What is the diagnosis and treatment of hepatorenal syndrome (HRS) from cirrhosis, including management of impaired renal function?

From the Guidelines

Hepatorenal syndrome (HRS) is a serious complication of cirrhosis that requires prompt diagnosis and treatment to improve morbidity, mortality, and quality of life, with first-line treatment being terlipressin (1-2 mg IV every 4-6 hours) plus albumin (20-40 g/day) for a maximum of 14 days, as recommended by the most recent guidelines 1.

Diagnosis of HRS

The diagnosis of HRS requires excluding other causes of acute kidney injury, including prerenal azotemia, acute tubular necrosis, and medication-induced nephrotoxicity. The diagnostic criteria include:

• Cirrhosis with ascites
• Serum creatinine >1.5 mg/dL
• No improvement in renal function after albumin challenge and diuretic withdrawal
• Absence of shock
• No recent nephrotoxic drugs
• No evidence of parenchymal kidney disease HRS is classified into type 1 (rapid progression) and type 2 (slower progression).

Treatment of HRS

Treatment focuses on vasoconstrictor therapy combined with albumin.

• First-line treatment is terlipressin (1-2 mg IV every 4-6 hours) plus albumin (20-40 g/day), continued until serum creatinine decreases to <1.5 mg/dL or for a maximum of 14 days 1.
• Alternatives include norepinephrine (0.5-3 mg/hour) with albumin, or midodrine (7.5-12.5 mg orally three times daily) plus octreotide (100-200 mcg subcutaneously three times daily) with albumin.
• Albumin is given at 1 g/kg on day 1, followed by 20-40 g/day.

Supportive Care and Prevention

Supportive care includes:

• Careful fluid management
• Avoiding nephrotoxic drugs
• Treating infections promptly
• Discontinuing diuretics Renal replacement therapy may be needed as a bridge to liver transplantation, which is the definitive treatment for HRS in eligible patients. Prevention strategies include:
• Prophylactic albumin during large-volume paracentesis
• Antibiotic prophylaxis for spontaneous bacterial peritonitis in high-risk patients

Recent Guidelines and Recommendations

Recent guidelines and recommendations from reputable sources such as the American Association for the Study of Liver Diseases (AASLD) 1 and the American Gastroenterological Association (AGA) 1 support the use of terlipressin and albumin as first-line treatment for HRS. These guidelines emphasize the importance of prompt diagnosis and treatment to improve outcomes in patients with HRS.

From the FDA Drug Label

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.

TERLIVAZ is a vasopressin receptor agonist indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.

Patients with a serum creatinine >5 mg/dL are unlikely to experience benefit

Diagnosis of Hepatorenal Syndrome (HRS):

• HRS is diagnosed based on a rapidly progressive worsening in renal function, as indicated by a serum creatinine (SCr) ≥2.25 mg/dL
• Patients must meet a trajectory for SCr to double over two weeks
• Diagnosis is also based on the absence of 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

Treatment of HRS:

• TERLIVAZ (terlipressin) is indicated to improve kidney function in adults with HRS with rapid reduction in kidney function
• The recommended dosage regimen is 0.85 mg (1 vial) intravenously every 6 hours for Days 1 to 3
• On Day 4, the dose may be increased to 1.7 mg (2 vials) intravenously every 6 hours if SCr has decreased by less than 30% from baseline
• Treatment is continued until 24 hours after two consecutive SCr ≤1.5 mg/dL values at least 2 hours apart or a maximum of 14 days

Important Considerations:

• Patients with a serum creatinine >5 mg/dL are unlikely to experience benefit from TERLIVAZ
• TERLIVAZ may cause serious or fatal respiratory failure, and patients with volume overload or ACLF Grade 3 are at increased risk
• Patients should be monitored for hypoxia using continuous pulse oximetry during treatment, and TERLIVAZ should be discontinued if SpO2 decreases below 90% 2, 2, 2

From the Research

Diagnosis of Hepatorenal Syndrome (HRS)

• HRS is a functional renal disorder that occurs in patients with advanced liver cirrhosis, characterized by impaired kidney function due to circulatory and hemodynamic alterations 3.
• The diagnosis of HRS is based on the presence of liver cirrhosis, impaired kidney function, and the absence of other causes of kidney dysfunction 3.
• Differential diagnosis with other causes of acute kidney injury (AKI) is crucial, and kidney biomarkers may be useful in this setting 3.

Treatment of HRS

• The treatment of HRS is based on the administration of vasoconstrictor drugs, such as terlipressin, midodrine, and octreotide, in combination with volume expansion with albumin 4, 5, 6.
• Terlipressin plus albumin has been shown to be more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS 4.
• The combination of octreotide, midodrine, and albumin has also been shown to improve survival and renal function in patients with HRS type 1 and type 2 6.
• Transjugular intrahepatic portosystemic stent shunt (TIPS) may be an effective treatment for type 1 HRS in suitable patients with cirrhosis and ascites, following the improvement of renal function with combination therapy of midodrine, octreotide, and albumin 5.

Management of Impaired Renal Function

• The management of impaired renal function in patients with HRS is crucial to improve outcomes 7, 6.
• A standardized approach to the treatment of HRS, including the use of albumin, midodrine, and octreotide, may improve treatment response rates and reduce the need for renal replacement therapy and liver transplantation 7.
• Liver transplantation or simultaneous liver-kidney transplantation is the ideal definitive treatment for HRS, and may improve prognosis and quality of life 3.

Differences in Ideologies and Other Important Things to Know

• There are different types of HRS, including acute kidney injury (HRS-AKI) and chronic kidney disease, which require different approaches to diagnosis and treatment 3.
• The prognosis of HRS-AKI is poor, and the ideal definitive treatment consists of liver transplantation or simultaneous liver-kidney transplantation 3.
• Developing preventive measures for HRS-AKI, improving its early identification, discovering new biomarkers for differential diagnosis, and improving the response to therapy are some of the unmet needs in the field of HRS-AKI 3.