Author Interviews, Hepatitis - Liver Disease, Kidney Disease / 14.12.2020
Hepatorenal Syndrome-Acute Kidney Injury: Predictors of Response to Terlipressin
MedicalResearch.com Interview with:
[caption id="attachment_56229" align="alignleft" width="133"] Dr. Moore[/caption]
Kevin Moore, MD
UCL Institute of Liver and Digestive Health
Royal Free Hospital, University College London
MedicalResearch.com: What is hepatorenal syndrome – acute kidney injury (HRS-AKI) and how does terlipressin fit into the treatment landscape?
Response: HRS-AKI, also known as hepatorenal syndrome type 1 (HRS-1), is an acute and life-threatening syndrome involving acute kidney failure in people with cirrhosis.[i] HRS-1 can progress to life-threatening renal failure within daysi and has a median survival time of approximately two weeks and greater than 80 percent mortality within three months if left untreated.[ii],[iii]
Terlipressin, a potent vasopressin analogue selective for V1 receptors, is an investigational agent, and its safety and effectiveness have not yet been established by the U.S. Food and Drug Administration. In the U.S., there are currently no approved pharmacologic treatments for HRS-1; however, terlipressin is approved in most other countries, where it has been a standard of care for the last 20 years in the treatment of patients with HRS-1.[iv],[v]
The current standard of care for HRS-1 in the U.S. includes other vasoconstrictors such as midodrine (a drug which can increase blood pressure and potentially improve blood flow into the kidneys) along with concomitant albumin and frequent monitoring, but current data do not support good efficacy.2 Dialysis (a type of renal replacement therapy) is sometimes used in hepatorenal syndrome, but dialysis is not curative and it can be costly.
Dr. Moore[/caption]
Kevin Moore, MD
UCL Institute of Liver and Digestive Health
Royal Free Hospital, University College London
MedicalResearch.com: What is hepatorenal syndrome – acute kidney injury (HRS-AKI) and how does terlipressin fit into the treatment landscape?
Response: HRS-AKI, also known as hepatorenal syndrome type 1 (HRS-1), is an acute and life-threatening syndrome involving acute kidney failure in people with cirrhosis.[i] HRS-1 can progress to life-threatening renal failure within daysi and has a median survival time of approximately two weeks and greater than 80 percent mortality within three months if left untreated.[ii],[iii]
Terlipressin, a potent vasopressin analogue selective for V1 receptors, is an investigational agent, and its safety and effectiveness have not yet been established by the U.S. Food and Drug Administration. In the U.S., there are currently no approved pharmacologic treatments for HRS-1; however, terlipressin is approved in most other countries, where it has been a standard of care for the last 20 years in the treatment of patients with HRS-1.[iv],[v]
The current standard of care for HRS-1 in the U.S. includes other vasoconstrictors such as midodrine (a drug which can increase blood pressure and potentially improve blood flow into the kidneys) along with concomitant albumin and frequent monitoring, but current data do not support good efficacy.2 Dialysis (a type of renal replacement therapy) is sometimes used in hepatorenal syndrome, but dialysis is not curative and it can be costly. 
Dr. LaMoreaux[/caption]
Brian LaMoreaux, M.D., M.S.
Medical Director, Medical Affairs
Horizon Therapeutics
MedicalResearch.com: What is the background for this study?
Response: Hyperuricemia is associated with non-alcoholic fatty liver disease (NAFLD) but the relationship to fibrosis remains uncertain. Moreover, it is not known whether lowering serum urate will affect the course of NAFLD.
Dr. Hui Wang[/caption]
Prof Hui Wang PhD
Wuhan University
China
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: We started our work in the adverse outcome of maternal caffeine intake during pregnancy about 15 years ago. Then, we found that prenatal caffeine intake could result in nonalcoholic fatty liver disease in the offspring. However, the underlying mechanism was unclear.
So, we start the current work, and found that hat maternal caffeine intake disrupts liver development before and after birth, which might be the trigger of the adult non-alcoholic fatty liver disease in the offspring rats. Moreover, we further found that the fetal programming of liver glucocorticoid – insulin like growth factor 1 axis, a new endocrine axis first reported by our team, might participate in such process.
Dr. Kenneth Cusi[/caption]
Kenneth Cusi, M.D., F.A.C.P., F.A.C.E.
Professor of Medicine
VAMC staff
Chief, Division of Endocrinology, Diabetes and Metabolism
The University of Florida
Gainesville, FL 32610-0226
MedicalResearch.com: What is the background for this study?
