Niewoehner
- Mallinckrodt Pharmaceuticals, 440 Route 22 East, Bridgewater, NJ, USA
| | - George J Wan
- Mallinckrodt Pharmaceuticals, 440 Route 22 East, Bridgewater, NJ, USA
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Weinberg E, Rahematpura S, Gonzalez SA, Izzy MJ, Simonetto DA, Frederick RT, Rubin RA, Ikahihifo-Bender J, Harte M, Kim-Lee G, Witkiewicz S, Tobin W, Jamil K, Fricker Z, Reddy KR. INFUSE: Rationale and design of a multi-center, open label, collaborative study to treat HRS-AKI with continuous terlipressin infusion. Contemp Clin Trials Commun 2023; 36:101211. [PMID: 37953795 PMCID: PMC10632660 DOI: 10.1016/j.conctc.2023.101211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/25/2023] [Accepted: 10/01/2023] [Indexed: 11/14/2023] Open
Abstract
Background Hepatorenal syndrome-acute kidney injury (HRS-AKI) carries significant morbidity and mortality among those with end-stage liver disease. Bolus terlipressin for treatment of HRS-AKI received FDA approval in September 2022. US implementation of terlipressin, however, is hindered by the paucity of local data on the optimal patient population and administration mode, as well as the effect on transplant priority. The INFUSE study is designed to evaluate the use of continuous terlipressin infusion among transplant candidates with advanced liver disease and HRS-AKI. Methods Fifty prospective patients with HRS-AKI will receive a single bolus of terlipressin 0.5 mg followed by continuous infusions of terlipressin from 2 to 8 mg/day for up to 14 days. The cohort will be enriched with those listed, in evaluation, or eligible for liver transplantation, while those with ACLF grade 3, MELD ≥35, and serum creatinine >5.0 mg/dL will be excluded. Fifty patients who received midodrine plus octreotide or norepinephrine for HRS-AKI will serve as a retrospective comparator cohort. Conclusion The INFUSE study aims to assess the safety and efficacy of continuous terlipressin infusion among largely transplant-eligible patients with HRS-AKI, and to provide US-based data on transplant outcomes. This novel study design simultaneously mitigates terlipressin adverse events while providing renal benefits to patients, thus addressing the unmet medical need of those with HRS-AKI who have limited treatment options and are awaiting liver transplantation in the US.
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Affiliation(s)
- Ethan Weinberg
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Suditi Rahematpura
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Stevan A. Gonzalez
- Division of Hepatology, Simmons Transplant Institute, Baylor Scott and White All Saints Medical Center, Fort Worth, TX, USA
| | - Manhal J. Izzy
- Department of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - R. Todd Frederick
- Department of Hepatology and Liver Transplantation, California Pacific Medical Center, San Francisco, CA, USA
| | - Raymond A. Rubin
- Department of Transplantation, Piedmont Transplant Institute, Atlanta, GA, USA
| | - Jade Ikahihifo-Bender
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Maggie Harte
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Grace Kim-Lee
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | | | | | - Khurram Jamil
- Mallinckrodt Ltd, Scientific Affairs, Hampton, NJ, USA
| | - Zachary Fricker
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - K. Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Ayyad A, Al-Horani RA. Terlipressin for the Prevention and Treatment of Renal Decline in Hepatorenal Syndrome: A Drug Profile. GASTROENTEROLOGY INSIGHTS 2023; 14:420-430. [PMID: 37873544 PMCID: PMC10587779 DOI: 10.3390/gastroent14040031] [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] [Indexed: 10/25/2023] Open
Abstract
Hepatorenal syndrome stands as one of several potential triggers of acute kidney injury in individuals grappling with either acute or persistent liver ailments. The nature of the decline in kidney function has led to the identification of two variants of hepatorenal syndrome. In cases where terlipressin therapy is accessible, the initial approach involves administering terlipressin alongside albumin. Terlipressin, a synthetic analog of vasopressin, boasts double the preference for vasopressin V1 receptors compared to V2 receptors. The FDA granted approval to terlipressin in September 2022, demonstrating its intrinsic activity, although a significant portion of its function arises from its transformation into lysine vasopressin. This article provides a comprehensive examination of terlipressin's various pharmacodynamic and pharmacokinetic facets, as well as its clinical utility, aiming to keep the scientific community well informed about its safe and efficient utilization.
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Affiliation(s)
- Ahlam Ayyad
- Division of Clinical and Administrative Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA
| | - Rami A. Al-Horani
- Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA
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28
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Choi JC, Yoo JJ. [Hepatorenal Syndrome]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2023; 82:224-232. [PMID: 37997218 DOI: 10.4166/kjg.2023.108] [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: 09/06/2023] [Revised: 09/16/2023] [Accepted: 09/19/2023] [Indexed: 11/25/2023]
Abstract
Hepatorenal syndrome (HRS) is a critical and potentially life-threatening complication of advanced liver disease, including cirrhosis. It is characterized by the development of renal dysfunction in the absence of underlying structural kidney pathology. The pathophysiology of HRS involves complex interactions between systemic and renal hemodynamics, neurohormonal imbalances, and the intricate role of vasoconstrictor substances. Understanding these mechanisms is crucial for the timely identification and management of HRS. The diagnosis of HRS is primarily clinical and relies on specific criteria that consider the exclusion of other causes of renal dysfunction. The management of HRS comprises two main approaches: vasoconstrictor therapy and albumin infusion, which aim to improve renal perfusion and mitigate the hyperdynamic circulation often seen in advanced liver disease. Additionally, strategies such as liver transplantation and renal replacement therapy are essential considerations based on individual patient characteristics and disease severity. This review article provides a comprehensive overview of hepatorenal syndrome, focusing on its pathophysiology, diagnostic criteria, and current management strategies.
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Affiliation(s)
- Jun Cheol Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Jeong-Ju Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
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Pompili E, Zaccherini G, Baldassarre M, Iannone G, Caraceni P. Albumin administration in internal medicine: A journey between effectiveness and futility. Eur J Intern Med 2023; 117:28-37. [PMID: 37423819 DOI: 10.1016/j.ejim.2023.07.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/11/2023]
Abstract
Albumin is the most abundant circulating protein and provides about 70% of the plasma oncotic power. The molecule also carries many other biological functions (binding, transport and detoxification of endogenous and exogenous compounds, antioxidation, and modulation of inflammatory and immune responses). Hypoalbuminemia is a frequent finding in many diseases, representing usually only a biomarker of poor prognosis rather than a primary pathophysiological event. Despite that, albumin is prescribed in many conditions based on the assumption that correction of hypoalbuminemia would lead to clinical benefits for the patients. Unfortunately, many of these indications are not supported by scientific evidence (or have been even disproved), so that a large part of albumin use is nowadays still inappropriate. Decompensated cirrhosis is the clinical area where albumin administration has been extensively studied and solid recommendations can be made. Besides prevention and treatment of acute complications, long-term albumin administration in patients with ascites has emerged in the last decade has a potential new disease-modifying treatment. In non-hepatological settings, albumin is widely used for fluid resuscitation in sepsis and critical illnesses, with no clear superiority over crystalloids. In many other conditions, scientific evidence supporting albumin prescription is weak or even absent. Thus, given its high cost and limited availability, action is needed to avoid the use of albumin for inappropriate and futile indications to ensure its availability in those conditions for which albumin has been demonstrated to have a real effectiveness and an advantage for the patient.
