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Cullaro G, Allegretti AS, Patidar KR, Jamil K, Velez JCQ. The relationship between mean arterial pressure and terlipressin in hepatorenal syndrome-acute kidney injury reversal: A post hoc analysis. Hepatology 2025:01515467-990000000-01190. [PMID: 40053863 DOI: 10.1097/hep.0000000000001295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 02/12/2025] [Indexed: 03/09/2025]
Abstract
BACKGROUND AND AIMS Terlipressin reverses hepatorenal syndrome-acute kidney injury (HRS-AKI) by increasing mean arterial pressure (MAP). To further characterize the relationship between terlipressin and MAP and their impact on HRS-AKI reversal, we used patient-level data from phase 3 clinical trials REVERSE and CONFIRM. APPROACH AND RESULTS In this post hoc analysis we employed a linear mixed-effects model to assess terlipressin's impact on MAP, exploring the relationship between MAP, treatment group, and time, incorporating a random intercept for individual patients. Time-dependent Cox models analyzed MAP's role in HRS-AKI reversal. We conducted a mediation analysis to evaluate how time-weighted MAP mediated HRS-AKI reversal. This analysis included 487 patients (60% terlipressin, 40% placebo). At baseline, there were no differences in median MAP between terlipressin and placebo (77 mm Hg vs. 76 mm Hg, p =0.3); the terlipressin group had significantly higher MAPs after randomization (day 1: 85 mm Hg vs. 75 mm Hg; day 3: 81 mm Hg vs. 76 mm Hg; all: p <0.001). In mixed-effects models, terlipressin was associated with a 6.0 mm Hg increase in MAP over placebo occurring on day 1, with no significant interaction between the treatment group and time ( p >0.05). In time-dependent Cox models, each 5 mm Hg increase in MAP was associated with 1.17× the hazard of HRS-AKI reversal (95% CI: 1.11-1.22). In mediation analysis, MAP significantly mediated HRS-AKI reversal, regardless of treatment group (average proportion mediated: 33%, 95% CI: 14-76). CONCLUSIONS These data highlight that terlipressin leads to an early, sustained increase in MAP, which is a key pharmacodynamic target for HRS-AKI reversal.
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Affiliation(s)
- Giuseppe Cullaro
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Andrew S Allegretti
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kavish R Patidar
- Department of Medicine, Section of Gastroenterology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Khurram Jamil
- Mallinckrodt Pharmaceuticals, Bridgewater, New Jersey, USA
| | - Juan Carlos Q Velez
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana, USA
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
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2
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Fadlallah H, El Masri D, Bahmad HF, Abou-Kheir W, El Masri J. Update on the Complications and Management of Liver Cirrhosis. Med Sci (Basel) 2025; 13:13. [PMID: 39982238 PMCID: PMC11843904 DOI: 10.3390/medsci13010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/01/2025] [Accepted: 02/02/2025] [Indexed: 02/22/2025] Open
Abstract
Liver cirrhosis represents the advanced pathological stage of chronic liver disease, characterized by the progressive destruction and regeneration of the hepatic parenchyma over years, culminating in fibrosis and disruption of the vascular architecture. As a leading global cause of morbidity and mortality, it continues to affect millions worldwide, imposing a substantial burden on healthcare systems. Alcoholic/nonalcoholic fatty liver disease and chronic viral hepatitis infection, hepatitis C (HCV) in particular, remain leading causes of cirrhosis. Despite significant advances in understanding the pathogenesis of cirrhosis, its management is still complex due to the multifaceted complications, including ascites, hepatic encephalopathy, variceal bleeding, and hepatocellular carcinoma, all of which severely compromise the patient outcomes and quality of life. This review aims at filling a critical gap by providing a comprehensive summary of the latest evidence on the complications and management of liver cirrhosis. Evidence-based therapies targeting both the etiologies and complications of cirrhosis are essential for improving outcomes. While liver transplantation is considered a definitive cure, advancements in pharmacological therapies offer promising avenues for halting and potentially reversing disease progression. This review summarizes the latest management strategies for cirrhosis and its associated complications, emphasizing the importance of early intervention and novel therapeutic options for improving outcomes and quality of life in affected individuals.
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Affiliation(s)
- Hiba Fadlallah
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (H.F.); (J.E.M.)
| | - Diala El Masri
- Faculty of Medicine, University of Balamand, Al-Kurah, Tripoli P.O. Box 100, Lebanon;
| | - Hisham F. Bahmad
- Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA;
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (H.F.); (J.E.M.)
| | - Jad El Masri
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (H.F.); (J.E.M.)
- Faculty of Medical Sciences, Lebanese University, Beirut 1107-2020, Lebanon
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3
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Velez JCQ, Wickman TJ, Tayebi K, Mohamed MM, Yousuf A, Kanduri SR, Lukitsch I, Vonderhaar D, Kovvuru K, Wentowski C. Addition of a Loop Diuretic to Norepinephrine During Treatment of Hepatorenal Syndrome Type 1. Kidney Int Rep 2025; 10:466-474. [PMID: 39990915 PMCID: PMC11843126 DOI: 10.1016/j.ekir.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 10/21/2024] [Accepted: 11/12/2024] [Indexed: 02/25/2025] Open
Abstract
Introduction Diuretics are commonly discontinued in patients with cirrhosis with acute kidney injury (AKI) because they are presumed to trigger hepatorenal syndrome type 1 (HRS-1). We hypothesized that if HRS-1 is adequately treated with a vasoconstrictor (mean arterial pressure [MAP] effectively increased), diuretics are safe and effective. Methods Records of hospitalized patients with cirrhosis who received i.v. furosemide while receiving i.v. norepinephrine as a vasoconstrictor to treat HRS-1 were examined. We assessed change in urine output (UOP), trajectory of serum creatinine (sCr), and impact of portopulmonary hypertension (PoPHTN) on the therapeutic response. Results Twenty-six patients with HRS-1 received i.v. furosemide (median: 2 days, 160 mg boluses every 6-24 hours) added to i.v. norepinephrine. Median age was 51 years; 91% were of White race, 36% were women, and median model for end-stage liver disease score was 32. The median initial sCr was 4.0 mg/dl. Before treatment, median UOP was 358 ml/d. Norepinephrine alone led to a median increase in UOP to 850 ml/d. Addition of furosemide to norepinephrine induced a subsequent increase in median UOP to 2072 ml/d (P < 0.0001), which was not observed in a control group (n = 22) who did not receive furosemide. Nineteen patients (73%) treated with norepinephrine plus furosemide (median MAP increase, 16 mm Hg) either maintained or improved their sCr trajectory. The magnitude of norepinephrine-induced increase in MAP correlated with the norepinephrine plus furosemide-induced UOP (r = 0.67, P = 0.0002), and the correlation coefficient was numerically stronger among those with PoPHTN. Conclusion In patients with HRS-1 who are adequately treated with norepinephrine and achieved an optimal MAP increment, addition of i.v. furosemide enhances diuresis without negatively affecting renal recovery.
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Affiliation(s)
- Juan Carlos Q. Velez
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana, USA
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | | | - Kasra Tayebi
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | - Muner M.B. Mohamed
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana, USA
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | - Adil Yousuf
- Department of Cardiology, Ochsner Health, New Orleans, Louisiana, USA
| | - Swetha R. Kanduri
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana, USA
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | - Ivo Lukitsch
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana, USA
| | - Derek Vonderhaar
- Department of Pulmonary and Critical Care Medicine, Ochsner Health, New Orleans, Louisiana, USA
| | - Karthik Kovvuru
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana, USA
| | - Cathy Wentowski
- Department of Pulmonary and Critical Care Medicine, Ochsner Health, New Orleans, Louisiana, USA
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Cullaro G, Allegretti AS, Fenton C, Ge J, Patidar KR, Rubin J, Sharma A, Lai JC. The association between mean arterial pressure and acute kidney injury reversal among patients with decompensated cirrhosis. Hepatology 2025; 81:126-135. [PMID: 38537129 PMCID: PMC11427603 DOI: 10.1097/hep.0000000000000858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 03/06/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND AND AIMS This study informs how mean arterial pressure (MAP) impacts acute kidney injury (AKI) recovery among all patients hospitalized with cirrhosis, regardless of etiology. APPROACH AND RESULTS We identified incident AKI episodes among subjects in our cohort of patients with decompensated cirrhosis. AKI was defined as a ≥50% increase in creatinine from an outpatient baseline (≥7 days prior) that required hospitalization. Linear mixed effects models were completed to determine the impact between AKI recovery, MAP, and time. To determine the impact of MAP on AKI reversal, we completed time-dependent Cox regression models with time beginning at the time of peak creatinine and ending at death, discharge, or AKI reversal, among those hospitalized with AKI and those with persistent AKI (≥48 h) We identified 702 hospitalized patients with cirrhosis with AKI. We found those with AKI reversal had, on average, higher MAP (2.1 mm Hg, p <0.05) and a greater increase in MAP over time (0.1 mm Hg per hour, p <0.001). Among all 702 hospitalized patients with AKI and adjusted for confounders, each 5 mm Hg increase in MAP was associated with 1.07× the hazard of AKI reversal ( p <0.01). Similarly, among those with persistent AKI after adjusting for confounders, each 5 mm Hg increase in MAP was associated with a 1.19× greater likelihood of AKI reversal ( p <0.001). DISCUSSION Our data demonstrate that MAP significantly increases the likelihood of AKI recovery regardless of severity or injury or AKI phenotype. We believe these data highlight the importance of MAP as a clinical tool to promote kidney function recovery among patients with cirrhosis hospitalized with AKI.
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Affiliation(s)
- Giuseppe Cullaro
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Andrew S. Allegretti
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Cynthia Fenton
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Jin Ge
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Kavish R. Patidar
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston Texas, USA
| | - Jessica Rubin
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Arjun Sharma
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Jennifer C. Lai
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
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5
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Trebicka J, Garcia-Tsao G. Controversies regarding albumin therapy in cirrhosis. Hepatology 2025; 81:288-303. [PMID: 37540192 PMCID: PMC11643133 DOI: 10.1097/hep.0000000000000521] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/26/2023] [Indexed: 08/05/2023]
Abstract
Albumin is the most abundant protein in the human body and is synthetized exclusively by the liver. Therefore, serum albumin levels are reduced in acute and/or chronic liver disease. In cirrhosis, low levels of albumin predict the outcome. In advanced cirrhosis, the quality of albumin is decreased due to high oxidative stress and a proinflammatory state. Therefore, the administration of i.v. albumin would seem to be of pathophysiological relevance and benefit. Yet, the questions that remain are who, when, how much, and how often. While albumin infusion is recommended after large-volume paracentesis, at diagnosis of spontaneous bacterial peritonitis, in acute kidney injury, and in hepatorenal syndrome, the amount and schedule of albumin to be administered require refinement, particularly given complications related to volume overload that have become increasingly apparent. Other indications for albumin such as infections other than spontaneous bacterial peritonitis, hyponatremia, HE, prevention of poor outcomes in hospitalized, and in outpatients with cirrhosis are still debated. The results of studies in these settings are either negative, controversial, or inconclusive. This sheds some doubts regarding the use of albumin as a "one size fits all" strategy. The indication and patient selection are crucial and not always intuitive. The amount and frequency also seem to play a role in the success or failure of albumin. This review will critically discuss the evidence and underline areas where there are indications for albumin use and others where evidence is still insufficient and will have to await the development/results of randomized controlled trials.
