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Hepatorenal syndrome (HRS) is one of the most ominous complications of portal hypertension in patients with decompensated cirrhosis and ascites. It is associated with very high mortality on the wait list. Liver transplantation (LT) is the most successful therapeutic option for patients with HRS. However, not all the LT candidates with HRS are able to receive a deceased donor allograft in a timely manner because it is a scarce resource and patients may need alternative best supportive treatment with systemic splanchnic vasoconstrictors and albumin as a bridge to transplant. The combination of terlipressin and albumin is efficacious in the reversal of HRS and is used worldwide. More recently, the multicenter, randomized, placebo-controlled double-blind study to confirm efficacy and safety of terlipressin in subjects with hepatorenal syndrome type 1 (the CONFIRM study) trial demonstrated the efficacy of terlipressin and albumin in the reversal of HRS in a North American cohort. The aim of this article is to review the role of terlipressin and albumin in LT candidates with HRS in the United States., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background: Hepatorenal syndrome and acute kidney injury are common complications of decompensated cirrhosis, and terlipressin is recommended as first-line vasoconstrictor therapy. However, data on its use outside of clinical trials are lacking., Aims: To assess practice patterns and outcomes around vasoconstrictor use for hepatorenal syndrome in UK hospitals., Methods: This was a multicentre chart review study. Data were extracted from medical records of patients diagnosed with hepatorenal syndrome and treated by vasoconstrictor drugs between January 2013 and December 2017 at 26 hospitals in the United Kingdom. The primary outcome was improvement of kidney function, defined as complete response (serum creatinine improved to ≤1.5 mg/dL), partial response (serum creatinine reduction of ≥20% but >1.5 mg/dL) and overall response (complete or partial response). Other outcomes included need for dialysis, mortality, liver transplantation and adverse events., Results: Of the 225 patients included in the analysis, 203 (90%) were treated with terlipressin (median duration, 6 days; range: 2-24 days). Mean (±standard deviation) serum creatinine at vasopressor initiation was 3.25 ± 1.64 mg/dL. Terlipressin overall response rate was 73%. Overall response was higher in patients with mild acute kidney injury (baseline serum creatinine <2.25 mg/dL), compared to those with moderate (serum creatinine ≥2.25 mg/dL and <3.5 mg/dL) or severe (serum creatinine ≥3.5 mg/dL). Ninety-day survival was 86% for all patients (93% for overall responders vs 66% for treatment nonresponders, P < 0.0001)., Conclusion: Terlipressin is the most commonly prescribed vasoconstrictor for patients with hepatorenal syndrome in the United Kingdom. Treatment with terlipressin in patients with less severe acute kidney injury (serum creatinine <2.25 mg/dL) was associated with higher treatment responses, and 90-day survival., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: It has been proposed that activation of the sympathetic nervous system causes a rightward shift in the renal autoregulatory curve such that renal blood flow is critically dependent on renal perfusion pressure and that this contributes to the development of the hepatorenal syndrome. The aims of the study were to determine the relationship of renal blood flow and renal perfusion pressure in patients with liver cirrhosis and the effect on renal hemodynamics following insertion of a transjugular intrahepatic portosystemic shunt (TIPS)., Methods: Fifty-six patients were recruited into groups (1) with no ascites, (2) with diuretic-responsive ascites, (3) with intractable ascites, (4) with type II hepatorenal syndrome, and (5) requiring a TIPSs for refractory ascites. We measured cardiac hemodynamics, renal blood flow, renal perfusion pressure, and portal pressure and norepinephrine levels and mathematically modeled the renal autoregulatory curve., Results: Renal blood flow correlated with renal perfusion pressure (r(2) = 0.78; P < .001) and inversely with the hepatic venous pressure gradient (r(2) = 0.61; P < .0001) and plasma norepinephrine levels (r(2) = 0.78; P < .0001). Norepinephrine levels increased with increasing disease severity, and this was associated with a rightward and downward shift of the renal blood flow/renal perfusion pressure autoregulatory curve. TIPS insertion reduced portal pressure and plasma norepinephrine levels (P < .001), and the renal blood flow/renal perfusion pressure curve was shifted upward., Conclusions: The relationship between renal blood flow and renal perfusion pressure involves a critical interplay between the sympathetic nervous system and the kidney. TIPS insertion decreases sympathetic activation and improves renal function through positive effects on renal blood flow autoregulation.