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Affiliation(s)
- Enrico Pompili
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Maurizio Baldassarre
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Centre for Applied Biomedical Research (CRBA), Alma Mater Studiorum of Bologna, Italy
| | - Giulia Iannone
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy.
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30
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Jung CY, Chang JW. Hepatorenal syndrome: Current concepts and future perspectives. Clin Mol Hepatol 2023; 29:891-908. [PMID: 37050843 PMCID: PMC10577351 DOI: 10.3350/cmh.2023.0024] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 04/10/2023] [Accepted: 04/10/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, remains a major complication in patients with advanced cirrhosis, often leading to death before liver transplantation (LT). Recent updates in the pathophysiology, definition, and classification of HRS have led to a complete revision of the nomenclature and diagnostic criteria for HRS type 1, which was renamed HRS-acute kidney injury (AKI). HRS is characterized by severe impairment of kidney function due to increased splanchnic blood flow, activation of several vasoconstriction factors, severe vasoconstriction of the renal arteries in the absence of kidney histologic abnormalities, nitric oxide dysfunction, and systemic inflammation. Diagnosis of HRS remains a challenge because of the lack of specific diagnostic biomarkers that accurately distinguishes structural from functional AKI, and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis. The optimal treatment of HRS is LT. While awaiting LT, treatment options include vasoconstrictor drugs to counteract splanchnic arterial vasodilation and plasma volume expansion by intravenous albumin infusion. In patients with HRS unresponsive to pharmacological treatment and with conventional indications for kidney replacement therapy (KRT), such as volume overload, uremia, or electrolyte imbalances, KRT may be applied as a bridging therapy to transplantation. Other interventions, such as transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Although recently developed novel therapies have potential to improve outcomes of patients with HRS, further studies are warranted to validate the efficacy of these novel agents.
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Affiliation(s)
- Chan-Young Jung
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jai Won Chang
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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31
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Deorukhkar D, Sonawale A, Goyal A, Sonawale K. Deranged Biochemical Markers As Early Predictors for the Development of Hepatorenal Syndrome in Patients With Alcoholic Liver Cirrhosis. Cureus 2023; 15:e47927. [PMID: 38034151 PMCID: PMC10684394 DOI: 10.7759/cureus.47927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2023] [Indexed: 12/02/2023] Open
Abstract
Objective To investigate predictive biomarkers correlated with the onset of hepatorenal syndrome (HRS) in individuals with alcoholic liver cirrhosis using various factors, including age, sex, and laboratory indicators such as serum sodium, bilirubin, PT/INR, and albumin levels. Additionally, we sought to establish a correlation between the occurrence of hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and the model for end-stage liver disease (MELD) score at the time of diagnosis and the development of HRS in cirrhotic patients. Methods This cross-sectional study spanned 12 months and included a total of 83 patients as its sample size. This study was conducted at the Department of Internal Medicine, a tertiary care hospital situated in Mumbai, India. Two distinct groups were formed: one consisted of patients diagnosed with HRS, and the other group comprised patients with alcoholic liver cirrhosis but without HRS. This study aimed to investigate potential relationships with the suggested risk factors. To discern statistically meaningful distinctions among categorical variables, the chi-square test was employed, whereas for continuous variables, analysis of variance (ANOVA) was used. Only patients who provided written informed consent were included in this study. Results No correlation was found between patients with and without HRS with respect to age (p=0.056) and sex (p=0.067). The presence of HE (p<0.001), SBP (p=0.021), hyponatremia (p=0.0001), hypoalbuminemia (p<0.0001), higher PT/INR (p=0.03), and higher MELD score (p=0.0002) were found to be correlated with an increased risk of developing HRS. Hyperbilirubinemia was not correlated with an increased risk of developing HRS (p=0.157). Conclusions HRS is a severe and potentially avoidable complication associated with advanced liver cirrhosis, characterized by a notably high mortality rate. By closely monitoring key biomarkers, such as serum sodium, PT/INR, and albumin levels, in addition to assessing the presence of SBP and HE during the initial presentation of patients with alcoholic cirrhosis, medical professionals may be able to identify those at a heightened risk of developing HRS. This, in turn, enables the swift diagnosis and implementation of aggressive treatment strategies. Such measures not only hold the potential to reverse HRS but also enhance survival rates among individuals with alcoholic liver cirrhosis, thereby increasing the pool of candidates eligible for liver transplantation, which remains the cornerstone of treatment.
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Affiliation(s)
- Durga Deorukhkar
- Department of Internal Medicine, Seth Gordhandas Sunderdas (GS) Medical College and King Edward Memorial (KEM) Hospital, Mumbai, IND
| | - Archana Sonawale
- Department of Internal Medicine, Seth Gordhandas Sunderdas (GS) Medical College and King Edward Memorial (KEM) Hospital, Mumbai, IND
| | - Aman Goyal
- Department of Internal Medicine, Seth Gordhandas Sunderdas (GS) Medical College and King Edward Memorial (KEM) Hospital, Mumbai, IND
| | - Kshitij Sonawale
- Department of Internal Medicine, Seth Gordhandas Sunderdas (GS) Medical College and King Edward Memorial (KEM) Hospital, Mumbai, IND
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Scheinberg AR, Martin P, Turkeltaub JA. Terlipressin in the management of liver disease. Expert Opin Pharmacother 2023; 24:1665-1671. [PMID: 37535437 DOI: 10.1080/14656566.2023.2244427] [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: 06/11/2023] [Revised: 07/26/2023] [Accepted: 08/01/2023] [Indexed: 08/05/2023]
Abstract
INTRODUCTION Terlipressin is a synthetic vasopressin analog which has been recently approved in the United States by the Food and Drug Administration for the treatment of hepatorenal syndrome. Terlipressin stimulates vasopressin receptors located on the smooth muscle vasculature of the splanchnic circulation and renal tubules which results in splanchnic vasoconstriction with improved renal perfusion and antidiuretic activity, respectively. AREAS COVERED In this review, we discuss available data regarding the FDA approved use of terlipressin, safety, and tolerability, as well as highlight alternative uses in chronic liver disease currently still under investigation. EXPERT OPINION Terlipressin is more efficacious compared to other vasoactive agents including midodrine octreotide and norepinephrine in reversal of hepatorenal syndrome and improves short-term survival. Other potential applications of terlipressin's vasoconstrictor actions reported in the literature include management of variceal hemorrhage and other complications of portal hypertension.