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Affiliation(s)
- Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
- European Foundation for Study of Chronic Liver Failure, EASL-CLIF-Consortium, Barcelona, Spain
- Department of Gastroenterology and Hepatology, University of Southern Denmark, Odense, Denmark
| | - Guadalupe Garcia-Tsao
- Digestive Diseases Section, Department of Medicine, Yale University, New Haven, Connecticut, USA
- Digestive Diseases Section, Department of Medicine, VA-CT Healthcare System, West Haven, Connecticut, USA
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6
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Jan MY, Patidar KR, Ghabril MS, Kubal CA. Optimization of Kidney Health in Liver Transplant Candidates: Pretransplant Considerations and Modalities. Transplantation 2024; 108:1542-1550. [PMID: 38192019 PMCID: PMC11188627 DOI: 10.1097/tp.0000000000004851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 08/11/2023] [Accepted: 08/24/2023] [Indexed: 01/10/2024]
Abstract
Patients with decompensated end-stage liver disease (ESLD) are at increased risk for mortality, and only liver transplantation (LT) offers meaningful hope for survival. These patients are at risk for kidney dysfunction through the continuum of care for ESLD including LT. We discuss the role of accurate estimation and measurement of baseline glomerular filtration rate in assessment of kidney dysfunction among those with ESLD. Optimizing kidney function is a vital goal in the management of these patients before LT. In this review, we summarize salient aspects of assessing and optimizing kidney function in this patient population. Precipitating factors and different causes of acute kidney injury are discussed, including hepatorenal syndrome. We further review treatment options for acute kidney injury including volume management. The role of vasopressor therapy, renal replacement therapy, and transjugular intrahepatic portosystemic shunting are discussed.
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Affiliation(s)
- Muhammad Y. Jan
- Division of Transplant Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Kavish R. Patidar
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Marwan S. Ghabril
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Chandrashekhar A. Kubal
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
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7
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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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8
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Berger O, Choi W, Ko CH, Thompson MP, Avram MJ, Scott DJ, Hoare BL, Cridge R, Wheatley M, Bathgate RAD, Batlle D, Gianneschi NC. Long-Circulating Vasoactive 1,18-Octadecanedioic Acid-Terlipressin Conjugate. ACS Pharmacol Transl Sci 2024; 7:1252-1261. [PMID: 38751631 PMCID: PMC11092119 DOI: 10.1021/acsptsci.3c00305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 03/29/2024] [Accepted: 04/15/2024] [Indexed: 05/18/2024]
Abstract
Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease first reported over a century ago, but its management still poses an unmet challenge. A therapeutic agent found to stabilize the condition is a short cyclic peptide, vasopressin analogue, terlipressin (TP). While TP is commonly prescribed for HRS patients in most parts of the world, it was only recently approved for use in the United States. TP exhibits short circulation half-lives and adverse side effects associated with the dose required. Herein, we present a 1,18-octadecanedioic acid (ODDA) conjugate of the cyclic peptide (ODDA-TP), which enables noncovalent binding to serum albumin via native fatty acid binding modes. ODDA-TP is demonstrated to outperform TP alone in studies including in vitro cellular receptor activation, stability in plasma, pharmacokinetics, and performance in vivo in rats. Specifically, ODDA-TP had an elimination half-life 20 times that of TP alone while exhibiting a superior safety profile.
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Affiliation(s)
- Or Berger
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
| | - Wonmin Choi
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
| | - Caroline H. Ko
- NewCures,
Innovation and Ventures Office, Northwestern
University, Evanston, Illinois 60208, United States
| | - Matthew P. Thompson
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
| | - Michael J. Avram
- Feinberg
Medical School, Northwestern University, Chicago, Illinois 60611, United States
- Department
of Anesthesiology, Northwestern University, Chicago, Illinois 60611, United States
| | - Daniel J. Scott
- The
Florey,Parkville, Victoria 3010, Australia
- Department
of Biochemistry and Pharmacology, The University
of Melbourne, Parkville, Victoria 3010, Australia
| | | | | | - Mark Wheatley
- Centre
for Sport, Exercise and Life Sciences, Coventry
University, Coventry CV1 5FB, U.K.
- Centre
of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands B15 2TT, U.K.
| | - Ross A. D. Bathgate
- The
Florey,Parkville, Victoria 3010, Australia
- Department
of Biochemistry and Pharmacology, The University
of Melbourne, Parkville, Victoria 3010, Australia
| | - Daniel Batlle
- Feinberg
Medical School, Northwestern University, Chicago, Illinois 60611, United States
- Department
of Medicine Division of Nephrology and Hypertension, Chicago, Illinois 60611, United States
| | - Nathan C. Gianneschi
- Department
of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
- Department
of Materials Science and Engineering, Northwestern
University, Evanston, Illinois 60208, United States
- Department of Biomedical Engineering, Northwestern
University, Evanston, Illinois 60208, United States
- Department of Pharmacology, Northwestern
University, Chicago, Illinois 60611, United States
- International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States
- Simpson-Querrey Institute, Northwestern
University, Chicago, Illinois 60611, United States
- Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States
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9
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Tamargo C, Hanouneh M, Cervantes CE. Treatment of Acute Kidney Injury: A Review of Current Approaches and Emerging Innovations. J Clin Med 2024; 13:2455. [PMID: 38730983 PMCID: PMC11084889 DOI: 10.3390/jcm13092455] [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: 03/28/2024] [Revised: 04/12/2024] [Accepted: 04/18/2024] [Indexed: 05/13/2024] Open
Abstract
Acute kidney injury (AKI) is a complex and life-threatening condition with multifactorial etiologies, ranging from ischemic injury to nephrotoxic exposures. Management is founded on treating the underlying cause of AKI, but supportive care-via fluid management, vasopressor therapy, kidney replacement therapy (KRT), and more-is also crucial. Blood pressure targets are often higher in AKI, and these can be achieved with fluids and vasopressors, some of which may be more kidney-protective than others. Initiation of KRT is controversial, and studies have not consistently demonstrated any benefit to early start dialysis. There are no targeted pharmacotherapies for AKI itself, but some do exist for complications of AKI; additionally, medications become a key aspect of AKI management because changes in renal function and dialysis support can lead to issues with both toxicities and underdosing. This review will cover existing literature on these and other aspects of AKI treatment. Additionally, this review aims to identify gaps and challenges and to offer recommendations for future research and clinical practice.
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Affiliation(s)
- Christina Tamargo
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Mohamad Hanouneh
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Nephrology Center of Maryland, Baltimore, MD 21239, USA
| | - C. Elena Cervantes
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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10
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Belcher JM. Hepatorenal Syndrome Type 1: Diagnosis and Treatment. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:100-110. [PMID: 38649214 DOI: 10.1053/j.akdh.2023.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 04/16/2023] [Accepted: 05/08/2023] [Indexed: 04/25/2024]
Abstract
Hepatorenal syndrome (HRS) is a feared complication in patients with advanced cirrhosis and is associated with significant morbidity and mortality. While recognized as a distinct physiologic condition for well over one hundred years, a lack of objective diagnostic tests has made the diagnosis one of exclusion. Since 1979, multiple sets of diagnostic criteria have been proposed. Though varying in detail, the principal intent of these criteria is to identify patients with severe, functional acute kidney injury that is unresponsive to volume resuscitation and exclude those with structural injury. However, accurate differential diagnosis remains challenging. Recently, multiple urinary biomarkers of kidney injury, including neutrophil gelatinase-associated lipocalin, have been studied as a means of objectively phenotyping etiologies of acute kidney injury in patients with cirrhosis. Along with markers reflecting tubular functional integrity, including the fractional excretion of sodium, injury markers will likely be incorporated into future diagnostic criteria. Making an accurate diagnosis is critical, as therapeutic options exist for HRS but must be given in a timely manner and only to those patients likely to benefit. Terlipressin, an analog of vasopressin, is the first line of therapy for HRS in much of the world and has recently been approved for use in the United States. Significant questions remain regarding the optimal dosing strategy, metrics for titration, and the potential role of point-of-care ultrasound to help guide concurrent albumin administration.
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Affiliation(s)
- Justin M Belcher
- Yale University School of Medicine, Department of Internal Medicine, Section of Nephrology, New Haven, CT; Department of Internal Medicine, Section of Nephrology, VA Connecticut Healthcare, West Haven, CT.
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11
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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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12
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Badura K, Frąk W, Hajdys J, Majchrowicz G, Młynarska E, Rysz J, Franczyk B. Hepatorenal Syndrome-Novel Insights into Diagnostics and Treatment. Int J Mol Sci 2023; 24:17469. [PMID: 38139297 PMCID: PMC10744165 DOI: 10.3390/ijms242417469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/09/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS.
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Affiliation(s)
- Krzysztof Badura
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Weronika Frąk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Hajdys
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Gabriela Majchrowicz
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
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13
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Pyrsopoulos NT, Bernstein D, Kugelmas M, Owen EJ, Reddy KR, Reau N, Saab S, Wadei HM. Improving Outcomes in Hepatorenal Syndrome-Acute Kidney Injury With Early Diagnoses and Implementation of Approved Treatment Regimens. Gastroenterol Hepatol (N Y) 2023; 19:3-13. [PMID: 38444690 PMCID: PMC10910386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
Decompensated cirrhosis, defined by the overt manifestations of liver failure and portal hypertension (eg, ascites, hepatic encephalopathy, variceal bleeding), is the inflection point associated with increased morbidity and mortality in chronic liver disease. Acute kidney injury in the setting of cirrhosis (hepatorenal syndrome-acute kidney injury [HRS-AKI]) is a severe and often fatal complication. The goals of treatment of HRS-AKI are to reverse renal failure and prolong survival in these critically ill patients or perhaps to allow the transplant team to complete the pretransplant evaluation and bridge the patient to transplant. Historically, in the United States, standard-of-care treatments for HRS-AKI were chosen by default despite lack of data, off-label use, and suboptimal results. Terlipressin represents the first drug in the United States indicated for the treatment of HRS-AKI. This review provides an up-to-date overview of HRS-AKI, discusses terlipressin and how to incorporate this new treatment into patient care and streamline society guidelines on HRS diagnosis and treatment in a practical way for clinical use, and concludes with a sample order set that highlights the recommendations discussed throughout the supplement.
