Hepatorenal Syndrome: Do the Vasoconstrictors Work?

Hepatorenal syndrome (HRS) is a potentially reversible clinical syndrome that occurs in patients with cirrhosis, ascites and liver failure, as well as in patients with acute liver failure or alcoholic hepatitis. It is characterized by impaired renal function, marked alterations in cardiovascular function and overactivity of the sympathetic nervous (SNS) and renin–angiotensin–aldosterone systems.

The incidence of functional renal failure including HRS in nonazotemic patients with cirrhosis after the onset of ascites is estimated to be 23.6% at 1 year and 42% by 5 years. Older age, higher Child–Pugh score, and higher baseline creatinine are strong predictors for the development functional renal failure including HRS, reflecting that a longer duration of disease, and more severe liver and renal dysfunction are strong risk factors for the development of HRS.

The diagnosis of HRS must be based on excluding other causes of acute kidney injury, because there are no specific tests for the syndrome. The HRS is diagnosed by a serum creatinine higher than 1.5 mg/dL (133 μmol/L) after the exclusion of reversible functional renal failure with volume expansion using albumin at a dose of 1 g/kg body weight (maximum 100 g/d), and withdrawal of diuretic therapy for at least 2 days. The diagnostic criteria of HRS were updated by the International Ascites Club in 2007 ( Box 1 ).

Box 1

Cirrhosis with ascites.

Serum creatinine >133 μmol/L (1.5 mg/dL).

No improvement of serum creatinine (decrease to a level of ≤133 μmol/L) after ≥2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/d.

Absence of shock.

No current or recent treatment with nephrotoxic drugs.

Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/d, microhematuria (>50 red blood cells per high power field), and/or abnormal renal ultrasonography.

Criteria for diagnosis of HRS in cirrhosis

Data from Salerno F, Gerbes A, Ginès P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–8.

Clinically, there are 2 types of HRS, each with different clinical presentation and different prognostic implications. Type 1 HRS (HRS-1) is a rapidly progressive acute renal failure that occurs in cirrhosis and ascites either spontaneously or in the context of various precipitating factors ( Box 2 ). HRS-1 is diagnosed when the serum creatinine doubles from baseline to a level higher than 2.5 mg/dL (221 μmol/L) in less than 2 weeks. The patient is usually very ill with jaundice and marked coagulopathy. If untreated, median survival is several days. In contrast, type 2 HRS (HRS-2) occurs in patients with cirrhosis and refractory ascites, and the renal function slowly deteriorates over the course of weeks to months as reflected by a chronic, slowly progressive rise in serum creatinine eventually reaching 1.5 mg/dL (133 μmol/L). Because the major clinical problem in patients with HRS-2 is refractory ascites, they are usually less ill with lesser degrees of liver dysfunction. Their prognosis is therefore slightly better than patients with HRS-1 with median survival of several weeks to months.

Box 2

Spontaneous bacterial peritonitis.

Other bacterial infections.

Intravascular volume depletion: Overly rapid diuresis, excess vomiting, gastrointestinal bleeding.

Large volume paracentesis without adequate intravascular volume replacement.

Nephrotoxic drugs including radiocontrast dye.

Surgical jaundice.

Common precipitants for type I HRS

Recent recognition that serum creatinine may underestimate the severity of renal dysfunction has led to the proposal to diagnose renal dysfunction in cirrhosis with lower levels of serum creatinine than traditionally recognized ( Table 1 ). This is because even smaller rises of serum creatinine have been associated with poorer prognosis both in patients with cirrhosis and ascites and in those without underlying liver disease. If accepted, this will allow patients with cirrhosis and renal dysfunction to be treated at an earlier stage of renal impairment, potentially improving their overall prognosis.

Table 1

Proposed diagnostic criteria of kidney dysfunction in cirrhosis

Diagnosis	Definition
Acute kidney injury	A rise in serum creatinine of ≥50% from baseline, or a rise of serum creatinine by ≥0.3 mg/dL (≥26.4 μmol/L) in <48 hours. HRS type I is a specific form of acute kidney injury.
Chronic kidney disease	Glomerular filtration rate of <60 mL/min for >3 mos calculated using the MDRD6 formula. HRS type II is a specific form of chronic kidney disease.
Acute-on-chronic kidney disease	Rise in serum creatinine of ≥50% from baseline or a rise of serum creatinine by ≥0.3 mg/dL (≥26.4 μmol/L) in <48 hours in a patient with cirrhosis whose glomerular filtration rate is <60 mL/min for >3 mos calculated using the MDRD6 formula.