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Affiliation(s)
- Andrew R Scheinberg
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami, Miami, FL, USA
| | - Paul Martin
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami, Miami, FL, USA
| | - Joshua A Turkeltaub
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami, Miami, FL, USA
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Duong N, Kakadiya P, Bajaj JS. Current Pharmacologic Therapies for Hepatorenal Syndrome-Acute Kidney Injury. Clin Gastroenterol Hepatol 2023; 21:S27-S34. [PMID: 37625864 DOI: 10.1016/j.cgh.2023.06.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/30/2023] [Accepted: 06/03/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND & AIMS Hepatorenal syndrome (HRS) can occur in patients with cirrhosis and ascites due to splanchnic vasodilation, renal hypoperfusion, and vasoconstriction. HRS is a diagnosis of exclusion and portends a poor prognosis, with upward of 80% mortality at 2 weeks without treatment. This review will highlight randomized controlled trials for HRS pharmacotherapy. METHODS A PubMed review of randomized controlled trials conducted over the past 25 years was undertaken; 18 studies were included. RESULTS Initial studies showed that norepinephrine is as effective as terlipressin for HRS reversal. Midodrine with octreotide and albumin is less effective than terlipressin but better than albumin alone at improving 30-day mortality. Recently, terlipressin with albumin led to significantly higher rates of HRS reversal compared to albumin alone. Non-response to terlipressin can predict 90-day mortality in acute-on-chronic-liver failure. CONCLUSIONS Our current understanding of HRS treatment is improved by recent randomized clinical trials. Previous studies using varying medication doses along with the "old" definition of hepatorenal syndrome (HRS type 1) rather than HRS-AKI means that there is still a need for future multicenter prospective studies further refining the risk-benefit ratio of vasoconstrictors for HRS-AKI patients. The Food and Drug Administration has approved terlipressin for use in September 2022. Because it will take time to adapt into clinical practice, less cost-prohibitive vasoconstrictors should still be considered. Opportunities also exist to clarify the safety, timing of initiation, as well as possible discontinuation of terlipressin.
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Affiliation(s)
- Nikki Duong
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia
| | - Payal Kakadiya
- Division of Pharmacy, Virginia Commonwealth University Health, Richmond, Virginia
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia.
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Singh V, De A, Mehtani R, Angeli P, Maiwall R, Satapathy S, Singal AK, Saraya A, Sharma BC, Eapen CE, Rao PN, Shukla A, Shalimar, Choudhary NS, Alcantara-Payawal D, Arora V, Aithal G, Kulkarni A, Roy A, Shrestha A, Mamun Al Mahtab, Niriella MA, Siam TS, Zhang CQ, Huei LG, Yu ML, Roberts SK, Peng CY, Chen T, George J, Wong V, Yilmaz Y, Treeprasertsuk S, Kurniawan J, Kim SU, Younossi ZM, Sarin SK. Asia-Pacific association for study of liver guidelines on management of ascites in liver disease. Hepatol Int 2023; 17:792-826. [PMID: 37237088 DOI: 10.1007/s12072-023-10536-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 04/08/2023] [Indexed: 05/28/2023]
Affiliation(s)
- Virendra Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India.
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rohit Mehtani
- Department of Hepatology, Amrita Institute of Medical Sciences and Research, Faridabad, India
| | - Paolo Angeli
- Department of Internal Medicine and Hepatology, University of Padova, Padua, Italy
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sanjaya Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY, USA
| | - Ashwini K Singal
- University of South Dakota Sanford School of Medicine, Sioux Falls, USA
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - B C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, Delhi, India
| | - C E Eapen
- Department of Hepatology, Christian Medical College, Vellore, India
| | - P N Rao
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Akash Shukla
- Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Sion, Mumbai, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | | | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guru Aithal
- Biomedical Research Unit, NIHR Nottingham Digestive Diseases, Nottingham, UK
| | - Anand Kulkarni
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Akash Roy
- Institute of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, India
| | - Ananta Shrestha
- Department of Hepatology, The Liver Clinic, Liver Foundation, Kathmandu, Nepal
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Madunil A Niriella
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
| | - Tan Soek Siam
- Department of Hepatology, Hospital Selayang, Selangor Darul Ehsan, Malaysia
| | - Chun-Qing Zhang
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Lee Guan Huei
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Ming-Lung Yu
- School of Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | | | - Cheng-Yuan Peng
- Centre for Digestive Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Tao Chen
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jacob George
- University of Sydney School of Medicine, Sydney, Australia
| | - Vincent Wong
- Mok Hing Yiu Professor of Medicine, Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Yusuf Yilmaz
- Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | | | - Juferdy Kurniawan
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital Jakarta, Jakarta, Indonesia
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Abraldes JG, Caraceni P, Ghabril M, Garcia-Tsao G. Update in the Treatment of the Complications of Cirrhosis. Clin Gastroenterol Hepatol 2023; 21:2100-2109. [PMID: 36972759 PMCID: PMC11097249 DOI: 10.1016/j.cgh.2023.03.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 02/17/2023] [Accepted: 03/07/2023] [Indexed: 03/29/2023]
Abstract
Cirrhosis consists of 2 main stages: compensated and decompensated, the latter defined by the development/presence of ascites, variceal hemorrhage, and hepatic encephalopathy. The survival rate is entirely different, depending on the stage. Treatment with nonselective β-blockers prevents decompensation in patients with clinically significant portal hypertension, changing the previous paradigm based on the presence of varices. In patients with acute variceal hemorrhage at high risk of failure with standard treatment (defined as those with a Child-Pugh score of 10-13 or those with a Child-Pugh score of 8-9 with active bleeding at endoscopy), a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) improves the mortality rate and has become the standard of care in many centers. In patients with bleeding from gastrofundal varices, retrograde transvenous obliteration (in those with a gastrorenal shunt) and/or variceal cyanoacrylate injection have emerged as alternatives to TIPS. In patients with ascites, emerging evidence suggests that TIPS might be used earlier, before strict criteria for refractory ascites are met. Long-term albumin use is under assessment for improving the prognosis of patients with uncomplicated ascites and confirmatory studies are ongoing. Hepatorenal syndrome is the least common cause of acute kidney injury in cirrhosis, and first-line treatment is the combination of terlipressin and albumin. Hepatic encephalopathy has a profound impact on the quality of life of patients with cirrhosis. Lactulose and rifaximin are first- and second-line treatments for hepatic encephalopathy, respectively. Newer therapies such as L-ornithine L-aspartate and albumin require further assessment.