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Affiliation(s)
- Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Liver Transplantation, Rutgers New Jersey Medical School University Hospital, Newark, New Jersey
| | - David Bernstein
- NYU Grossman School of Medicine, Gastroenterology and Hepatology Ambulatory Network-Long Island, NYU Langone Health, New York, New York
| | | | - Emily J Owen
- Critical Care, Surgical Burn Trauma Intensive Care Unit, Department of Pharmacy, Barnes-Jewish Hospital, St. Louis, Missouri
| | - K Rajender Reddy
- Division of Gastroenterology, University of Pennsylvania Health Services, Philadelphia, Pennsylvania
| | - Nancy Reau
- Rush University Medical Center, Chicago, Illinois
| | - Sammy Saab
- Department of Internal Medicine and Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Hani M Wadei
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida
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14
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Wahid N, Duarte-Rojo A, Boike JR. Terlipressin for hepatorenal syndrome: The practical choice for clinicians. Clin Liver Dis (Hoboken) 2023; 22:162-165. [PMID: 38026120 PMCID: PMC10653601 DOI: 10.1097/cld.0000000000000086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/03/2023] [Indexed: 12/01/2023] Open
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15
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Loftus M, Brown RS, El-Farra NS, Owen EJ, Reau N, Wadei HM, Bernstein D. Improving the Management of Hepatorenal Syndrome-Acute Kidney Injury Using an Updated Guidance and a New Treatment Paradigm. Gastroenterol Hepatol (N Y) 2023; 19:527-536. [PMID: 37771795 PMCID: PMC10524408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
Cirrhosis, or advanced scarring of the liver, represents the end stage of chronic liver disease and is associated with high morbidity and mortality. Hepatorenal syndrome-acute kidney injury (HRS -AKI), a condition causing functional and progressive kidney failure, is a complication of cirrhosis that contributes to its high mortality rate. In the United States, the standard-of-care treatments for HRS -AKI have historically been suboptimal. Recently, terlipressin became the first drug approved for HRS -AKI in the United States, and the American Association for the Study of Liver Diseases updated its guidance document on HRS diagnosis and management. Clinical practice guidelines and guidance documents have a variable effect on physician behavior owing to a lack of awareness, familiarity, and education. The imple mentation of standardized order sets can improve guidance adherence and the quality of care delivered by encouraging data-driven treatment administration, especially for new therapies. This review seeks to facilitate improvements in the management of HRS -AKI by discussing early HRS -AKI interventions, which will streamline diagnosis and treatment in a practical way for clinical use, and how to incorporate new treatments into patient care to improve survival in this subset of patients. Finally, these recommendations are integrated into a sample order set developed by members of the Chronic Liver Disease Foundation and experts in the management of HRS-AKI.
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Affiliation(s)
- Michelle Loftus
- North Shore University Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
| | - Robert S. Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York
| | - Neveen S. El-Farra
- UCLA Health, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Emily J. Owen
- Critical Care, Surgical Burn Trauma Intensive Care Unit, Department of Pharmacy, Barnes–Jewish Hospital, St. Louis, Missouri
| | - Nancy Reau
- Rush University Medical Center, Chicago, Illinois
| | - Hani M. Wadei
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida
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16
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Bagger Y, Ravis WR, Harris G, Bukofzer S. OCE-205, A Novel, Selective Vasopressin Receptor Mixed Agonist-Antagonist: Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics from a Phase 1 Study in Healthy Volunteers. Clin Drug Investig 2023; 43:709-717. [PMID: 37606870 PMCID: PMC10514109 DOI: 10.1007/s40261-023-01299-y] [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] [Accepted: 08/06/2023] [Indexed: 08/23/2023]
Abstract
BACKGROUND OCE-205, a novel, selective vasopressin V1a receptor mixed agonist/antagonist with no V2 receptor activity, may treat the portal hypertension-related complications of end-stage liver disease with an improved therapeutic profile over currently utilized nonselective full-agonist vasopressin analogs. OBJECTIVES This Phase 1, double-blind, placebo-controlled, within-dose-group randomized trial investigated the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of OCE-205 in healthy adults. METHODS Subjects received a single intravenous dose of OCE-205 0.1, 0.3, 0.45, 0.6, or 0.9 mg, or placebo infused over 6 h. Safety and tolerability were assessed, and blood samples were obtained for pharmacokinetic analyses. Sixty-four subjects were randomized and treated. RESULTS Area under the concentration-time curve (AUC) and maximum plasma concentrations (Cmax) were approximately dose-proportional across doses from 0.1 to 0.9 mg. OCE-205 terminal half-life was ~ 1.5 h. Diastolic, and to a lesser extent systolic, blood pressure increased in all OCE-205 dose groups; pulse rate decreased. Overall changes in mean arterial pressure were similar to changes in diastolic blood pressure. Absolute changes in cardiac output, by echocardiogram, were somewhat dose-dependent, with mean reductions of 3-12% after the 0.9 mg dose, and individual reductions ≤ 20 to 25% across all doses. The most frequent adverse events were abdominal pain, abnormal gastrointestinal sounds, and diarrhea, with no reported cases of mesenteric ischemia. Adverse events were generally mild or moderate in severity. CONCLUSION OCE-205 was safe and well tolerated, with a pharmacodynamic profile achieving submaximal partial agonism consistent with mixed agonism-antagonism of the V1a receptor. OCE-205 shows promise as a treatment for some complications of end-stage liver disease.
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Affiliation(s)
- Yu Bagger
- Ferring Pharmaceuticals A/S, Copenhagen, Denmark
| | - William R Ravis
- Ocelot Bio, Inc., 601 Marshall Street, Redwood City, CA, 94063, USA
| | - Geoff Harris
- Ocelot Bio, Inc., 601 Marshall Street, Redwood City, CA, 94063, USA
| | - Stan Bukofzer
- Ocelot Bio, Inc., 601 Marshall Street, Redwood City, CA, 94063, USA.
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17
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Arnold J, Avila E, Idalsoaga F, Diaz LA, Ayala Valverde M, Ayares G, Arrese M, Roessler E, Huidobro JP, Hudson D, Khan MQ, Arab JP. Advances in the diagnosis and management of hepatorenal syndrome: insights into HRS-AKI and liver transplantation. EGASTROENTEROLOGY 2023; 1:e100009. [PMID: 39943997 PMCID: PMC11770447 DOI: 10.1136/egastro-2023-100009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 09/27/2023] [Indexed: 01/04/2025]
Abstract
In hepatorenal syndrome-acute kidney injury (HRS-AKI), accurate and early diagnosis is crucial. HRS is a severe condition seen in advanced cirrhosis, requiring prompt recognition and proper management to enhance patient outcomes. Diagnosis of HRS-AKI relies on serum creatinine elevations, similar to other AKI cases in cirrhosis. However, distinguishing HRS-AKI from other renal impairments in these patients can be challenging. Biomarkers and clinical criteria aid in diagnosis and guide treatment. The management of HRS-AKI initially involves improving the haemodynamic profile using albumin and vasoconstrictors like terlipressin, a synthetic vasopressin analogue. Despite some reports linking terlipressin to increased adverse events compared with norepinephrine, it remains the preferred choice in HRS-AKI and acute-on-chronic liver failure due to its faster, stronger response and improved survival. Additional therapies like midodrine (alpha-1 adrenergic agonist), octreotide (somatostatin analogue) and transjugular intrahepatic portosystemic shunt are proposed as adjuvant treatments for HRS-AKI, aiming to improve vasoconstriction and renal blood flow. However, these adjunctive therapies cannot replace the definitive treatment for HRS-AKI-liver transplantation (LT). In cases unresponsive to medical management, LT is the only option to restore liver function and improve renal outcomes. Current evidence favours combined liver and kidney transplantation (CLKT) in certain situations. This review aims to evaluate the present evidence and recommendations on AKI in patients with cirrhosis, the pathophysiology of HRS-AKI, different treatments and indications for LT and CLKT. Understanding the complexities of managing HRS-AKI is crucial for optimising patient care and achieving better outcomes in this challenging clinical setting.
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Affiliation(s)
- Jorge Arnold
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Eduardo Avila
- Departamento de Nefrología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco Idalsoaga
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis Antonio Diaz
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Gustavo Ayares
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Eric Roessler
- Departamento de Nefrología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Pablo Huidobro
- Departamento de Nefrología, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - David Hudson
- Department of Medicine, London Health Sciences Centre, London, Ontario, Canada
| | - Mohammad Qasim Khan
- Department of Medicine, London Health Sciences Centre, London, Ontario, Canada
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
- Department of Medicine, London Health Sciences Centre, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
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18
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Attieh RM, Wadei HM. Acute Kidney Injury in Liver Cirrhosis. Diagnostics (Basel) 2023; 13:2361. [PMID: 37510105 PMCID: PMC10377915 DOI: 10.3390/diagnostics13142361] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/01/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Acute kidney injury (AKI) is common in cirrhotic patients affecting almost 20% of these patients. While multiple etiologies can lead to AKI, pre-renal azotemia seems to be the most common cause of AKI. Irrespective of the cause, AKI is associated with worse survival with the poorest outcomes observed in those with hepatorenal syndrome (HRS) and acute tubular necrosis (ATN). In recent years, new definitions, and classifications of AKI in cirrhosis have emerged. More knowledge has also become available regarding the benefits and drawbacks of albumin and terlipressin use in these patients. Diagnostic tools such as urinary biomarkers and point-of-care ultrasound (POCUS) became available and they will be used in the near future to differentiate between different causes of AKI and direct management of AKI in these patients. In this update, we will review these new classifications, treatment recommendations, and diagnostic tools for AKI in cirrhotic patients.
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Affiliation(s)
- Rose Mary Attieh
- Department of Transplant, Division of Kidney and Pancreas Transplant, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Hani M Wadei
- Department of Transplant, Division of Kidney and Pancreas Transplant, Mayo Clinic, Jacksonville, FL 32224, USA
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19
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Bukofzer S, Harris G, Song S, Cable EE. OCE-205, a Selective V1a Partial Agonist, Reduces Portal Pressure in Rat Models of Portal Hypertension. J Exp Pharmacol 2023; 15:279-290. [PMID: 37469992 PMCID: PMC10352125 DOI: 10.2147/jep.s416673] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/04/2023] [Indexed: 07/21/2023] Open
Abstract
Purpose Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a receptor partial agonist, intended to have a wider therapeutic window than full vasopressin agonists. Methods We aimed to characterize the activity of OCE-205 treatment in two rat models of portal hypertension (PHT). For both models, OCE-205 was administered as a subcutaneous bolus injection. Thirty male Wistar rats were fed a methionine/choline-deficient (MCD) diet to model PHT. Animals received OCE-205 (10, 25, 100, or 500 µg/kg) or intra-arterial terlipressin (100 µg/kg). In a more severe model of PHT, 11 male Sprague Dawley rats had the common bile duct surgically ligated (BDL) and received OCE-205. Portal pressure (PP) and mean arterial pressure (MAP) were measured. Results For PP in the MCD model, MAP increased while PP decreased in rats treated with OCE-205 or terlipressin; the peak changes to MAP were 14.7 and 33.5 mmHg, respectively. Changes in MAP began to plateau after 10 min in the OCE-205 groups, whereas in the terlipressin group, MAP rapidly increased and peaked after 20 min. Across all treatment groups in the BDL model, a dose-related decrease from baseline in PP was observed following OCE-205, plateauing as the dose increased. In all treatment groups, PP change remained negative throughout the 30-min testing period. In both PHT rat models, a reduction in PP was coupled to an increase in MAP, with both plateauing in dose-response curves. Conclusion Data support OCE-205 as a promising candidate for further development. Institutional Protocol Number Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee on July 13, 2011, under protocol FRI-07-0002.
