What is Hepatorenal Syndrome (HRS), a type of progressive kidney dysfunction (Impaired Renal Function)?

From the Guidelines

Hepatorenal syndrome (HRS) should be treated with terlipressin, a vasopressin analog, as the first-line vasoconstrictor therapy, given its ability to reverse splanchnic vasodilatation and improve renal function, as evidenced by a response rate of 36-44% in randomized controlled trials 1. The treatment of HRS aims to improve circulatory function and reduce mortality, with vasoconstrictor medications being the mainstay of pharmacological treatment.

• The use of terlipressin has been shown to be effective in reversing HRS, with a response rate of 36-44% in randomized controlled trials, and is associated with a 27% reduction in the relative risk for mortality for every 1-mg/dL drop in serum creatinine 1.
• Predictors of response to terlipressin include a baseline bilirubin of <10 mg/dL, a baseline serum creatinine of <5 mg/dL, and lower stage of acute-on-chronic liver failure, as well as a sustained increase in mean arterial pressure (MAP) by 5-10 mm Hg with treatment 1.
• Terlipressin is typically administered as intravenous bolus doses at 1-2 mg every 6 hours for up to 14 days, but can be discontinued if there is no response on day 3 or 4, and continuous infusion has similar efficacy with lower total daily dose and fewer side effects 1.
• Norepinephrine and midodrine are alternative vasoconstrictor agents that can be used if terlipressin is unavailable, with norepinephrine improving renal function in 39-70% of patients in small randomized controlled trials 1.
• Patients with HRS require close monitoring of fluid status, electrolytes, and renal function, and dialysis may serve as a bridge to liver transplantation, which is the definitive treatment 1.

From the FDA Drug Label

TERLIVAZ is a vasopressin receptor agonist indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function. The efficacy of TERLIVAZ was assessed in a multicenter, double-blind, randomized, placebo-controlled study (CONFIRM) (NCT02770716). Patients with cirrhosis, ascites, and a diagnosis of HRS-1 with a rapidly progressive worsening in renal function to a serum creatinine (SCr) ≥2.25 mg/dL and meeting a trajectory for SCr to double over two weeks, and without sustained improvement in renal function (<20% decrease in SCr and SCr ≥2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin were eligible to participate.

Hepatorenal Syndrome Treatment: Terlipressin (IV) is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function 2.

• The primary efficacy endpoint was the incidence of Verified HRS Reversal, defined as the percentage of patients with 2 consecutive SCr values of ≤1.5 mg/dL, obtained at least 2 hours apart while on treatment by Day 14 or discharge.
• A greater proportion of patients achieved Verified HRS Reversal in the TERLIVAZ arm compared to the placebo arm 2. Key Points:
• Terlipressin is a vasopressin receptor agonist.
• It is used to improve kidney function in adults with hepatorenal syndrome.
• The medication has been shown to be effective in achieving Verified HRS Reversal in patients with HRS-1 2.

From the Research

Definition and Pathophysiology of Hepatorenal Syndrome

• Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems, and extreme kidney vasoconstriction leading to decreased GFR 3.
• The pathophysiologic cascade that leads to hepatorenal syndrome begins with pooling of blood in the splanchnic system, resulting in a decrease in effective circulating arterial volume 4.
• Systemic inflammation, a key feature of cirrhosis, contributes to the development of hepatorenal syndrome, but the mechanisms by which it precipitates kidney circulatory changes need to be clarified 3.

Diagnosis and Treatment of Hepatorenal Syndrome

• Early diagnosis is central in the management of hepatorenal syndrome, and recent changes in the definition help identify patients at an earlier stage 3.
• Vasoconstrictive agents (terlipressin in particular) and albumin are the first-line treatment option for hepatorenal syndrome 3, 4.
• Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with hepatorenal syndrome 5.
• Norepinephrine can be effectively used in a non-ICU setting as rescue therapy in patients who have not responded to midodrine and octreotide 6.
• A standardized approach with albumin, midodrine, and octreotide may improve treatment response rates and reduce the need for renal replacement therapy and liver transplantation 7.

Prognosis and Outcomes

• Liver transplantation is the only curative treatment of hepatorenal syndrome, and patients transplanted with hepatorenal syndrome tend to have lower GFR compared with patients without hepatorenal syndrome 3.
• Even with treatment, early mortality rates are very high in the absence of liver transplantation, and not all patients respond to treatment 3, 5.
• Achieving an increase in mean arterial pressure is associated with a greater probability of response to treatment, and improvement in renal function and lower baseline Model for End-Stage Liver Disease score are associated with better survival 5, 6.