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Affiliation(s)
- Juan G Abraldes
- Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | - Paolo Caraceni
- Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera-Universitaria di Bologna, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Marwan Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Guadalupe Garcia-Tsao
- Yale University School of Medicine, Veterans Administration - Connecticut Healthcare System, West Haven, Connecticut.
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Kulkarni AV, Lee J, Reddy KR. Terlipressin in the management of adults with hepatorenal syndrome-acute kidney injury (HRS-AKI). Expert Rev Gastroenterol Hepatol 2023; 17:1067-1079. [PMID: 37856367 DOI: 10.1080/17474124.2023.2273494] [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: 07/03/2023] [Accepted: 10/17/2023] [Indexed: 10/21/2023]
Abstract
INTRODUCTION Kidney is the most common extra-hepatic organ involved in patients with advanced liver cirrhosis and acute-on-chronic liver failure. Hepatorenal syndrome-acute kidney injury (HRS-AKI) accounts for most hospitalizations, and liver transplantation (LT) remains the ultimate and long-term treatment in such patients. However, HRS-AKI, being a functional renal failure, has a fair chance of reversal, and as such, patients who achieve reversal of HRS-AKI have better outcomes post-LT. AREAS COVERED In this review, we discuss the pharmacokinetics, pharmacodynamics and evidence to support the use of terlipressin in HRS-AKI while we also address predictors of response and the associated adverse events. Further, we discuss the role of terlipressin in the context of LT. EXPERT OPINION The recommended treatment for HRS-AKI reversal includes a vasoconstrictor in addition to volume expansion with albumin. The three vasoconstrictor regimens generally used to treat HRS-AKI include octreotide plus midodrine, noradrenaline, and terlipressin. Of these, terlipressin is a widely used drug and has been recently approved by US Food and Drug Administration (USFDA) for HRS-AKI. Terlipressin is the most effective drug for HRS-AKI reversal and is associated with a decreased need for renal replacement therapy pre- and post-transplant. Furthermore, terlipressin responders have improved transplant-free and post-transplant survival.
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Affiliation(s)
- Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Jason Lee
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, USA
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, USA
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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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Okushin K, Yamana H, Tateishi R, Sato M, Tsutsumi T, Matsui H, Fushimi K, Yasunaga H, Koike K, Fujishiro M. Treatment and outcome of hepatorenal syndrome in Japan: a retrospective cohort study using a national inpatient database. BMC Gastroenterol 2023; 23:218. [PMID: 37353737 DOI: 10.1186/s12876-023-02858-5] [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: 03/01/2023] [Accepted: 06/18/2023] [Indexed: 06/25/2023] Open
Abstract
BACKGROUND Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease. This study aimed to clarify the status of HRS in Japan by analyzing the Japanese Diagnosis Procedure Combination database. METHODS Patients hospitalized for cirrhosis and HRS from July 2010 to March 2019 were sampled. They were divided into two groups according to their prognosis upon discharge: the transplant-free survival group and the death or liver transplantation group. The two groups' baseline patient characteristics and treatments were compared. RESULTS The mean age of the 1,412 participants was 67.3 years (standard deviation: 12.3 years), and 65.4% were male. The Child-Pugh grades was B and C in 18.8% and 81.2%, respectively. Hepatocellular carcinoma was present in 27.1% of the patients, and the proportion of spontaneous bacterial peritonitis was 2.3%. Albumin, noradrenaline, and dopamine were administered to 57.9%, 8.0%, and 14.9% of the patients, respectively; 7.0% of the patients underwent renal replacement therapy; and 5.0% were admitted to the intensive care unit. Intravenous antibiotics were administered to 30.8% of the patients. A total of 925 patients (65.5%) died or underwent liver transplantation. In addition to a higher proportion of patients with poor baseline liver function, the death or liver transplantation group included more males, patients with hepatocellular carcinoma, and those with spontaneous bacterial peritonitis. CONCLUSIONS HRS in Japan has a high mortality rate. Albumin was administered to over 50% of participants. Although noradrenaline is recommended in Japanese clinical guidelines, dopamine was more frequently used as a vasoconstrictor in clinical practice.
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Affiliation(s)
- Kazuya Okushin
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hayato Yamana
- Data Science Center, Jichi Medical University, Shimotsuke, Japan
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Takeya Tsutsumi
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroki Matsui
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan
| | - Kiyohide Fushimi
- Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
- Kanto Central Hospital, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Singh V, Jayachandran A, De A, Singh A, Chandel S, Sharma N. Combination of terlipressin and noradrenaline versus terlipressin in hepatorenal syndrome with early non-response to terlipressin infusion: A randomized trial. Indian J Gastroenterol 2023; 42:388-395. [PMID: 37145232 DOI: 10.1007/s12664-023-01356-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 02/03/2023] [Indexed: 05/06/2023]
Abstract
BACKGROUND Terlipressin and noradrenaline are effective in the management of hepatorenal syndrome (HRS). There are no reports on the combination of these vasoconstrictors in type-1 HRS. AIM To evaluate terlipressin with or without noradrenaline in type-1 HRS not responding to terlipressin at 48 hours. METHODS Sixty patients were randomized to receive either terlipressin (group A; n = 30) or a combination of terlipressin and noradrenaline infusion (group B; n = 30). In group A, terlipressin infusion was started at 2 mg/day and increased by 1 mg/day (maximum 12 mg/day). In group B, terlipressin was given at a constant dose of 2 mg/day. Noradrenaline infusion was started at 0.5 mg/h at baseline and increased to 3 mg/h in a stepwise manner. The primary outcome was treatment response at 15 days. Secondary outcomes were 30-day survival, cost-benefit analysis and adverse events. RESULTS There was no significant difference in the response rate between the groups (50% vs. 76.7%, p = 0.06) and 30-day survival was similar (36.7% vs. 53.3%, p = 0.13). Treatment was more expensive in group A (USD 750 vs. 350, p < 0.001). Adverse events were more frequent in group A (36.7% vs. 13.3%, p < 0.05). CONCLUSIONS The combination of noradrenaline and terlipressin infusion results in a non-significantly higher rate of HRS resolution with significantly fewer adverse effects in HRS patients who do not respond to terlipressin within 48 hours. TRIAL REGISTRATION CLINICALTRIALS gov (NCT03822091).
