Hepatorenal syndrome

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Hepatorenal syndrome (HRS) is a functional kidney injury in patients with decompensated cirrhosis and ascites. There are two subtypes: HRS-acute kidney injury (HRS-AKI) and HRS-nonacute kidney injury (HRS-NAKI). The pathophysiology involves splanchnic vasodilation and decreased effective arterial blood volume, leading to reduced glomerular filtration rate (GFR). Common risk factors include spontaneous bacterial peritonitis (SBP), gastrointestinal bleeding, and large volume paracentesis without albumin administration. Clinical features typically include signs of AKI (e.g., oliguria) and decompensated cirrhosis (e.g., ascites). Diagnosis involves evaluating for other causes of AKI and confirming specific criteria, including no improvement in kidney function after diuretic withdrawal and plasma volume expansion with albumin. Pharmacological treatment consists of intravenous albumin and vasoconstrictors (preferably terlipressin). Kidney replacement therapy may be used as a bridge to liver transplant in eligible patients; liver transplant is the only curative treatment.

• Hepatorenal syndrome (HRS): a functional kidney injury in patients with decompensated cirrhosis and ascites
• HRS-acute kidney injury (HRS-AKI)
  • AKI in patients with decompensated cirrhosis that persists despite diuretic withdrawal and plasma volume expansion with albumin and cannot be attributed to other causes of kidney disease
  • Formerly called type 1 HRS
  • See “Diagnostic criteria for HRS-AKI.”
• HRS-nonacute kidney injury (HRS-NAKI)
  • Kidney dysfunction in patients with decompensated cirrhosis that does not fulfill the diagnostic criteria for HRS-AKI
  • Formerly called type 2 HRS
  • Classified into two subtypes:
    • HRS-acute kidney disease (HRS-AKD): HRS-NAKI with an eGFR < 60 mL/min/1.73m² for < 3 months
    • HRS-chronic kidney disease (HRS-CKD): HRS-NAKI with an eGFR < 60 mL/min/1.73m² for ≥ 3 months

The prevalence of AKI in hospitalized patients with decompensated cirrhosis is 27–53%; HRS-AKI accounts for 15–43% of these cases.

Epidemiological data refers to the US, unless otherwise specified.

Risk factors for HRS include: ^[1]

• Infections (e.g., SBP) ^[2]
• Drainage of large volume ascites without concurrent albumin administration
• Gastrointestinal bleeding
• Nephrotoxin drugs (e.g., NSAIDs)
• Excessive use of diuretics and/or nonselective beta blockers
• Alcohol use

• The pathophysiology of HRS is not completely understood. ^[3]
• Cirrhosis and portal hypertension → ↑ splanchnic vasodilators (e.g., nitric oxide) → ↓ effective arterial blood volume → activation of vasoconstrictor systems (e.g., RAAS, sympathetic nervous system) → renal vasoconstriction → ↓ GFR → HRS

• Clinical features of AKI (e.g., oliguria or anuria)
• Clinical features of portal hypertension and decompensated cirrhosis

Approach ^[1]

• Obtain laboratory studies and imaging to:
  • Confirm diagnostic criteria of AKI
  • Evaluate for additional causes of AKI (e.g., infection, hypovolemia, nephrotoxins)
  • Assess for structural kidney disease (i.e., with urinalysis and renal ultrasound)
• Initiate IV albumin challenge (off-label). ^[1]
• Evaluate for diagnostic criteria for HRS-AKI.

In patients with cirrhosis, AKI can have multiple overlapping causes. ^[3]

Laboratory studies ^[1]

• BMP
• Urine studies: to differentiate between HRS-AKI and intrinsic kidney disease (e.g., acute tubular necrosis)
  • Urinalysis: bland urine sediment
  • Fractional excretion of sodium (FENa): typically < 0.1% in HRS-AKI ^[3]
  • Fractional excretion of urea: typically < 21% in HRS-AKI ^[3]
• Microbiological studies
  • Blood cultures
  • Urine cultures
  • Ascitic fluid cell count with differential and cultures: to evaluate for SBP (see "Peritoneal fluid analysis in SBP")

Imaging ^[1]

• Renal and bladder ultrasound: to assess kidney size and echogenicity and exclude kidney obstruction
• Chest x-ray: to assess for respiratory infection

Diagnostic criteria for HRS-AKI ^[1][2][5]

• Presence of cirrhosis with ascites
• Diagnostic criteria of AKI
• No improvement after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin ^[6]
• No signs of shock
• No current or recent use of nephrotoxic agents
• No signs of structural kidney disease

HRS-NAKI is not defined by discrete diagnostic thresholds; it is diagnosed in patients with functional kidney dysfunction and decompensated cirrhosis who do not meet criteria for HRS-AKI. ^[1]

Approach ^[1][7]

• Manage patients with HRS as part of a multisciplinary team.
• Start initial management of AKI in cirrhosis.
• Initiate pharmacological treatment for HRS-AKI if kidney injury persists despite initial management.
• Liver transplant may be necessary in patients with HRS-AKI refractory to pharmacological treatment.

Initial management of AKI in cirrhosis ^[7]

• Pause diuretics and nonselective beta blockers, if feasible.
• Discontinue nephrotoxic agents.
• Start broad-spectrum antibiotics if infection is suspected.
• Correct hypovolemia guided by volume status.
• Initiate IV albumin challenge (off-label) unless already started as part of the diagnostic workup of HRS. ^[1]

Monitor volume status closely due to the risk for pulmonary edema with excessive IV albumin administration. ^[1]

Pharmacological treatment for HRS-AKI ^[1]

• Albumin (off-label) ^[1]
• PLUS one of the following vasoconstrictors:
  • Terlipressin (preferred) : Adjust dose based on day 4 serum creatinine levels.
    • Creatinine decreased ≥ 30% from baseline: Continue terlipressin until 24 hours after two consecutive creatinine values ≤ 1.5 mg/dL (≥ 2 hours apart), or up to 14 days.
    • Creatinine decreased < 30% from baseline: Increase terlipressin until 24 hours after two consecutive creatinine values ≤ 1.5 mg/dL (≥ 2 hours apart), or up to 14 days.
    • Creatinine ≥ baseline: Discontinue terlipressin.
  • Norepinephrine (off-label) : titrated until MAP ≥ 10 mm Hg and/or urine output > 50 ml/hour for ≥ 4 hours ^[1]
  • Midodrine ; (off-label) PLUS octreotide (off-label) ^[1]

Terlipressin is contraindicated in patients with oxygen saturation < 90% and/or ongoing ischemia. Avoid terlipressin when serum creatinine is ≥ 5 mg/dL due to limited benefit. ^[1]

Monitor for ischemic complications (e.g., angina, peripheral ischemia) during vasoconstrictor use. ^[1]

Management of refractory HRS-AKI ^[1]

• Liver transplant is the only curative treatment.
• Kidney replacement therapy (KRT) may be considered as a bridging therapy to liver transplant in eligible patients.
• TIPS placement is not recommended.

• The 90-day mortality rate of HRS is ∼ 50%. ^[3]
• Patients with HRS are less likely to recover kidney function or discontinue KRT than patients with ATN in cirrhosis. ^[3]