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Affiliation(s)
| | | | - Susan Song
- Ferring Research Institute Inc., San Diego, CA, USA
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20
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Patidar KR, Naved MA, Kabir S, Grama A, Allegretti AS, Cullaro G, Asrani SK, Worden A, Desai AP, Ghabril MS, Nephew LD, Orman ES. Longer time to recovery from acute kidney injury is associated with major adverse kidney events in patients with cirrhosis. Aliment Pharmacol Ther 2023; 57:1397-1406. [PMID: 36883210 PMCID: PMC10441172 DOI: 10.1111/apt.17457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/27/2022] [Accepted: 02/25/2023] [Indexed: 03/09/2023]
Abstract
BACKGROUND In patients with cirrhosis and acute kidney injury (AKI), longer time to AKI-recovery may increase the risk of subsequent major-adverse-kidney-events (MAKE). AIMS To examine the association between timing of AKI-recovery and risk of MAKE in patients with cirrhosis. METHODS Hospitalised patients with cirrhosis and AKI (n = 5937) in a nationwide database were assessed for time to AKI-recovery and followed for 180-days. Timing of AKI-recovery (return of serum creatinine <0.3 mg/dL of baseline) from AKI-onset was grouped by Acute-Disease-Quality-Initiative Renal Recovery consensus: 0-2, 3-7, and >7-days. Primary outcome was MAKE at 90-180-days. MAKE is an accepted clinical endpoint in AKI and defined as the composite outcome of ≥25% decline in estimated-glomerular-filtration-rate (eGFR) compared with baseline with the development of de-novo chronic-kidney-disease (CKD) stage ≥3 or CKD progression (≥50% reduction in eGFR compared with baseline) or new haemodialysis or death. Landmark competing-risk multivariable analysis was performed to determine the independent association between timing of AKI-recovery and risk of MAKE. RESULTS 4655 (75%) achieved AKI-recovery: 0-2 (60%), 3-7 (31%), and >7-days (9%). Cumulative-incidence of MAKE was 15%, 20%, and 29% for 0-2, 3-7, >7-days recovery groups, respectively. On adjusted multivariable competing-risk analysis, compared to 0-2-days, recovery at 3-7 and >7-days was independently associated with an increased risk for MAKE: sHR 1.45 (95% CI 1.01-2.09, p = 0.042), sHR 2.33 (95% CI 1.40-3.90, p = 0.001), respectively. CONCLUSION Longer time to recovery is associated with an increased risk of MAKE in patients with cirrhosis and AKI. Further research should examine interventions to shorten AKI-recovery time and its impact on subsequent outcomes.
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Affiliation(s)
- Kavish R. Patidar
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Mobasshir A. Naved
- Department of Computer Science, Purdue University, West Lafayette, Indiana, USA
| | - Shaowli Kabir
- College of Public Health, University of Kentucky, Lexington, Kentucky, USA
| | - Ananth Grama
- Department of Computer Science, Purdue University, West Lafayette, Indiana, USA
| | - Andrew S. Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Giuseppe Cullaro
- Division of Gastroenterology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | | | - Astin Worden
- Division of Internal Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Archita P. Desai
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Marwan S. Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Lauren D. Nephew
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Eric S. Orman
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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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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22
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Velez JCQ, Karakala N, Tayebi K, Wickman TJ, Mohamed MMB, Kovacic RA, Therapondos G, Kanduri SR, Allegretti AS, Belcher JM, Regner KR, Wentowski C. Responsiveness to Vasoconstrictor Therapy in Hepatorenal Syndrome Type 1. KIDNEY360 2023; 4:e448-e456. [PMID: 36763632 PMCID: PMC10278824 DOI: 10.34067/kid.0000000000000068] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 01/13/2023] [Indexed: 02/12/2023]
Abstract
Key Points Raising the mean arterial pressure (MAP) during management of hepatorenal syndrome type 1 (HRS-1) is associated with improvement in kidney function, independently of baseline MAP or model for end-stage liver disease. Raising the MAP by 15 mm Hg or greater leads to greater reduction in serum creatinine in HRS-1. Norepinephrine use confers greater probability of improvement in kidney function in HRS-1 compared with midodrine/octreotide. Background Raising mean arterial pressure (MAP) during treatment of hepatorenal syndrome type 1 (HRS-1) with vasoconstrictors (VCs) is associated with renal recovery. However, the optimal MAP target and factors associated with response to VCs remain unclear. Methods Records from hospitalized patients with HRS-1 treated with VCs without shock were reviewed searching for those who achieved ≥5 mm Hg rise in MAP within 48 hours. We examined the relationship between the mean MAP achieved during the first 48–72 hours of VC therapy and the change in serum creatinine (sCr) up to day 14. Endpoints were >30% reduction in sCr without need for dialysis or death by day 14 (primary) or by day 30 (secondary). Results Seventy-seven patients with HRS-1 treated for 2–10 days with either norepinephrine (n =49) or midodrine/octreotide (n =28) were included. The median age was 52 years (interquartile range [IQR], 46–60), 40% were female, and 48% had alcoholic cirrhosis. At VC initiation, median MAP was 70 mm Hg (IQR, 66–73), and median sCr was 3.8 mg/dl (IQR, 2.6–4.9). When analyzed by tertiles of mean MAP increment (5–9, 10–14, ≥15 mm Hg), there was greater reduction in sCr with greater rise in MAP (ANOVA for trend, P < 0.0001). By multivariate logistic regression analysis, mean MAP rise during the first 48–72 hours (odds ratio [OR], 1.15 [1.02 to 1.299], P =0.025), norepinephrine as VC (OR, 5.46 [1.36 to 21.86], P =0.017), and baseline sCr [OR, 0.63 [0.41 to 0.97], P =0.034) were associated with the primary endpoint, whereas mean MAP rise during the first 48–72 hours (OR, 1.17 [1.04 to 1.33], P =0.012) and baseline sCr (OR, 0.63 [0.39 to 0.98], P =0.043) were associated with the secondary endpoint. Conclusions Greater magnitude of rise in MAP with VC therapy in HRS-1, lower baseline sCr, and use of norepinephrine over midodrine/octreotide are associated with kidney recovery. Targeting an increment of MAP ≥15 mm Hg may lead to favorable renal outcomes.
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Affiliation(s)
- Juan Carlos Q. Velez
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
- HRS-HARMONY Consortium
| | - Nithin Karakala
- HRS-HARMONY Consortium
- Division of Nephrology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Kasra Tayebi
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | | | - Muner M. B. Mohamed
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | | | | | - Swetha R. Kanduri
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | - Andrew S. Allegretti
- HRS-HARMONY Consortium
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Justin M. Belcher
- HRS-HARMONY Consortium
- Division of Nephrology, Department of Medicine, Yale University, New Haven, Connecticut
- Veterans Affairs Connecticut Healthcare, West Haven, Connecticut
| | - Kevin R. Regner
- HRS-HARMONY Consortium
- Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Cathy Wentowski
- Department of Pulmonary and Critical Care Medicine, Ochsner Health, New Orleans, Louisiana
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Affiliation(s)
- Mitra K Nadim
- From the Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles (M.K.N.); and the Section of Digestive Diseases, Yale University School of Medicine, New Haven, and the Section of Digestive Diseases, Veterans Affairs Connecticut Healthcare System, West Haven - both in Connecticut (G.G.-T.)
| | - Guadalupe Garcia-Tsao
- From the Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles (M.K.N.); and the Section of Digestive Diseases, Yale University School of Medicine, New Haven, and the Section of Digestive Diseases, Veterans Affairs Connecticut Healthcare System, West Haven - both in Connecticut (G.G.-T.)
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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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Abstract
AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal syndrome type 1, also referred to as hepatorenal syndrome-AKI, is the most salient and unique etiology. Patients with cirrhosis are vulnerable to traditional causes of AKI, such as prerenal azotemia, acute tubular injury, and acute interstitial nephritis. In addition, other less common etiologies of AKI specifically related to chronic liver disease should be considered, including abdominal compartment syndrome, cardiorenal processes linked to cirrhotic cardiomyopathy and portopulmonary hypertension, and cholemic nephropathy. Furthermore, certain types of GN can cause AKI in cirrhosis, such as IgA nephropathy or viral hepatitis related. Therefore, a comprehensive diagnostic approach is needed to evaluate patients with cirrhosis presenting with AKI. Management should be tailored to the specific underlying etiology. Albumin-based volume resuscitation is recommended in prerenal AKI. Acute tubular injury and acute interstitial nephritis are managed with supportive care, withdrawal of the offending agent, and, potentially, corticosteroids in acute interstitial nephritis. Short of liver transplantation, vasoconstrictor therapy is the primary treatment for hepatorenal syndrome type 1. Timing of initiation of vasoconstrictors, the rise in mean arterial pressure, and the degree of cholestasis are among the factors that determine vasoconstrictor responsiveness. Large-volume paracentesis and diuretics are indicated to relieve intra-abdominal hypertension and renal vein congestion. Direct-acting antivirals with or without immunosuppression are used to treat hepatitis B/C-associated GN. In summary, AKI in cirrhosis requires careful consideration of multiple potentially pathogenic factors and the implementation of targeted therapeutic interventions.
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Affiliation(s)
- Giuseppe Cullaro
- Department of Medicine, University of California, San Francisco, California
| | - Swetha Rani Kanduri
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | - Juan Carlos Q. Velez
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
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26
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Zhang W, Zhang Y, Liu Q, Nie Y, Zhu X. Development and validation of a prognostic nomogram for decompensated liver cirrhosis. World J Clin Cases 2022; 10:10467-10477. [PMID: 36312496 PMCID: PMC9602236 DOI: 10.12998/wjcc.v10.i29.10467] [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: 05/30/2022] [Revised: 08/31/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Decompensated liver cirrhosis (DLC) is a stage in the progression of liver cirrhosis and has a high mortality.
AIM To establish and validate a novel and simple-to-use predictive nomogram for evaluating the prognosis of DLC patients.
METHODS A total of 493 patients with confirmed DLC were enrolled from The First Affiliated Hospital of Nanchang University (Nanchang, Jiangxi Province, China) between December 2013 and August 2019. The patients were divided into two groups: a derivation group (n = 329) and a validation group (n = 164). Univariate and multivariate Cox regression analyses were performed to assess prognostic factors. The performance of the nomogram was determined by its calibration, discrimination, and clinical usefulness.
RESULTS Age, mechanical ventilation application, model for end-stage liver disease (MELD) score, mean arterial blood pressure, and arterial oxygen partial pressure/inhaled oxygen concentration were used to construct the model. The C-indexes of the nomogram in the derivation and validation groups were 0.780 (95%CI: 0.670-0.889) and 0.792 (95%CI: 0.698-0.886), respectively. The calibration curve exhibited good consistency with the actual observation curve in both sets. In addition, decision curve analysis indicated that our nomogram was useful in clinical practice.
CONCLUSION A simple-to-use novel nomogram based on a large Asian cohort was established and validated and exhibited improved performance compared with the Child-Turcotte-Pugh and MELD scores. For patients with DLC, the proposed nomogram may be helpful in guiding clinicians in treatment allocation and may assist in prognosis prediction.
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Affiliation(s)
- Wang Zhang
- Department of Gastroenterology, Jiangxi Clinical Research Center for Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yue Zhang
- Department of Gastroenterology, Jiangxi Clinical Research Center for Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Qi Liu
- Department of Gastroenterology, Jiangxi Clinical Research Center for Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yuan Nie
- Department of Gastroenterology, Jiangxi Clinical Research Center for Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xuan Zhu
- Department of Gastroenterology, Jiangxi Clinical Research Center for Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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Garcia-Saenz-de-Sicilia M, Al-Obaid L, Hughes DL, Duarte-Rojo A. Mastering Core Recommendations during HEPAtology ROUNDS in Patients with Advanced Chronic Liver Disease. Semin Liver Dis 2022; 42:341-361. [PMID: 35764316 DOI: 10.1055/a-1886-5909] [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: 02/07/2023]
Abstract
Efficient and thorough care of hospitalized patients with advanced chronic liver disease is of utter importance to improve outcomes and optimize quality of life. This requires understanding current evidence and best practices. To facilitate focus on up-to-date knowledge and a practical approach, we have created the HEPA-ROUNDS mnemonic while outlining a practical review of the literature with critical appraisal for the busy clinician. The HEPA-ROUNDS mnemonic provides a structured approach that incorporates critical concepts in terms of prevention, management, and prognostication of the most common complications frequently encountered in patients with advanced chronic liver disease. In addition, implementing the HEPA-ROUNDS mnemonic can facilitate education for trainees and staff caring for patients with advanced chronic liver disease.