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Affiliation(s)
- Virendra Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India.
| | - Akshaya Jayachandran
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Akash Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Shivani Chandel
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Navneet Sharma
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
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Ibáñez-Samaniego L, Baines A, Bañares R. Afectación renal en la enfermedad hepática crónica avanzada. Síndrome hepatorrenal. MEDICINE - PROGRAMA DE FORMACIÓN MÉDICA CONTINUADA ACREDITADO 2023; 13:4841-4849. [DOI: 10.1016/j.med.2023.06.010] [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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Abstract
Importance Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people. Observations The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men. Conclusions and Relevance Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.
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Affiliation(s)
- Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor
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Claudel SE, Jaganathan J, Patel A, Tapper EB, Verma A. Review article: Practical considerations for fluid resuscitation in cirrhosis. Aliment Pharmacol Ther 2023; 57:1066-1082. [PMID: 36998204 PMCID: PMC11839201 DOI: 10.1111/apt.17458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/25/2022] [Accepted: 02/26/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND Standard clinical methods of assessing volume and providing resuscitation are not always applicable to patients with advanced or decompensated cirrhosis. Despite this being well known from a clinical perspective, there remains relatively little evidence to guide clinicians though fluid management in patients with cirrhosis and, often, multi-organ system dysfunction. AIMS This review summarises the current understanding of the circulatory dysfunction in cirrhosis, modalities for assessing volume status, and considerations for fluid selection. It additionally provides a practical approach to fluid resuscitation. METHODS We review current literature on cirrhosis pathophysiology in steady-state and shock, clinical implications of fluid resuscitation, and strategies to assess intravascular volume. Literature reviewed here was identified by the authors through PubMed search and review of selected papers' references. RESULTS Clinical management of resuscitation in advanced cirrhosis remains relatively stagnant. Although several trials have attempted to establish the superior resuscitative fluid, the lack of improvement in hard clinical outcomes leaves clinicians without clear guidance. CONCLUSIONS The absence of consistent evidence for fluid resuscitation in patients with cirrhosis limits our ability to produce a clearly evidence-based protocol for fluid resuscitation in cirrhosis. However, we propose a preliminary practical guide to managing fluid resuscitation in patients with decompensated cirrhosis. Further studies are needed to develop and validate volume assessment tools in the specific context of cirrhosis, while randomised clinical trials of protocolized resuscitation may improve care of this patient population.
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Affiliation(s)
- Sophie E. Claudel
- Department of Internal Medicine, Boston Medical Center, Boston, Massachusetts, USA
| | - Jeeva Jaganathan
- Digestive Sciences and Nutrition, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Ankit Patel
- Department of Medicine, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Elliot B. Tapper
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ashish Verma
- Department of Internal Medicine, Section on Nephrology, Boston Medical Center, Boston, Massachusetts, USA
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Abstract
Ascites is the most common complication of cirrhosis, with 5-year mortality reaching 30%. Complications of ascites (ie, spontaneous bacterial peritonitis, hepatorenal syndrome, recurrent/refractory ascites, and hepatic hydrothorax) further worsen survival. The development of ascites is driven by portal hypertension, systemic inflammation, and splanchnic arterial vasodilation. Etiologic treatment and nonselective beta-blockers can prevent ascites in compensated cirrhosis. The treatment of ascites is currently based on the management of fluid overload (eg, diuretics, sodium restriction, and/or paracenteses). In selected patients, long-term albumin use, norfloxacin prophylaxis, and transjugular intrahepatic portosystemic shunt reduce the risk of further decompensation and improve survival.
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Matchett CL, Simonetto DA, Kamath PS. Renal Insufficiency in Patients with Cirrhosis. Clin Liver Dis 2023; 27:57-70. [PMID: 36400467 DOI: 10.1016/j.cld.2022.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Renal failure is one of the most prevalent complications in patients with cirrhosis and is of the utmost prognostic relevance. Acute kidney injury (AKI) in cirrhosis results from a spectrum of etiologies, of which hepatorenal syndrome (HRS) carries the worst prognosis. Correct differentiation of the etiology of AKI in cirrhosis is imperative, as treatment defers substantially. This review summarizes the current diagnostic criteria, pathophysiology, diagnosis, and therapeutic concepts for AKI and HRS-AKI in cirrhosis.
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Affiliation(s)
- Caroline L Matchett
- Internal Medicine Residency Program, Department of Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, 55902 MN, USA
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, 55902 MN, USA
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 1st Street Southwest, Rochester, 55902 MN, USA.
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Singal AK, Palmer G, Melick L, Abdallah M, Kwo P. Vasoconstrictor Therapy for Acute Kidney Injury Hepatorenal Syndrome: A Meta-Analysis of Randomized Studies. GASTRO HEP ADVANCES 2023; 2:455-464. [PMID: 39132033 PMCID: PMC11308464 DOI: 10.1016/j.gastha.2023.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 01/11/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Type 1 hepatorenal syndrome (HRS) is a rapid deterioration in kidney function in patients with cirrhosis. Data on efficacy of vasoconstrictors for type 1 HRS have shown mixed results. Methods Literature searched for randomized controlled trials comparing pharmacological therapy for HRS vs placebo or another drug for HRS. Primary outcome was HRS reversal (serum creatinine <1.5mg/dL on 2 readings), and secondary outcomes were liver transplant (LT) free survival and serious adverse events (SAE). Results Sixteen studies on 1244 patients (mean age 50.3 yrs., 67.5% males, serum creatinine of 3.07 mg/dL, serum sodium 127.2 mEq/liter, and Model for End-stage Liver Disease (MELD) score of 30.9, and Child-Pugh score 11) with type 1 HRS treated with vasoconstrictors vs placebo or another drug were analyzed. All the patients received intravenous albumin infusion. (A) terlipressin vs placebo: Odds of HRS reversal were 3.3 folds with terlipressin without difference on LT-free patient survival. Terlipressin was associated with higher odds of SAE. (B) Nor-epinephrine (NE) vs terlipressin: No difference on HRS reversal, LT-free survival, and SAE. (C) Terlipressin or NE vs midodrine and octreotide: 91% lower odds of HRS reversal with midodrine and octreotide. There were no differences on SAE (10 of 64 vs 10 of 58, P = .812). Non-responders vs responders had higher mean MELD score (29 vs 27.8), P = .014 and serum creatinine (3.5 vs 3.1), P = .027. Conclusion Terlipressin and NE are similar and superior to midodrine octreotide combination for HRS reversal. No therapy improves LT-free patient survival. Response to treatment is better with lower baseline serum creatinine and MELD score. The risk of adverse effects is similar with terlipressin and NE. Studies are needed as basis to identify candidates with best response to treatment with excellent safety profile.