Dr. Cusi: Many patients with prediabetes or Type 2 Diabetes Mellitus (T2DM) are not diagnosed with Nonalcoholic steatohepatitis (NASH), a disease that is the second cause of liver transplantation in the United States. It is also associated with worse cardiovascular disease and harder to control T2DM. We had done in this population a proof-of-concept study published in Nov 2006 in the NEJM. But we lacked a larger, long-term study for definitive proof. This is the largest SINGLE center study, and the longest ever (3 years).
NASH is an overlooked problem for perhaps as many as one-third of patients with Type 2 Diabetes Mellitus. There is now a safe and effective treatment option for patients with T2DM and NASH – pioglitazone will become for NASH what metformin is to the treatment of T2DM: a safe, effective, the “backbone therapy" to which other treatments will be added.
Dr. Sikarin Upala[/caption]
Sikarin Upala MD, MS, LLB
Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, New York
Preventive and Social Medicine
Mahidol University, Bangkok, Thailand
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Upala: Chronic hepatitis C virus infection is the most common cause of chronic liver disease and cirrhosis as well as the most common cause of liver transplantation in the United States. As caffeine has been found to be related to decreased liver enzymes, chronic liver disease,cirrhosis, and risk of hepatocellular carcinoma in several liver disease pathologies. There is inconclusive findings on the effect of caffeine on hepatitis C infected patients. Thus, we conducted a systematic review and meta-analysis to summarize the effect of caffeine consumption in patients with chronic hepatitis C.
We found that caffeine consumers have a 61% reduced risk of developing advanced hepatic fibrosis, which is one of the consequence of chronic hepatitis C. Our meta-analysis result is in the same way with other studies who found that coffee consumption could prevent the development of hepatic fibrosis in patients with liver disease. However, we cannot conclude about the effect of caffeine on HCV viral load as there is not enough information.
Dr. Annette Schürmann[/caption]
Prof-Dr. Annette Schürmann
Department of Experimental Diabetology
German Institute of Human Nutrition Potsdam-Rehbruecke
Nuthetal, Germany
MedicalResearch.com: What is the background for this study?
Dr. Schürmann: The aim of our study was to clarify why genetically identical mice respond very different to a high fat diet. Some of the mice react with an elevated body weight, others not. We analyzed the expression pattern
of liver at two time points, at the age of 6 weeks, (the earliest time
point to distinguish between those that respond to the diet (responder
mice) and those that did not (non-responders)), and at the age of 20
weeks. One transcript that was significantly reduced in the liver of
responder mice at both time points was Igfbp2. The reason for the
reduced expression was an elevated DNA-methylation at a position that is
conserved in the mouse and human sequence. The elevated DNA-methylation
of this specific site in human was recently described to associate with
elevated fat storage (hepatosteatosis) and NASH. However, as 6 weeks old
mice did not show differences in liver fat content between responder and
non-responder mice we conclude that the alteration of Igfbp2 expression
and DNA methylation occurs before the development of fatty liver.
Our data furthermore showed that the epigenetic inhibition of Igfbp2
expression was associated with elevated blood glucose and insulin
resistance but not with fatty liver.
Dr. Curry[/caption]
MedicalResearch.com Interview with:
Dr. Michael P. Curry, MD
Medical Director for Liver Transplantation
Harvard Medical Faculty Physicians
Beth Israel Deaconess Medical Center
Medical Research: What is the background for this study? What are the main findings
Dr. Curry: As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. For many years, the only treatment option for these patients was liver transplantation. Recently, however, clinical trials of newly approved direct-acting antiviral agents (DAAs) have shown that it is possible to treat HCV infection safely and effectively in patients with decompensated cirrhosis. We conducted this Phase 3, open-label trial to assess the efficacy and safety of a fixed dose combination of sofosbuvir/velpatasvir with or without ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks in patients infected with hepatitis C virus genotypes 1 through 6 and with decompensated cirrhosis. We found that treatment with sofosbuvir/velpatasvir resulted in high rates of sustained virologic response (SVR) and early improvements in hepatic function in this patient population. SVR rates were 83 percent in patients who received sofosbuvir/velpatasvir for 12 weeks, 94 percent among those who received sofosbuvir/velpatasvir plus ribavirin, and 86 percent among those who received sofosbuvir/velpatasvir for 24 weeks.