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Affiliation(s)
| | - Lolwa Al-Obaid
- Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Dempsey L Hughes
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Andrés Duarte-Rojo
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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28
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Patidar KR, Naved MA, Grama A, Adibuzzaman M, Aziz Ali A, Slaven JE, Desai AP, Ghabril MS, Nephew L, Chalasani N, Orman ES. Acute kidney disease is common and associated with poor outcomes in patients with cirrhosis and acute kidney injury. J Hepatol 2022; 77:108-115. [PMID: 35217065 DOI: 10.1016/j.jhep.2022.02.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/03/2022] [Accepted: 02/04/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Acute kidney disease (AKD) is the persistence of acute kidney injury (AKI) for up to 3 months, which is proposed to be the time-window where critical interventions can be initiated to alter downstream outcomes of AKI. In cirrhosis, AKD and its impact on outcomes have been scantly investigated. We aimed to define the incidence and outcomes associated with AKD in a nationwide US cohort of hospitalized patients with cirrhosis and AKI. METHODS Hospitalized patients with cirrhosis and AKI in the Cerner-Health-Facts database from 1/2009-09/2017 (n = 6,250) were assessed for AKD and were followed-up for 180 days. AKI and AKD were defined based on KDIGO and ADQI AKD and renal recovery consensus criteria, respectively. The primary outcome measure was mortality, and the secondary outcome measure was de novo chronic kidney disease (CKD). Competing-risk multivariable models were used to determine the independent association of AKD with primary and secondary outcomes. RESULTS AKD developed in 32% of our cohort. On multivariable competing-risk analysis adjusting for significant confounders, patients with AKD had higher risk of mortality at 90 (subdistribution hazard ratio [sHR] 1.37; 95% CI 1.14-1.66; p = 0.001) and 180 (sHR 1.37; 95% CI 1.14-1.64; p = 0.001) days. The incidence of de novo CKD was 37.5%: patients with AKD had higher rates of de novo CKD (64.0%) compared to patients without AKD (30.7%; p <0.001). After adjusting for confounders, AKD was independently associated with de novo CKD (sHR 2.52; 95% CI 2.01-3.15; p <0.001) on multivariable competing-risk analysis. CONCLUSIONS AKD develops in 1 in 3 hospitalized patients with cirrhosis and AKI and it is associated with worse survival and de novo CKD. Interventions that target AKD may improve outcomes of patients with cirrhosis and AKI. LAY SUMMARY In a nationwide US cohort of hospitalized patients with cirrhosis and acute kidney injury, acute kidney disease developed in 1 in 3 patients and was associated with worse survival and chronic kidney disease. Interventions that target acute kidney disease may improve outcomes of patients with cirrhosis and acute kidney injury.
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Affiliation(s)
- Kavish R Patidar
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA.
| | - Mobasshir A Naved
- Department of Computer Science, Purdue University, West Lafayette, IN USA
| | - Ananth Grama
- Department of Computer Science, Purdue University, West Lafayette, IN USA
| | - Mohammad Adibuzzaman
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health Sciences University, OR USA
| | - Arzina Aziz Ali
- Division of Internal Medicine, Indiana University School of Medicine, Indianapolis IN, USA
| | - James E Slaven
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis IN, USA
| | - Archita P Desai
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
| | - Marwan S Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
| | - Lauren Nephew
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
| | - Eric S Orman
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
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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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Buccheri S, Da BL. Hepatorenal Syndrome: Definitions, Diagnosis, and Management. Clin Liver Dis 2022; 26:181-201. [PMID: 35487604 DOI: 10.1016/j.cld.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatorenal syndrome (HRS) is a hemodynamically driven process mediated by renal dysregulation and inflammatory response. Albumin, antibiotics, and β-blockers are among therapies that have been studied in HRS prevention. There are no Food and Drug Administration-approved treatments for HRS although multiple liver societies have recommended terlipressin as first-line pharmacotherapy. Renal replacement therapy is the primary modality used to bridge to definitive therapy with orthotopic liver transplant or simultaneous liver-kidney transplant. Advances in our understanding of HRS pathophysiology and emerging therapeutic modalities are needed to change outcomes for this vulnerable population.
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Affiliation(s)
- Sebastiano Buccheri
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA
| | - Ben L Da
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases & Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
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31
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Velez JCQ. Hepatorenal Syndrome Type 1: From Diagnosis Ascertainment to Goal-Oriented Pharmacologic Therapy. KIDNEY360 2022; 3:382-395. [PMID: 35373127 PMCID: PMC8967638 DOI: 10.34067/kid.0006722021] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/02/2021] [Indexed: 05/05/2023]
Abstract
Hepatorenal syndrome type 1 (HRS-1) is a serious form of AKI that affects individuals with advanced cirrhosis with ascites. Prompt and accurate diagnosis is essential for effective implementation of therapeutic measures that can favorably alter its clinical course. Despite decades of investigation, HRS-1 continues to be primarily a diagnosis of exclusion. Although the diagnostic criteria dictated by the International Club of Ascites provide a useful framework to approach the diagnosis of HRS-1, they do not fully reflect the complexity of clinical scenarios that is often encountered in patients with cirrhosis and AKI. Thus, diagnostic uncertainty is often faced. In particular, the distinction between HRS-1 and acute tubular injury is challenging with the currently available clinical tools. Because treatment of HRS-1 differs from that of acute tubular injury, distinguishing these two causes of AKI has direct implications in management. Therefore, the use of the International Club of Ascites criteria should be enhanced with a more individualized approach and attention to the other phenotypic aspects of HRS-1 and other types of AKI. Liver transplantation is the most effective treatment for HRS-1, but it is only available to a small fraction of the affected patients worldwide. Thus, pharmacologic therapy is necessary. Vasoconstrictors aimed to increase mean arterial pressure constitute the most effective approach. Administration of intravenous albumin is an established co-adjuvant therapy. However, the risk for fluid overload in patients with cirrhosis with AKI is not negligible, and interventions intended to expand or remove volume should be tailored to the specific needs of the patient. Norepinephrine and terlipressin are the most effective vasoconstrictors, and their use should be determined by availability, ease of administration, and attention to optimal risk-benefit balance for each clinical scenario.
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Affiliation(s)
- Juan Carlos Q. Velez
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, University of Queensland, Brisbane, Australia
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32
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Terres AZ, Balbinot RS, Muscope ALF, Longen ML, Schena B, Cini BT, Luis Rost G, Balensiefer JIL, Eberhardt LZ, Balbinot RA, Balbinot SS, Soldera J. Evidence-based protocol for diagnosis and treatment of hepatorenal syndrome is independently associated with lower mortality. GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 45:25-39. [PMID: 33746028 DOI: 10.1016/j.gastrohep.2021.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/22/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatorenal syndrome (HRS) is the deadliest complication of cirrhosis. The purpose of this study is to analyze if the use of a protocol for HRS is associated with higher survival in these patients. METHODS An evidence-based protocol for the diagnosis and treatment of HRS was instituted in 2013. Data from medical records from 2010 to 2016 were obtained by searching the hospital database for patients who received terlipressin, in the three years before and after the institution of the protocol. Data were reviewed to confirm the diagnosis of HRS and multiple variables were collected. Liver-specific scores were calculated and a stepwise Cox regression approach was used for univariate and multivariate analysis. RESULTS The study included 46 patients, 20 from the pre-protocol period and 26 from the post-protocol period. Respectively, mortality at 30 days, 90 days and 365 days was 75%, 75% and 90% for the pre-protocol period, and 61%, 69% and 80% for the post-protocol period. In the multivariate analysis, an aspartate aminotransferase (AST) of <40U/L, the pre-protocol period and higher Child-Turcotte-Pugh scores were associated with higher 30-day and 90-day mortality. The total mean dose of terlipressin and human albumin used per patient was reduced from 27mg to 22mg and from 236g to 144g, respectively, after the institution of the protocol. This was not associated with higher mortality. CONCLUSION The use of an evidence-based protocol for the treatment of HRS translated into a higher survival. The authors suggest that the use of evidence-based protocols for the diagnosis and treatment of HRS could reduce cost and mortality in tertiary hospitals.
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Affiliation(s)
- Alana Zulian Terres
- Internal Medicine, Hospital Pompeia, Caxias do Sul, RS, Brazil; Gastroenterology, Hospital Geral de Caxias do Sul (RS), Brazil
| | - Rafael Sartori Balbinot
- Residency in Internal Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil; Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | | | | | - Bruna Schena
- Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | - Bruna Teston Cini
- Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | - Gilberto Luis Rost
- Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | | | | | - Raul Angelo Balbinot
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil; Department of Gastroenterology, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Silvana Sartori Balbinot
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil; Department of Gastroenterology, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Jonathan Soldera
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil; Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
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Fabes J, Ambler G, Shah B, Williams NR, Martin D, Davidson BR, Spiro M. Protocol for a prospective double-blind, randomised, placebo-controlled feasibility trial of octreotide infusion during liver transplantation. BMJ Open 2021; 11:e055864. [PMID: 34857585 PMCID: PMC8640665 DOI: 10.1136/bmjopen-2021-055864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
INTRODUCTION Liver transplantation is a complex operation that can provide significant improvements in quality of life and survival to the recipients. However, serious complications are common and include major haemorrhage, hypotension and renal failure. Blood transfusion and the development of acute kidney injury lead to both short-term and long-term poor patient outcomes, including an increased risk of death, graft failure, length of stay and reduced quality of life. Octreotide may reduce the incidence of renal dysfunction, perioperative haemorrhage and enhance intraoperative blood pressure. However, octreotide does have risks, including resistant bradycardia, hyperglycaemia and hypoglycaemia and QT prolongation. Hence, a randomised controlled trial of octreotide during liver transplantation is needed to determine the cost-efficacy and safety of its use; this study represents a feasibility study prior to this trial. METHODS AND ANALYSIS We describe a multicentre, double-blind, randomised, placebo-controlled feasibility study of continuous infusion of octreotide during liver transplantation surgery. We will recruit 30 adult patients at two liver transplant centres. A blinded infusion during surgery will be administered in a 2:1 ratio of octreotide:placebo. The primary outcomes will determine the feasibility of this study design. These include the recruitment ratio, correct administration of blinded study intervention, adverse event rates, patient and clinician enrolment refusal and completion of data collection. Secondary outcome measures of efficacy and safety will help shape future trials by assessing potential primary outcome measures and monitoring safety end points. No formal statistical tests are planned. This manuscript represents study protocol number 1.3, dated 2 June 2021. ETHICS AND DISSEMINATION This study has received Research Ethics Committee approval. The main study outcomes will be submitted to an open-access journal. TRIAL SPONSOR The Joint Research Office, University College London, UK.Neither the sponsor nor the funder have any role in study design, collection, management, analysis and interpretation of data, writing of the study report or the decision to submit the report for publication. TRIAL REGISTRATION The study is registered with ClinicalTrials.gov (NCT04941911) with recruitment due to start in August 2021 with anticipated completion in July 2022. CLINICAL TRIALS UNIT Surgical and Interventional Group, Division of Surgery & Interventional Science, University College London.