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Affiliation(s)
- Ashwani K. Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
- Transplant Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota
| | - Geralyn Palmer
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
| | - Lauren Melick
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
| | - Mohamed Abdallah
- Division of Gastroenterology, University of Minnesota, Minneapolis, Minnesota
| | - Paul Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
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Carter JA, Huang X, Jamil K, Corman S, Ektare V, Niewoehner J. Cost-effectiveness of terlipressin for hepatorenal syndrome: the United States hospital perspective. J Med Econ 2023; 26:1342-1348. [PMID: 37729445 DOI: 10.1080/13696998.2023.2260693] [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: 05/05/2023] [Accepted: 09/15/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Hepatorenal syndrome (HRS) is characterized by severely reduced renal perfusion that precipitates rapid morbidity and mortality. Terlipressin is the only US Food and Drug Administration-approved treatment to improve kidney function for adults with HRS with a rapid reduction in kidney function. Prior to the approval of terlipressin, unapproved vasoconstrictive agents used in HRS treatment were octreotide/midodrine and norepinephrine with albumin. METHODS A cohort decision-tree model representing a US hospital perspective assessed the clinical outcomes and direct medical costs (based primarily on hospital charges) of treating HRS with terlipressin + albumin (ALB) versus midodrine/octreotide (MID/OCT)+ALB, or norepinephrine (NorEp)+ALB. Treatment efficacy was defined by clinical response (complete/HRS reversal, partial, or no response) based on change of serum creatinine derived from published clinical trial reports. The proportions of patients with complete response were: terlipressin + ALB (36.2%), NorEp + ALB (19.1%), and MID/OCT + ALB (3.1%). Model outcomes included utilization of HRS-related healthcare resources (hospital and intensive care, outpatient and emergency department, dialysis, and transplantations), adverse events, and HRS-related mortality. Outcomes were assessed for the initial hospitalization in the base case and at 30, 60, and 90 days post-discharge. RESULTS Total costs incurred over the initial hospitalization with terlipressin + ALB were lower vs NorEp + ALB, primarily due to higher ICU costs with NorEp + ALB ($7,433 vs $61,897). TER + ALB was associated with higher total costs vs MID/OCT + ALB due to higher pharmacy costs with terlipressin + ALB. The cost per complete response achieved of terlipressin + ALB ($451,605) was half that of NorEp + ALB ($930,571) and one-tenth that of MID/OCT + ALB ($4,942,123). CONCLUSIONS HRS patients treated with terlipressin experienced better clinical outcomes and a lower cost per treatment response vs other unapproved treatments. ICU days and pharmacy costs were key cost drivers distinguishing the treatment groups. These outcomes suggest that terlipressin is cost-effective on the basis of total cost per response achieved.
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Flamm SL, Wong F, Ahn J, Kamath PS. AGA Clinical Practice Update on the Evaluation and Management of Acute Kidney Injury in Patients With Cirrhosis: Expert Review. Clin Gastroenterol Hepatol 2022; 20:2707-2716. [PMID: 36075500 DOI: 10.1016/j.cgh.2022.08.033] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 02/07/2023]
Abstract
DESCRIPTION The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available published evidence and expert advice regarding the clinical management of patients with suspected acute kidney injury in patients with cirrhosis. METHODS This article provides practical advice for the management of patients with cirrhosis and acute kidney injury based on the best available published evidence. This best practice document is not based on a formal systematic review. This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through the standard procedures of Clinical Gastroenterology & Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: Acute kidney injury (AKI) should be diagnosed when the serum creatinine increases by ≥0.3 mg/dL within 48 hours or is ≥50% from baseline or when the urine output is reduced below 0.5 mL/kg/h for >6 hours. BEST PRACTICE ADVICE 2: Preventive measures against the development of AKI in cirrhosis include (1) avoidance of potentially nephrotoxic medications like nonsteroidal anti-inflammatory drugs (NSAIDs), (2) avoidance of excessive or unmonitored diuretics or nonselective beta-blockade, (3) avoidance of large-volume paracentesis without albumin replacement, and (4) counseling patients to avoid alcohol use. BEST PRACTICE ADVICE 3: (A) Investigation is directed to determining the cause of AKI, which can be due to hypovolemic causes (volume responsive, and the most common cause of AKI in patients with cirrhosis); acute tubular necrosis; hepatorenal syndrome with AKI (HRS-AKI) (a functional renal failure that persists despite volume repletion); HRS with acute kidney disease, a type of functional renal failure of <3 months- duration in which criteria for HRS-AKI are not met; or postrenal, which occurs only rarely. (B) The specific type of AKI should be identified through a careful history, physical examination, blood biochemistry, urine microscopic examination, urine chemistry (Na+ and urea) and selected urinary biomarkers, and renal ultrasound. BEST PRACTICE ADVICE 4: A rigorous search for infection is required in all patients with AKI. A diagnostic paracentesis should be carried out to evaluate for spontaneous bacterial peritonitis; blood and urine cultures and chest radiograph are also required. There is no role for routine prophylactic antibiotics in patients with AKI, but broad-spectrum antibiotics should be started whenever infection is strongly suspected. BEST PRACTICE ADVICE 5: When AKI is diagnosed, diuretics and nonselective beta-blockers should be held, NSAIDs discontinued, the precipitating cause of AKI treated, and fluid losses replaced, administering albumin 1 g/kg/d for 2 days if the serum creatinine shows doubling from baseline. Urine output, vital signs, and when indicated, echocardiography or CVP (if there is a pre-existing central line) should be used to monitor fluid status. BEST PRACTICE ADVICE 6: When the serum creatinine remains higher than twice the baseline value despite these measures, treatment of HRS-AKI should be initiated with albumin at a dose of 1 g/kg intravenously on day 1 followed by 20-40 g daily along with vasoactive agents (terlipressin; if terlipressin is not available, either a combination of octreotide and midodrine; or norepinephrine, depending on institutional preferences) and continued either until 24 hours following the return of the serum creatinine level to within ≤0.3 mg/dL of baseline for 2 consecutive days or for a total of 14 days of therapy. BEST PRACTICE ADVICE 7: Terlipressin should be initiated as a bolus dose of 1 mg every 4-6 hours (total 4-6 mg/d). The dose should be increased to a maximum of 2 mg every 4-6 hours (total 8-12 mg/d) if there is no reduction in serum creatinine at day 3 of therapy by at least 25% compared to the baseline value. Alternatively, clinicians can administer terlipressin by continuous intravenous infusion at a lower starting dose of 2 mg/d, which may reduce ischemic side effects and increase the dose gradually every 24-48 hours up to a maximum dose of 12 mg/d, or reversal of HRS. As per Food and Drug Administration restrictions, terlipressin should not be used in patients with a serum creatinine ≥5 mg/dL, or oxygen saturation of <90%. BEST PRACTICE ADVICE 8: Oral midodrine when used should be initiated at doses of 7.5 mg and titrated upward to 12.5 mg 3 times daily with octreotide (starting with 100 μg and titrating upward to 200 μg subcutaneously 3 times daily). BEST PRACTICE ADVICE 9: Norepinephrine should be used as a continuous intravenous infusion at a starting dose of 0.5 mg/h and the dose increased every 4 hours by 0.5 mg/h to a maximum of 3 mg/h with the goal of increasing the mean arterial pressure by ≥10 mm Hg and/or the urine output to >50 mL/h for at least 4 hours. BEST PRACTICE ADVICE 10: The risks of ischemic side effects of terlipressin and norepinephrine include angina and ischemia of fingers, skin, and intestine. These side effects may be lowered by starting at the lowest dose and gradually titrating upward. BEST PRACTICE ADVICE 11: Fluid status should be closely monitored because of the risk of pulmonary edema with excessive use of albumin. BEST PRACTICE ADVICE 12: Renal replacement therapy (RRT) may be used in the management of (A) AKI secondary to acute tubular necrosis; (B) HRS-AKI in potential candidates for liver transplantation (that is, RRT should not be used in patients with HRS-AKI who are not candidates for liver transplantation); and (C) AKI of uncertain etiology in which the need for RRT may be considered on an individual basis. BEST PRACTICE ADVICE 13: Transjugular intrahepatic portosystemic shunts should not be used as a specific treatment of HRS-AKI. BEST PRACTICE ADVICE 14: Liver transplantation is the most effective treatment for HRS-AKI. Pharmacotherapy for HRS-AKI before proceeding with liver transplantation may be associated with better post-liver transplantation outcomes. Selected patients with HRS-AKI may require simultaneous liver kidney transplantation based on updated Organ Procurement and Transplantation Network listing criteria.
