What is the relationship between Hepatorenal Syndrome (HRS) and Acute Kidney Injury (AKI)?

From the Guidelines

Hepatorenal syndrome acute kidney injury (HRS-AKI) should be treated with terlipressin plus albumin as the first-line therapeutic option, as recommended by the most recent and highest quality study 1.

Treatment Approach

The treatment approach for HRS-AKI involves improving effective arterial blood volume and reversing splanchnic vasodilation.

• Albumin infusion should be started immediately, with a dose of 1 g/kg on day 1, followed by 20-40 g/day.
• Terlipressin, a vasopressin analog, should be administered at an initial dose of 1-2 mg IV every 4-6 hours, titrated up to 12 mg/day if needed, and combined with albumin for 3-14 days until kidney function improves.

Alternative Options

Alternative vasopressor therapies include:

• Norepinephrine (0.5-3 mg/hour continuous infusion)
• The combination of midodrine (7.5-12.5 mg orally three times daily) plus octreotide (100-200 mcg subcutaneously three times daily)

Monitoring and Precautions

Patients should be monitored for:

• Fluid status
• Electrolytes
• Vasopressor side effects, including cardiac arrhythmias and ischemic complications Discontinue diuretics, nephrotoxic medications, and NSAIDs. Maintain mean arterial pressure above 65 mmHg and avoid excessive paracentesis without albumin replacement.

Definitive Treatment

The definitive treatment for eligible patients is liver transplantation, as it addresses the underlying liver dysfunction that triggers the pathophysiological cascade, as supported by the EASL clinical practice guidelines 1.

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.

A greater proportion of patients achieved Verified HRS Reversal in the TERLIVAZ arm compared to the placebo arm (Table 2).

Terlipressin is thought to increase renal blood flow in patients with hepatorenal syndrome by reducing portal hypertension and blood circulation in portal vessels and increasing effective arterial volume and mean arterial pressure (MAP).

Hepatorenal Syndrome (HRS) and Acute Kidney Injury (AKI):

• Terlipressin (TERLIVAZ) is used to treat Hepatorenal Syndrome Type 1 (HRS-1), a type of AKI that occurs in patients with advanced liver disease.
• The CONFIRM study demonstrated that terlipressin increased the incidence of Verified HRS Reversal compared to placebo in patients with HRS-1.
• The mechanism of action of terlipressin involves increasing renal blood flow by reducing portal hypertension and increasing effective arterial volume and mean arterial pressure (MAP).
• Key points about terlipressin and HRS/AKI include:
  • Terlipressin is a vasopressin receptor agonist that acts as a prodrug for lysine-vasopressin.
  • The drug is administered as an IV bolus injection every 6 hours for a maximum of 14 days.
  • Patients with baseline serum creatinine >7.0 mg/dL, shock, sepsis, and/or uncontrolled bacterial infection were excluded from the study.
  • The use of vasopressors was prohibited during the treatment period.
  • The study results suggest that terlipressin may be an effective treatment for HRS-1, a type of AKI that is associated with high mortality rates 2.

From the Research

Definition and Pathophysiology of Hepatorenal Syndrome-AKI

• Hepatorenal syndrome-acute kidney injury (HRS-AKI) occurs in the setting of advanced chronic liver disease, portal hypertension, and ascites 3.
• The pathophysiologic cascade that leads to HRS begins with pooling of blood in the splanchnic system, resulting in a decrease in effective circulating arterial volume 4.
• HRS-AKI is characterized by a severe impairment of kidney function owing to vasoconstriction of the renal arteries in the absence of substantial abnormalities in kidney histology 5.

Diagnosis of HRS-AKI

• The diagnosis of AKI-HRS is a challenge because of a lack of specific diagnostic tools and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis 5.
• Novel biomarkers such as urinary neutrophil gelatinase-associated lipocalin may be useful in the diagnosis of HRS-AKI 3.

Treatment of HRS-AKI

• The mainstay of therapy is a vasoconstrictor (terlipressin or norepinephrine) combined with albumin, which achieves resolution of HRS in 40-50% of cases 3.
• Norepinephrine plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with hepatorenal syndrome 6.
• Liver transplantation is the only option for patients failing to respond to medical therapies 3, 4.
• Transjugular intrahepatic portosystemic stent shunt (TIPS) is 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 7.

Prognosis and Prevention of HRS-AKI

• The prognosis of patients with AKI-HRS is poor, with a median survival of ≤3 months 5.
• Effective measures to prevent AKI-HRS include early identification and treatment of bacterial infections and the administration of albumin in patients with spontaneous bacterial peritonitis 5.