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Affiliation(s)
- Jeremy Fabes
- Peninsula Medical School, University of Plymouth, Plymouth, Devon, UK
- Department of Anaesthesia, Royal Free London NHS Foundation Trust, London, UK
| | - Gareth Ambler
- Department of Statistical Science, University College London, London, UK
| | - Bina Shah
- Division of Surgery & Interventional Science, University College London, London, UK
| | - Norman R Williams
- Division of Surgery & Interventional Science, University College London, London, UK
| | - Daniel Martin
- Peninsula Medical School, University of Plymouth, Plymouth, Devon, UK
| | - Brian R Davidson
- Division of Surgery & Interventional Science, University College London, London, UK
| | - Michael Spiro
- Division of Surgery & Interventional Science, University College London, London, UK
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Singh J, Dahiya DS, Kichloo A, Singh G, Khoshbin K, Shaka H. Hepatorenal syndrome: a Nationwide Trend Analysis from 2008 to 2018. Ann Med 2021; 53:2018-2024. [PMID: 34985399 PMCID: PMC8604523 DOI: 10.1080/07853890.2021.1998595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE This study was designed to assess the epidemiological trends and outcomes associated with Hepatorenal Syndrome (HRS). METHODS This retrospective interrupted trend study used the Nationwide Inpatient Sample (NIS) database for the years 2008, 2012, 2014, 20z16 and 2018 to identify adult (≥18 years) hospitalizations with a primary diagnosis of HRS. We determined epidemiological characteristics and trends for HRS hospitalizations. Additionally, we also calculated the inpatient mortality, mean length of stay (LOS) and mean total hospital charge (THC) using a multivariate regression trend analysis. RESULTS There was an increase in the total number of HRS hospitalizations from 22,864 in 2008 to 42,985 in 2018 with a trend towards increasing hospitalizations (p-trend <.001). The mean age for these hospitalizations ranged from 57.4-59.0 years with a significantly rising trend (p-trend <.001). Although the majority of HRS hospitalizations were men, we observed a trend towards increasing hospitalizations for women with an increase from 35.7% in 2008 to 39% in 2018 (p-trend <.001). Additionally, Whites made up a majority of the sample size (Table 1). After a multivariate regression trend analysis, we found a statistically significant trend towards declining inpatient mortality from 36.2% in 2008 to 25.7% in 2018 (p-trend <.001) for HRS hospitalizations (Table 2). We did not find a statistically significant trend for LOS and THC.[Table: see text][Table: see text]. CONCLUSION Total hospitalizations, hospitalizations for women and the mean age for HRS hospitalizations were on the rise between 2008 and 2018. However, the inpatient mortality declined.KEY MESSAGESIn the United States, there was a trend towards increasing hospitalizations and mean age for HRS.Although a male predominance was noted, HRS hospitalizations for women were on the rise.The inpatient mortality for HRS hospitalizations was on a decline and may indicate significant improvements in management.
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Affiliation(s)
- Jagmeet Singh
- Department of Nephrology, Guthrie Robert Packer Hospital, Sayre, PA, USA
| | - Dushyant Singh Dahiya
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI, USA
| | - Asim Kichloo
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI, USA
- Department of Internal Medicine, Samaritan Medical Center, Watertown, NY, USA
| | - Gurdeep Singh
- Department of Medicine and Endocrinology, Lady of Lourdes Memorial Hospital, Binghamton, NY, USA
| | - Katayoun Khoshbin
- Department of Internal Medicine, John H Stroger Hospital of Cook County, Chicago, IL, USA
| | - Hafeez Shaka
- Department of Internal Medicine, John H Stroger Hospital of Cook County, Chicago, IL, USA
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Chandna S, Zarate ER, Gallegos-Orozco JF. Management of Decompensated Cirrhosis and Associated Syndromes. Surg Clin North Am 2021; 102:117-137. [PMID: 34800381 DOI: 10.1016/j.suc.2021.09.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Patients with cirrhosis account for 3% of intensive care unit admissions with hospital mortality exceeding 50%; however, improvements in survival among patients with acutely decompensated cirrhosis and organ failure have been described when treated in specialized liver transplant centers. Acute-on-chronic liver failure is a distinct clinical syndrome characterized by decompensated cirrhosis associated with one or more organ failures resulting in a significantly higher short-term mortality. In this review, we will discuss the management of common life-threatening complications in the patient with cirrhosis that require intensive care management including neurologic, cardiovascular, gastrointestinal, pulmonary, and renal complications.
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Affiliation(s)
- Shaun Chandna
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Utah School of Medicine, 30 N 1900 E, SOM-4R118, Salt Lake City, UT 84106, USA
| | - Eduardo Rodríguez Zarate
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Utah School of Medicine, 30 N 1900 E, SOM-4R118, Salt Lake City, UT 84106, USA
| | - Juan F Gallegos-Orozco
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Utah School of Medicine, 30 N 1900 E, SOM-4R118, Salt Lake City, UT 84106, USA.
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Belcher JM, Parada XV, Simonetto DA, Juncos LA, Karakala N, Wadei HM, Sharma P, Regner KR, Nadim MK, Garcia-Tsao G, Velez JCQ, Parikh SM, Chung RT, Allegretti AS. Terlipressin and the Treatment of Hepatorenal Syndrome: How the CONFIRM Trial Moves the Story Forward. Am J Kidney Dis 2021; 79:737-745. [PMID: 34606933 DOI: 10.1053/j.ajkd.2021.08.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022]
Abstract
Hepatorenal syndrome (HRS) is a form of acute kidney injury occurring in patients with advanced cirrhosis and is associated with significant morbidity and mortality. The pathophysiology underlying HRS begins with increasing portal pressures leading to the release of vasodilatory substances which result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and release of arginine vasopressin serve to defend mean arterial pressure but at the cost of severe constriction of the renal vasculature, leading to a progressive, often fulminant form of AKI. While there are no approved treatments for HRS in the United States, multiple countries, including much of Europe, utilize terlipressin, a synthetic vasopressin analogue, as first-line therapy. The recently published CONFIRM trial, the third randomized trial based in North America evaluating terlipressin, met its primary endpoint, showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about apparent increased rates of respiratory adverse events and a lack of evidence for mortality benefit, terlipressin was not approved by the Food and Drug Administration (FDA). In this Perspective, we explore the history of regulatory approval for terlipressin in the United States, examine the results from CONFIRM and the concerns they raised and consider the future role of terlipressin in this critical clinical area of continued unmet need.
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Affiliation(s)
- Justin M Belcher
- Department of Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA and Section of Nephrology, VA-Connecticut Healthcare System, West Haven, CT, USA.
| | - Xavier Vela Parada
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Luis A Juncos
- Department of Medicine, University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Nithin Karakala
- Department of Medicine, University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Hani M Wadei
- Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA
| | - Pratima Sharma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - Kevin R Regner
- Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Mitra K Nadim
- Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, VA-Connecticut Healthcare System, West Haven, CT, USA
| | | | - Samir M Parikh
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess and Harvard Medical School, Boston, MA, USA; Division of Nephrology, UT Southwestern, Dallas, TX
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Andrew S Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
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Nassar M, Nso N, Medina L, Ghernautan V, Novikov A, El-Ijla A, Soliman KM, Kim Y, Alfishawy M, Rizzo V, Daoud A. Liver Kidney Crosstalk: Hepatorenal Syndrome. World J Hepatol 2021; 13:1058-1068. [PMID: 34630874 PMCID: PMC8473490 DOI: 10.4254/wjh.v13.i9.1058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/12/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
The dying liver causes the suffocation of the kidneys, which is a simplified way of describing the pathophysiology of hepatorenal syndrome (HRS). HRS is characterized by reversible functional renal impairment due to reduced blood supply and glomerular filtration rate, secondary to increased vasodilators. Over the years, HRS has gained much attention and focus among hepatologists and nephrologists. HRS is a diagnosis of exclusion, and in some cases, it carries a poor prognosis. Different classifications have emerged to better understand, diagnose, and promptly treat this condition. This targeted review aims to provide substantial insight into the epidemiology, pathophysiology, diagnosis, and management of HRS, shed light on the various milestones of this condition, and add to our current understanding.
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Affiliation(s)
- Mahmoud Nassar
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Nso Nso
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Luis Medina
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Victoria Ghernautan
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Anastasia Novikov
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Alli El-Ijla
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Karim M Soliman
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Yungmin Kim
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Mostafa Alfishawy
- Department of Infectious Diseases, Infectious Diseases Consultants and Academic Researchers of Egypt IDCARE, Cairo 11562, Egypt
| | - Vincent Rizzo
- Department of Medicine, Icahn School of Medicine at Mount Sinai / NYC Health + Hospitals / Queens, New York, NY 11432, United States
| | - Ahmed Daoud
- Department of Medicine, Kasr Alainy Medical School, Cairo University, Cairo 11211, Egypt.
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Hepatorenal syndrome: pathophysiology and evidence-based management update. ROMANIAN JOURNAL OF INTERNAL MEDICINE 2021; 59:227-261. [DOI: 10.2478/rjim-2021-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Indexed: 11/20/2022] Open
Abstract
Abstract
Hepatorenal syndrome (HRS) is a functional renal failure that develops in patients with advanced hepatic cirrhosis with ascites and in those with fulminant hepatic failure. The prevalence of HRS varies among studies but in general it is the third most common cause of acute kidney injury (AKI) in cirrhotic patients after pre-renal azotemia and acute tubular necrosis. HRS carries a grim prognosis with a mortality rate approaching 90% three months after disease diagnosis. Fortunately, different strategies have been proven to be successful in preventing HRS. Although treatment options are available, they are not universally effective in restoring renal function but they might prolong survival long enough for liver transplantation, which is the ultimate treatment. Much has been learned in the last two decades regarding the pathophysiology and management of this disease which lead to notable evolution in the HRS definition and better understanding on how best to manage HRS patients. In the current review, we will summarize the recent advancement in epidemiology, pathophysiology, and management of HRS.
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Subedi A, Suresh Kumar VC, Sharma Subedi A, Sapkota B. A Review of Hepatorenal Syndrome. Cureus 2021; 13:e16084. [PMID: 34367745 PMCID: PMC8330394 DOI: 10.7759/cureus.16084] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2021] [Indexed: 12/21/2022] Open
Abstract
The development of acute kidney injury (AKI) is one of the most frequent complications in patients with cirrhosis. AKI due to volume depletion is the most common etiology and hepatorenal syndrome (HRS) is the second most common cause of AKI in these patients. HRS is the extreme form of kidney injury in patients with cirrhosis, which is caused due to a reduction in renal blood flow unresponsive to volume expansion. The literature involving HRS is rapidly evolving and newer tests and updated definitions have been proposed which allows timely identification and treatment. Here, we will discuss the definition, pathophysiology, prevention, diagnosis, and treatment of HRS.