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Affiliation(s)
- Steven L Flamm
- Division of Gastroenterology and Hepatology, Rush University Medical College, Chicago, Illinois
| | - Florence Wong
- Division of Gastroenterology and Hepatology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
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The Comparative Effectiveness of Vasoactive Treatments for Hepatorenal Syndrome: A Systematic Review and Network Meta-Analysis. Crit Care Med 2022; 50:1419-1429. [PMID: 35777925 DOI: 10.1097/ccm.0000000000005595] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Hepatorenal syndrome (HRS) is associated with high rates of morbidity and mortality. Evidence examining commonly used drug treatments remains uncertain. We assessed the comparative effectiveness of inpatient treatments for HRS by performing a network meta-analysis of randomized clinical trials (RCTs). DATA SOURCES We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process & Other Non-Indexed Citations, Scopus, and Web of Science from inception. STUDY SELECTION AND DATA EXTRACTION Pairs of reviewers independently identified eligible RCTs that enrolled patients with type 1 or 2 HRS. Pairs of reviewers independently extracted data. DATA SYNTHESIS We assessed risk of bias using the Cochrane tool for RCTs and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. Our main outcomes are all-cause mortality, HRS reversal, and serious adverse events. Of 3,079 citations, we included 26 RCTs examining 1,736 patients. Based on pooled analysis, terlipressin increases HRS reversal compared with placebo (142 reversals per 1,000 [95% CI, >87.7 to >210.9]; high certainty). Norepinephrine (112.7 reversals per 1,000 [95% CI, 52.6 to >192.3]) may increase HRS reversal compared with placebo (low certainty). The effect of midodrine+octreotide (67.8 reversals per 1,000 [95% CI, <2.8 to >177.4]; very low) on HRS reversal is uncertain. Terlipressin may reduce mortality compared with placebo (93.7 fewer deaths [95% CI, 168.7 to <12.5]; low certainty). Terlipressin probably increases the risk of serious adverse events compared with placebo (20.4 more events per 1,000 [95% CI, <5.1 to >51]; moderate certainty). CONCLUSIONS Terlipressin increases HRS reversal compared with placebo. Terlipressin may reduce mortality. Until access to terlipressin improves, initial norepinephrine administration may be more appropriate than initial trial with midodrine+octreotide. Our review has the potential to inform future guideline and practice in the treatment of HRS.
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Bera C, Wong F. Management of hepatorenal syndrome in liver cirrhosis: a recent update. Therap Adv Gastroenterol 2022; 15:17562848221102679. [PMID: 35721838 PMCID: PMC9201357 DOI: 10.1177/17562848221102679] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 05/07/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatorenal syndrome (HRS) is a serious form of renal dysfunction in patients with cirrhosis and ascites. It is an important component of the acute-on-chronic liver failure (ACLF) syndrome. Significant recent changes in the understanding of the pathophysiology of renal dysfunction in cirrhosis include the role of inflammation in addition to hemodynamic changes. The term acute kidney injury (AKI) is now adopted to include all functional and structural forms of acute renal dysfunction in cirrhosis, with various stages describing the severity of the condition. Type 1 hepatorenal syndrome (HRS1) is renamed HRS-AKI, which is stage 2 AKI [doubling of baseline serum creatinine (sCr)] while fulfilling all other criteria of HRS1. Albumin is used for its volume expanding and anti-inflammatory properties to confirm the diagnosis of HRS-AKI. Vasoconstrictors are added to albumin as pharmacotherapy to improve the hemodynamics. Terlipressin, although not yet available in North America, is the most common vasoconstrictor used worldwide. Patients with high grade of ACLF treated with terlipressin are at risk for respiratory failure if there is pretreatment respiratory compromise. Norepinephrine is equally effective as terlipressin in reversing HRS1. Recent data show that norepinephrine may be administered outside the intensive care setting, but close monitoring is still required. There has been no improvement in overall or transplant-free survival shown with vasoconstrictor use, but response to vasoconstrictors with reduction in sCr is associated with improvement in survival. Non-responders to vasoconstrictor plus albumin will need liver transplantation as definite treatment with renal replacement therapy as a bridge therapy. Combined liver and kidney transplantation is recommended for patients with prolonged history of AKI, underlying chronic kidney disease or with hereditary renal conditions. Future developments, such as the use of biomarkers and metabolomics, may help to identify at risk patients with earlier diagnosis to allow for earlier treatment with improved outcomes.