Unlabelled: Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 +/- 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at approximately 4 days because of concerns about worsening renal function (serum creatinine increased from 180 +/- 21 to 222 +/- 58 micromol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 +/- 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 +/- 0.3 pg/mL at the baseline to 19.1 +/- 7.3 pg/mL (P < 0.05)., Conclusion: An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients.

Background Patients with cirrhosis frequently develop renal dysfunction, a proportion of who do not fulfill criteria for hepatorenal syndrome ( HRS). We hypothesized that the kidneys in these patients would exhibit histological and biomarker evidence of kidney injury. We looked specifically for TLR expression as they may mediate kidney injury. Methods Sixty seven subjects (6); alcoholic cirrhosis: compensated (9), acute deterioration of alcoholic cirrhosis (52)] were included. Renal dysfunction was defined as a creatinine of >133 μmol/L and/or according to the AKI network criteria. Urinary biomarkers, KIM-1, π GST, α GST and a novel biomarker, urinary TLR4 were measured. Renal biopsies were also available from eight other alcoholic cirrhosis patients (three non- HRS renal dysfunction; five HRS) that were stained for TLR4 and caspase-3. Results Fourteen patients developed renal dysfunction, amongst these three had type 2 HRS. KIM-1, π GST and α GST were higher in patients with acute deterioration of cirrhosis compared with patients with compensated cirrhosis, but did not differ between those with and without renal dysfunction. Urinary TLR4 was significantly higher in patients with renal dysfunction associated with infection/inflammation. Kidney biopsies from non- HRS renal dysfunction patients showed tubular damage with evidence of increased tubular expression of TLR4, and caspase-3. Minor changes were observed in HRS patients. Conclusions The data provide proof of concept that renal dysfunction in patients with cirrhosis with superimposed inflammation is associated with significant tubular injury and apoptosis and with increased renal expression and urinary excretion of the TLR4, suggesting a potential role of TLR4 as mediator of renal injury. [ABSTRACT FROM AUTHOR]

The liver has been central to our understanding of the physiology and biology of the F2-isoprostanes. The discovery of F2-IsoPs and the initial demonstration that they could be used to localize oxidative stress was first demonstrated in a rat model of oxidative liver injury (carbon tetrachloride), and the first demonstration that plasma concentrations are increased in a human disease was in patients with liver failure and the hepatorenal syndrome [J. Clin. Invest. 90 (6) (1992b) 2502; J. Lipid Mediat. 6 (1/3) (1993) 417]. This article will cover the measurement of F2-IsoPs as markers of lipid peroxidation in vivo in liver disease, and review their biological activity as mediators of disease. [Copyright &y& Elsevier]

Leukotrienes are potent biological mediators implicated in an increasing number of disease processes. This review outlines the basic biology of leukotrienes and discusses recent developments in our understanding of the specific role of cysteinyl-leukotrienes (cLTs) in cholestasis, hepatic inflammation, portal hypertension, and the pathogenesis of the hepatorenal syndrome (HRS). [Copyright &y& Elsevier]

Hepatorenal syndrome may occur in any form of severe liver disease. It appears less common in children than adults, but still carries a poor prognosis. There are several factors involved in its aetiology, including a decreased renal perfusion pressure, activation of the renal sympathetic nervous system and increased synthesis of several vasoactive mediators, which may modulate glomerular filtration by acting as both renal vasoconstrictors and dynamic regulators of the glomerular capillary ultrafiltration coefficient, through their action on mesangial cells. This review will discuss the pathophysiology of the hepatorenal syndrome and some of the principles of management of patients with renal failure and severe liver disease. The role of renal support and liver transplantation will also be covered. [ABSTRACT FROM AUTHOR]

Presents evidence regarding the effects of N-acetylcysteine (NAC) therapy on patients with hepatorenal syndrome (HRS). HRS as the development of renal failure in patients with severe liver disease; How further clinical studies are needed to fully evaluate the effects of NAC in treating HRS.