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Affiliation(s)
- Abinash Subedi
- Internal Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, USA
| | | | | | - Bishnu Sapkota
- Gastroenterology, State University of New York (SUNY) Upstate Medical University, Syracuse, USA.,Gastroenterology, Veterans Affairs (VA) Medical Center, Syracuse, USA
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Simbrunner B, Trauner M, Reiberger T, Mandorfer M. Recent advances in the understanding and management of hepatorenal syndrome. Fac Rev 2021; 10:48. [PMID: 34131658 PMCID: PMC8170686 DOI: 10.12703/r/10-48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Renal dysfunction occurs frequently in hospitalized patients with advanced chronic liver disease (ACLD)/cirrhosis and has profound prognostic implications. In ACLD patients with ascites, hepatorenal syndrome (HRS) may result from circulatory dysfunction that leads to reduced kidney perfusion and glomerular filtration rate (in the absence of structural kidney damage). The traditional subclassification of HRS has recently been replaced by acute kidney injury (AKI) type of HRS (HRS-AKI) and non-AKI type of HRS (HRS-NAKI), replacing the terms “HRS type 1” and “HRS type 2”, respectively. Importantly, the concept of absolute serum creatinine (sCr) cutoffs for diagnosing HRS was partly abandoned and short term sCr dynamics now may suffice for AKI diagnosis, which facilitates early treatment initiation that may prevent the progression to HRS-AKI or increase the chances of AKI/HRS-AKI reversal. Recent randomized controlled trials have established (a) the efficacy of (long-term) albumin in the prevention of complications of ascites (including HRS-AKI), (b) the benefits of transjugular intrahepatic portosystemic shunt placement in patients with recurrent ascites, and (c) the superiority of terlipressin over noradrenaline for the treatment of HRS-AKI in the context of acute-on-chronic liver failure. This review article aims to summarize recent advances in the understanding and management of HRS.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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Associations Between Mean Arterial Pressure and Poor ICU Outcomes in Critically Ill Patients With Cirrhosis: Is 65 The Sweet Spot? Crit Care Med 2021; 48:e753-e760. [PMID: 32618694 DOI: 10.1097/ccm.0000000000004442] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Mean arterial pressure is critically important in patients with cirrhosis in the ICU, however, there is limited data to guide therapies and targets. DESIGN Retrospective observational study. SETTING Tertiary care ICU. PATIENTS Two hundred and seventy-three critically ill patients with cirrhosis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We performed a comprehensive time-weighted mean arterial pressure analysis (time-weighted-average-mean arterial pressure and cumulative-time-below various mean arterial pressure-thresholds) during the first 24-hours after ICU admission (median: 25 mean arterial pressure measurements per-patient). Time-weighted-average-mean arterial pressure captures both the severity and duration of hypotension below a mean arterial pressure threshold and cumulative-time-below is the total time spent below a mean arterial pressure threshold. Individual univariable and multivariable logistic regression models were assessed for each time-weighted-average-mean arterial pressure and cumulative-time-below mean arterial pressure threshold (55, 60, 65, 70, and 75 mm Hg) for ICU-mortality. Time-weighted-average-mean arterial pressure: for 1 mm Hg decrease in mean arterial pressure below 75, 70, 65, 60, and 55 mm Hg, the odds for ICU-mortality were 14%, 18%, 26%, 41%, and 74%, respectively (p < 0.01, all thresholds). The association between time-weighted-average-mean arterial pressure and ICU-mortality for each threshold remained significant after adjusting for model for end-stage liver disease-sodium score, mechanical ventilation, vasopressor use, renal replacement therapy, grade 3/4 hepatic encephalopathy, WBC count, and albumin. Cumulative-time-below: odds for ICU-mortality were 4%, 6%, 10%, 12%, and 12% for each-hour spent below 75, 70, 65, 60, and 55 mm Hg, respectively. In the adjusted models, significant associations only remained for mean arterial pressure less than 65 mm Hg (odds ratio, 1.07; 95% CI, 1.00-1.14; p = 0.05) and < 60 mm Hg (odds ratio, 1.10; 95% CI, 1.01-1.18; p = 0.04). CONCLUSIONS These data suggest that maintaining a mean arterial pressure of greater than 65 mm Hg may be a reasonable target in patients with cirrhosis admitted to the ICU. However, further prospective randomized trials are needed to determine the optimal mean arterial pressure-targets in this patient population.
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Juanola A, Solé C, Toapanta D, Ginès P, Solà E. Monitoring Renal Function and Therapy of Hepatorenal Syndrome Patients with Cirrhosis. Clin Liver Dis 2021; 25:441-460. [PMID: 33838860 DOI: 10.1016/j.cld.2021.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Acute kidney injury (AKI) is a frequent complication in patients with cirrhosis. Patients with cirrhosis can develop AKI due to different causes. Hepatorenal syndrome (HRS) is a unique cause of AKI occurring in patients with advanced cirrhosis and is associated with high short-term mortality. The differential diagnosis between different causes of AKI may be challenging. In this regard, new urine biomarkers may be helpful. Liver transplantation is the definitive treatment of patients with HRS-AKI. Vasoconstrictors and albumin represent the first-line pharmacologic treatment of HRS-AKI. This review summarizes current knowledge for the diagnosis and management of HRS in cirrhosis.
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Affiliation(s)
- Adrià Juanola
- Liver Unit, Hospital Clínic de Barcelona, 08036 Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain
| | - Cristina Solé
- Liver Unit, Hospital Clínic de Barcelona, 08036 Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - David Toapanta
- Liver Unit, Hospital Clínic de Barcelona, 08036 Barcelona, Catalonia, Spain
| | - Pere Ginès
- Liver Unit, Hospital Clínic de Barcelona, 08036 Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain.
| | - Elsa Solà
- Liver Unit, Hospital Clínic de Barcelona, 08036 Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
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Affiliation(s)
- Guadalupe Garcia-Tsao
- From the Section of Digestive Diseases, Yale School of Medicine, New Haven, and the Section of Digestive Diseases, Veterans Affairs Connecticut Healthcare System, West Haven - both in Connecticut
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Rajakumar A, Appuswamy E, Kaliamoorthy I, Rela M. Renal Dysfunction in Cirrhosis: Critical Care Management. Indian J Crit Care Med 2021; 25:207-214. [PMID: 33707901 PMCID: PMC7922436 DOI: 10.5005/jp-journals-10071-23721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Cirrhotic patients with manifestations of the end-stage liver disease have a high risk for developing renal dysfunction even with minor insults. The development of renal dysfunction increases the morbidity and mortality of these patients. Causes of renal dysfunction in cirrhotics can be due to hepatorenal syndrome (HRS) or acute kidney injury (AKI) resulting from prerenal, renal, and postrenal causes. Development of pretransplant renal dysfunction has been shown to affect post-liver transplantation outcomes. Early detection and aggressive strategies for the prevention of further progression of renal dysfunction seem to decrease the morbidity and improve survival in this group of patients. This article aims to outline the pathogenesis of renal dysfunction in cirrhosis, etiological factors, and evaluation of renal dysfunction, strategies for aggressive therapy for renal dysfunction, the indications of renal replacement therapy (RRT) in this group of patients, and the various modalities of RRT with their merits and demerits. A thorough understanding of the pathogenesis, early detection, and aggressive corrective measures for AKI can prevent further progression. In conclusion, a good knowledge of treatment modalities available for renal dysfunction in cirrhosis and institution of timely interventions can significantly improve survival in this group of patients.
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Affiliation(s)
- Akila Rajakumar
- Department of Liver Anaesthesia and Intensive Care, Dr. Rela Institute and Medical Centre, Chennai, Tamil Nadu, India
| | - Ellango Appuswamy
- Department of Liver Anaesthesia and Intensive Care, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Department of Liver Anaesthesia and Intensive Care, Dr. Rela Institute and Medical Centre, Chennai, Tamil Nadu, India
| | - Mohamed Rela
- Department of Liver Transplantation and HPB Surgery, Dr. Rela Institute and Medical Centre, Chennai, Tamil Nadu, India
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Abstract
Hepatorenal syndrome (HRS), the extreme manifestation of renal impairment in patients with cirrhosis, is characterized by reduction in renal blood flow and glomerular filtration rate. Hepatorenal syndrome is diagnosed when kidney function is reduced but evidence of intrinsic kidney disease, such as hematuria, proteinuria, or abnormal kidney ultrasonography, is absent. Unlike other causes of acute kidney injury (AKI), hepatorenal syndrome results from functional changes in the renal circulation and is potentially reversible with liver transplantation or vasoconstrictor drugs. Two forms of hepatorenal syndrome are recognized depending on the acuity and progression of kidney injury. The first represents an acute impairment of kidney function, HRS-AKI, whereas the second represents a more chronic kidney dysfunction, HRS-CKD (chronic kidney disease). In this review, we provide critical insight into the definition, pathophysiology, diagnosis, and management of hepatorenal syndrome.
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Affiliation(s)
- Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Pere Gines
- Liver Unit, Hospital Clinic, University of Barcelona IDIBAPS - CIBEReHD, Barcelona, Spain
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
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Arora V, Maiwall R, Rajan V, Jindal A, Muralikrishna Shasthry S, Kumar G, Jain P, Sarin SK. Terlipressin Is Superior to Noradrenaline in the Management of Acute Kidney Injury in Acute on Chronic Liver Failure. Hepatology 2020; 71:600-610. [PMID: 30076614 DOI: 10.1002/hep.30208] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/01/2018] [Indexed: 12/14/2022]
Abstract
Hepatorenal syndrome (HRS) carries a high short-term mortality in patients with cirrhosis and acute on chronic liver failure (ACLF). Terlipressin and noradrenaline are routinely used in cirrhosis with HRS and have been found to be equally effective. There are no data comparing the efficacy of terlipressin with noradrenaline in ACLF patients with HRS. In an open-label, randomized controlled trial (RCT), consecutive patients with ACLF diagnosed with HRS acute kidney injury (AKI) were randomized to albumin with infusion of terlipressin (2-12 mg/day; n = 60) or noradrenaline (0.5-3.0 mg/h; n = 60). Response to treatment, course of AKI, and outcome were studied. Baseline characteristics, including AKI stage and sepsis-related HRS-AKI, were comparable between groups. Compared to noradrenaline, terlipressin achieved greater day 4 (26.1% vs. 11.7%; P = 0.03) and day 7 (41.7% vs. 20%; P = 0.01) response. Reversal of HRS was also better with terlipressin (40% vs. 16.7%; P = 0.004), with a significant reduction in the requirement of renal replacement therapy (RRT; 56.6% vs. 80%; P = 0.006) and improved 28-day survival (48.3% vs. 20%; P = 0.001). Adverse events limiting use of drugs were higher with terlipressin than noradrenaline (23.3% vs. 8.3%; P = 0.02), but were reversible. On multivariate analysis, high Model for End-Stage Liver Disease (MELD; odds ratio [OR], 1.10; confidence interval [CI] = 1.009-1.20; P = 0.03) and noradrenaline compared to terlipressin (OR, 3.05; CI = 1.27-7.33; P = 0.01) predicted nonresponse to therapy. Use of noradrenaline compared to terlipressin was also predictive of higher mortality (hazard ratio [HR], 2.08; CI = 1.32-3.30; P = 0.002). Conclusion: AKI in ACLF carries a high mortality. Infusion of terlipressin gives earlier and higher response than noradrenaline, with improved survival in ACLF patients with HRS-AKI.