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Affiliation(s)
- Chinmay Bera
- Division of Gastroenterology and Hepatology,
Department of Medicine, Toronto General Hospital, University Health Network,
University of Toronto, Toronto, ON, Canada
| | - Florence Wong
- Division of Gastroenterology and Hepatology,
Department of Medicine, Toronto General Hospital, University Health Network,
University of Toronto, 9EN/222 Toronto General Hospital, 200 Elizabeth
Street, 9EN222, Toronto, ON M5G2C4, Canada
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50
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Qi X, Bai Z, Zhu Q, Cheng G, Chen Y, Dang X, Ding H, Han J, Han L, He Y, Ji F, Jin H, Li B, Li H, Li Y, Li Z, Liu B, Liu F, Liu L, Lin S, Ma D, Meng F, Qi R, Ren T, Shao L, Tang S, Tang Y, Teng Y, Wang C, Wang R, Wu Y, Xu X, Yang L, Yuan J, Yuan S, Yang Y, Zhao Q, Zhang W, Yang Y, Guo X, Xie W. Practice guidance for the use of terlipressin for liver cirrhosis-related complications. Therap Adv Gastroenterol 2022; 15:17562848221098253. [PMID: 35601800 PMCID: PMC9121451 DOI: 10.1177/17562848221098253] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/12/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Liver cirrhosis is a major global health burden worldwide due to its high risk of morbidity and mortality. Role of terlipressin for the management of liver cirrhosis-related complications has been recognized during recent years. This article aims to develop evidence-based clinical practice guidance on the use of terlipressin for liver cirrhosis-related complications. METHODS Hepatobiliary Study Group of the Chinese Society of Gastroenterology of the Chinese Medical Association and Hepatology Committee of the Chinese Research Hospital Association have invited gastroenterologists, hepatologists, infectious disease specialists, surgeons, and clinical pharmacists to formulate the clinical practice guidance based on comprehensive literature review and experts' clinical experiences. RESULTS Overall, 10 major guidance statements regarding efficacy and safety of terlipressin in liver cirrhosis were proposed. Terlipressin can be beneficial for the management of cirrhotic patients with acute variceal bleeding and hepatorenal syndrome (HRS). However, the evidence regarding the use of terlipressin in cirrhotic patients with ascites, post-paracentesis circulatory dysfunction, and bacterial infections and in those undergoing hepatic resection and liver transplantation remains insufficient. Terlipressin-related adverse events, mainly including gastrointestinal symptoms, electrolyte disturbance, and cardiovascular and respiratory adverse events, should be closely monitored. CONCLUSION The current clinical practice guidance supports the use of terlipressin for gastroesophageal variceal bleeding and HRS in liver cirrhosis. High-quality studies are needed to further clarify its potential effects in other liver cirrhosis-related complications.
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Affiliation(s)
- Xingshun Qi
- Department of Gastroenterology, General
Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang 110015,
Liaoning, China
| | - Zhaohui Bai
- Department of Gastroenterology, General
Hospital of Northern Theater Command, Shenyang, China
- Department of Life Sciences and
Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Qiang Zhu
- Department of Gastroenterology, Shandong
Provincial Hospital Affiliated to Shandong First Medical University, Jinan,
China
| | - Gang Cheng
- Department of Life Sciences and
Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Yu Chen
- Difficult and Complicated Liver Diseases and
Artificial Liver Center, Beijing You’an Hospital, Capital Medical
University, Beijing, China
| | - Xiaowei Dang
- Department of Hepatobiliary and Pancreatic
Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou,
China
| | - Huiguo Ding
- Department of Gastrointestinal and Hepatology,
Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Juqiang Han
- Institute of Liver Disease, The 7th Medical
Centre of Chinese People Liberation Army General Hospital, Beijing,
China
| | - Lei Han
- Department of Hepatobiliary Surgery, General
Hospital of Northern Theater Command, Shenyang, China
| | - Yingli He
- Department of Infectious Diseases, First
Affiliated Teaching Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Fanpu Ji
- Department of Infectious Diseases, The Second
Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Hongxu Jin
- Department of Emergency Medicine, General
Hospital of Northern Theater Command, Shenyang, China
| | - Bimin Li
- Department of Gastroenterology, The First
Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongyu Li
- Department of Gastroenterology, General
Hospital of Northern Theater Command, Shenyang, China
| | - Yiling Li
- Department of Gastroenterology, First
Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhiwei Li
- Department of Hepato-Biliary Surgery, Shenzhen
Third People’s Hospital, Shenzhen, China
| | - Bang Liu
- Department of Hepatobiliary Disease, 900
Hospital of the Joint Logistics Team, Fuzhou, China
| | - Fuquan Liu
- Department of Interventional Radiology,
Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lei Liu
- Department of Gastroenterology, Tangdu
Hospital of the Fourth Military Medical University, Xi’an, China
| | - Su Lin
- Liver Research Center, The First Affiliated
Hospital of Fujian Medical University, Fuzhou, China
| | - Dapeng Ma
- Department of Critical Care Medicine, The
Sixth People’s Hospital of Dalian, Dalian, China
| | - Fanping Meng
- Department of Infectious Diseases, The Fifth
Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ruizhao Qi
- Department of General Surgery, The Fifth
Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tianshu Ren
- Department of Pharmacy, General Hospital of
Northern Theater Command, Shenyang, China
| | - Lichun Shao
- Department of Gastroenterology, Air Force
Hospital of Northern Theater Command, Shenyang, China
| | - Shanhong Tang
- Department of Gastroenterology, General
Hospital of Western Theater Command, Chengdu, China
| | - Yufu Tang
- Department of Hepatobiliary Surgery, General
Hospital of Northern Theater Command, Shenyang, China
| | - Yue Teng
- Department of Emergency Medicine, General
Hospital of Northern Theater Command, Shenyang, China
| | - Chunhui Wang
- Department of Hepatobiliary Surgery, General
Hospital of Northern Theater Command, Shenyang, China
| | - Ran Wang
- Department of Gastroenterology, General
Hospital of Northern Theater Command, Shenyang, China
| | - Yunhai Wu
- Department of Critical Care Medicine, Sixth
People’s Hospital of Shenyang, Shenyang, China
| | - Xiangbo Xu
- Department of Gastroenterology, General
Hospital of Northern Theater Command, Shenyang, China
- Department of Life Sciences and
Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Ling Yang
- Department of Gastroenterology, Union
Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, China
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh
Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Shanshan Yuan
- Department of Gastroenterology, Xi’an Central
Hospital, Xi’an, China
| | - Yida Yang
- Collaborative Innovation Center for Diagnosis
and Treatment of Infectious Diseases, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou, China
| | - Qingchun Zhao
- Department of Pharmacy, General Hospital of
Northern Theater Command, Shenyang, China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, General
Hospital of Northern Theater Command, Shenyang, China
| | - Yongping Yang
- Department of Liver Disease, The Fifth Medical
Center of Chinese PLA General Hospital, 100 West Fourth Ring Middle Road,
Beijing 100039, China
| | - Xiaozhong Guo
- Department of Gastroenterology, General
Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang 110015,
Liaoning, China
| | - Weifen Xie
- Department of Gastroenterology, Changzheng
Hospital, Naval Medical University, Shanghai 200003, China
| |
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