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Affiliation(s)
- Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vijayaraghavan Rajan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Guresh Kumar
- Department of Clinical Research and Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Priyanka Jain
- Department of Clinical Research and Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Scarpellini E, Luigiano C, Svegliati-Baroni G, Dumitrascu D, Larussa T, Santori V, Luzza F, Abenavoli L. Liver Cirrhosis Complications Management at the Emergency Department. Rev Recent Clin Trials 2020; 15:331-338. [PMID: 32493202 DOI: 10.2174/1574887115666200603160816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/16/2020] [Accepted: 04/27/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Liver cirrhosis (LC) of any origin has always been a source of several emergencies for physicians working at the Emergency Department (ER). LC patients can present with several complications that are sometimes difficult to recognize and treat. Thus, we reviewed the literature evidence for the diagnosis and management of several LC related emergencies. METHODS We conducted a search on the main medical databases for papers, reviews, metanalyses, case series, and RCTs using the following keywords and their associations: liver cirrhosis, variceal hemorrhage, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepato-renal syndrome, emergency. RESULTS Main LC emergencies are upper gastrointestinal hemorrhage, decompensated ascites and spontaneous bacterial peritonitis, hepatic encephalopathy, hepato-renal syndrome. Their management is partly medical and interventional. Very often, the final cure of some complications, such as hepato-renal syndrome, is represented by liver transplantation. CONCLUSION Although LC prevalence is going to fall in the following years, due to HBV and HCV optimized treatments, its complications represent a significant admission percentage at the ER and challenge for physicians' skills.
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Affiliation(s)
- Emidio Scarpellini
- Internal Medicine Unit, "Madonna del Soccorso" General Hospital, San Benedetto del Tronto, Italy
| | | | - Gianluca Svegliati-Baroni
- Gastroenterology Clinic, "Riuniti University Hospital", Polytechnics University of Marche, Ancona, Italy
| | - Dan Dumitrascu
- Gastroenterology Unit, Cluj University, Cluj-Napoca, Romania
| | - Tiziana Larussa
- Department of Health Sciences, University "Magna Græcia", Catanzaro, Italy
| | - Valeria Santori
- Gastroenterology Clinic, "Riuniti University Hospital", Polytechnics University of Marche, Ancona, Italy
| | - Francesco Luzza
- Department of Health Sciences, University "Magna Græcia", Catanzaro, Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, University "Magna Græcia", Catanzaro, Italy
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48
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Velez JCQ, Therapondos G, Juncos LA. Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat Rev Nephrol 2019; 16:137-155. [PMID: 31723234 DOI: 10.1038/s41581-019-0218-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2019] [Indexed: 12/12/2022]
Abstract
The occurrence of acute kidney injury (AKI) in patients with end-stage liver disease constitutes one of the most challenging clinical scenarios in in-hospital and critical care medicine. Hepatorenal syndrome type 1 (HRS-1), which is a specific type of AKI that occurs in the context of advanced cirrhosis and portal hypertension, is associated with particularly high mortality. The pathogenesis of HRS-1 is largely viewed as a functional derangement that ultimately affects renal vasculature tone. However, new insights suggest that non-haemodynamic tubulo-toxic factors, such as endotoxins and bile acids, might mediate parenchymal renal injury in patients with cirrhosis, suggesting that concurrent mechanisms, including those traditionally associated with HRS-1 and non-traditional factors, might contribute to the development of AKI in patients with cirrhosis. Moreover, histological evidence of morphological abnormalities in the kidneys of patients with cirrhosis and renal dysfunction has prompted the functional nature of HRS-1 to be re-examined. From a clinical perspective, a diagnosis of HRS-1 guides utilization of vasoconstrictive therapy and decisions regarding renal replacement therapy. Patients with cirrhosis are at risk of AKI owing to a wide range of factors. However, the tools currently available to ascertain the diagnosis of HRS-1 and guide therapy are suboptimal. Short of liver transplantation, goal-directed haemodynamically targeted pharmacotherapy remains the cornerstone of treatment for this condition; improved understanding of the underlying pathogenic mechanisms might lead to better clinical outcomes. Here, we examine our current understanding of the pathophysiology of HRS-1 and existing challenges in its diagnosis and treatment.
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Affiliation(s)
- Juan Carlos Q Velez
- Department of Nephrology, Ochsner Clinic Foundation, New Orleans, LA, USA. .,Ochsner Clinical School, The University of Queensland, Brisbane, Australia.
| | - George Therapondos
- Department of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA, USA
| | - Luis A Juncos
- Division of Nephrology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.,Renal Section, Department of Medicine, Central Arkansas Veterans Affairs Medical Center, Little Rock, AR, USA
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Yan X, Shao R, Wang Y, Mao X, Lei J, Zhang L, Zheng J, Liu A, Zhao H, Gao F, Wang J, Li P, Yao S, Xu M, Xu J, Liu D, Mi Y, Gong X, Ye J, Deng M, Dang T, Ji J, Shao C, Liu C, Gu Y, Wu Y, Wang F, Teng G, Li X, Qi X, Ju S, Qi X. Functional magnetic resonance imaging-based assessment of terlipressin vs. octreotide on renal function in cirrhotic patients with acute variceal bleeding (CHESS1903): study protocol of a multicenter randomized controlled trial. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:586. [PMID: 31807567 PMCID: PMC6861789 DOI: 10.21037/atm.2019.09.141] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Acute variceal bleeding is one of the critical complications in patients with liver cirrhosis. Severe renal vasoconstriction in consequence of low peripheral vascular resistance triggers the reduction of glomerular filtration rate (GFR), and thus induces acute kidney injury (AKI)/hepato-renal syndrome (HRS). Terlipressin and octreotide have been used in the management of cirrhotic patients with variceal bleeding. Also, terlipressin has been recommended as the international first-line pharmacological therapy for the treatment of HRS. In addition, the use of renal functional magnetic resonance imaging (fMRI) has become increasingly prevalent in research and clinical applications. However, the renal function-protective effect of terlipressin and octreotide and the value of fMRI in monitoring renal function remains unclear in patients with cirrhosis undergoing acute variceal bleeding. METHODS This is a multicenter, randomized controlled trial (RCT). Participants will be 1:1 assigned randomly into either terlipressin or octreotide groups. Sixty participants with clinically and/or pathologically diagnosed cirrhosis and active gastroesophageal variceal bleeding (GVB) will be recruited in several sites in China. Participants will receive either the treatment of terlipressin or octreotide after assigned into each group. The primary end point for the trial is the renal function. The secondary end points are (I) renal perfusion; (II) renal blood oxygenation; (III) failure to control bleeding; (IV) intra-hospital rebleeding; (V) intra-hospital mortality; (VI) adverse events (AE); (VII) overall survival. Statistical analysis including multivariate Cox regression, Kaplan-Meier analysis with log-rank test, etc. will be conducted. DISCUSSION The study will provide new insight into the protection of renal function in the process of the treatment of variceal bleeding in patients with cirrhosis. TRIAL REGISTRATION NUMBER NCT04028323.
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Affiliation(s)
- Xinwen Yan
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Department of Hepatology Unit and Infectious Diseases, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ruoyang Shao
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Department of Hepatology Unit and Infectious Diseases, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuancheng Wang
- Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Xiaorong Mao
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Junqiang Lei
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Liting Zhang
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Jianjun Zheng
- Department of Radiology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo 315010, China
| | - Aimin Liu
- Department of Gastroenterology, Fuling Central Hospital of Chongqing City, Chongqing 404000, China
| | - Huimin Zhao
- CHESS Working Party, Xingtai People’s Hospital, Xingtai 054031, China
| | - Fengxiao Gao
- CHESS Working Party, Xingtai People’s Hospital, Xingtai 054031, China
| | - Jitao Wang
- CHESS Working Party, Xingtai People’s Hospital, Xingtai 054031, China
| | - Ping Li
- CHESS Working Party, Tianjin Second People’s Hospital, Tianjin 300192, China
| | - Shengjuan Yao
- CHESS Working Party, Tianjin Second People’s Hospital, Tianjin 300192, China
| | - Ming Xu
- Department of Gastroenterology, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Jian Xu
- Department of Hepatology & Translation Medicine, Fuling Center Hospital of Chongqing City, Chongqing 404000, China
| | - Dengxiang Liu
- CHESS Working Party, Xingtai People’s Hospital, Xingtai 054031, China
| | - Yuqiang Mi
- CHESS Working Party, Tianjin Second People’s Hospital, Tianjin 300192, China
| | - Xijun Gong
- Department of Radiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Jun Ye
- Department of Hepatology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Mingming Deng
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Tong Dang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou 014040, China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang Lishui, Lishui 323000, China
| | - Chuxiao Shao
- Department of Hepatobiliary and Pancreatic Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang Lishui, Lishui 323000, China
| | - Chao Liu
- CHESS Working Party, Hospital of Chengdu Office, People’s Government of Tibet Autonomous Region, Chengdu 610041, China
| | - Ye Gu
- Department of Gastroenterology, The Sixth Peoples Hospital of Shenyang, Shenyang 110006, China
| | - Yunhong Wu
- CHESS Working Party, Hospital of Chengdu Office, People’s Government of Tibet Autonomous Region, Chengdu 610041, China
| | - Fengmei Wang
- CHESS Working Party, Tianjin Second People’s Hospital, Tianjin 300192, China
| | - Gaojun Teng
- Department of Interventional Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Xun Li
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Xingshun Qi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110000, China
| | - Shenghong Ju
- Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Xiaolong Qi
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
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50
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Mattos ÂZ, Schacher FC, Mattos AA. Vasoconstrictors in hepatorenal syndrome - A critical review. Ann Hepatol 2019; 18:287-290. [PMID: 31023616 DOI: 10.1016/j.aohep.2018.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 12/31/2018] [Accepted: 12/31/2018] [Indexed: 02/04/2023]
Abstract
Hepatorenal syndrome has the worst prognosis among causes of acute kidney injury in cirrhotic patients. Its definitive treatment is liver transplantation. Nevertheless, considering its high short-term mortality rate and the shortage of liver grafts, a pharmacological treatment is of utmost importance, serving as a bridge to liver transplant. The clinical management of hepatorenal syndrome is currently based on the use of a vasoconstrictor in association with albumin. Terlipressin, noradrenaline and the combination of midodrine and octreotide could be used to treat hepatorenal syndrome. Among these options, terlipressin seems to gather the strongest body of evidence regarding efficacy and should be considered the first line of treatment whenever available and in the absence of contraindications. Treatment with a vasoconstrictor and albumin should be promptly initiated after the diagnosis of hepatorenal syndrome in order for patients to have higher chances of recovery.
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Affiliation(s)
- Ângelo Z Mattos
- Federal University of Health Sciences of Porto Alegre, Graduate Program in Medicine: Hepatology, Porto Alegre, Brazil; Irmandade Santa Casa de Misericórdia de Porto Alegre, Gastroenterology and Hepatology Unit, Porto Alegre, Brazil.
| | - Fernando C Schacher
- Irmandade Santa Casa de Misericórdia de Porto Alegre, Gastroenterology and Hepatology Unit, Porto Alegre, Brazil
| | - Angelo A Mattos
- Federal University of Health Sciences of Porto Alegre, Graduate Program in Medicine: Hepatology, Porto Alegre, Brazil; Irmandade Santa Casa de Misericórdia de Porto Alegre, Gastroenterology and Hepatology Unit, Porto Alegre, Brazil
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