What is the recommended management of hepatorenal syndrome, including albumin and vasoconstrictor dosing and criteria for TIPS or liver transplantation?

Management of Hepatorenal Syndrome

Terlipressin 1 mg IV every 4-6 hours plus albumin 1 g/kg (maximum 100 g) on day 1, followed by 20-40 g/day, is the first-line treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI), with dose escalation to 2 mg every 4 hours if serum creatinine fails to decrease by at least 25% after 3 days. 1, 2, 3

Diagnostic Confirmation

Before initiating treatment, confirm HRS-AKI diagnosis by ensuring all of the following criteria are met: 1, 3

• Cirrhosis with ascites
• Serum creatinine >1.5 mg/dL or AKI stage ≥2 (creatinine increase ≥0.3 mg/dL within 48 hours or ≥50% from baseline)
• No improvement after 2 consecutive days of diuretic withdrawal and volume expansion with albumin
• Absence of shock, nephrotoxic drug exposure, or structural kidney disease (proteinuria <0.5 g/day, no microhematuria <50 RBCs/HPF, normal renal ultrasound)

Perform diagnostic paracentesis immediately to exclude spontaneous bacterial peritonitis, which precipitates HRS in a significant proportion of cases. 1, 3, 4

First-Line Pharmacological Treatment: Terlipressin Plus Albumin

Dosing Protocol

Start terlipressin 1 mg IV bolus every 4-6 hours (equivalent to 0.85 mg terlipressin acetate) plus albumin. 1, 2, 5 Albumin dosing: 1 g/kg (maximum 100 g) on day 1, then 20-40 g/day thereafter. 1, 2, 3

On day 3-4, if serum creatinine has not decreased by at least 25-30% from baseline, increase terlipressin to 2 mg every 4 hours (maximum 12 mg/day). 1, 5 If serum creatinine remains at or above baseline on day 4, discontinue treatment. 5

Alternative Continuous Infusion

Terlipressin can be administered by continuous IV infusion at an initial dose of 2 mg/day, which reduces the total daily dose and adverse effects compared to bolus dosing. 1

Treatment Duration and Response

Continue treatment until serum creatinine decreases to ≤1.5 mg/dL or for a maximum of 14 days. 2, 3, 5 Complete response is defined as two consecutive serum creatinine values ≤1.5 mg/dL obtained at least 2 hours apart. 1, 5 The median time to response is 14 days. 3, 4

In the CONFIRM trial, terlipressin achieved verified HRS reversal in 29.1% of patients versus 15.8% with placebo (p=0.012). 5 Response rates of 64-76% have been reported in other studies. 3

Predictors of Response

Favorable response is more likely with: 1, 3, 4

• Baseline serum creatinine <3 mg/dL
• Serum bilirubin <10 mg/dL
• Mean arterial pressure increase ≥5 mmHg during treatment
• Lower MELD score and Child-Pugh score <13
• Younger age

Contraindications and Adverse Events

Terlipressin is absolutely contraindicated in patients with active coronary, peripheral, or mesenteric ischemia. 3 Common ischemic adverse events include angina, arrhythmias, and digital ischemia. 3 Perform electrocardiogram before starting treatment. 1

Patients with ACLF Grade 3 treated with terlipressin are at risk for respiratory failure, particularly if there is pretreatment respiratory compromise. 6 In the CONFIRM trial, approximately 30% of terlipressin-treated patients experienced respiratory failure. 3

Alternative Vasoconstrictor Regimens

Norepinephrine Plus Albumin

When terlipressin is unavailable or contraindicated, norepinephrine 0.5-3 mg/hour IV continuous infusion plus albumin is equally effective. 1, 3, 6 Start at 0.5 mg/hour and titrate every 4 hours to increase mean arterial pressure by 10-15 mmHg. 3, 4

Norepinephrine requires central venous access and ICU-level monitoring. 1, 3 Attempting peripheral administration risks tissue necrosis. 3

Midodrine Plus Octreotide Plus Albumin

In regions where terlipressin and norepinephrine are unavailable, use midodrine plus octreotide plus albumin, though efficacy is substantially lower than terlipressin. 1, 2

Dosing: 2, 3

• Midodrine: Start 7.5 mg orally three times daily, titrate up to 12.5 mg three times daily
• Octreotide: 100-200 μg subcutaneously three times daily
• Albumin: 10-20 g IV daily for up to 20 days

This regimen can be administered outside the ICU and even at home, but its efficacy is much lower than terlipressin. 1, 3

Special Consideration: Ischemic Heart Disease

In patients with known ischemic heart disease, the combination of midodrine, octreotide, and albumin is preferred because terlipressin is contraindicated in active coronary ischemia. 3 Octreotide offers a favorable cardiovascular safety profile without the systemic vasopressor effects of terlipressin. 3

Monitoring Parameters

Monitor the following during treatment: 1, 3, 4

• Serum creatinine every 2-3 days to assess response
• Mean arterial pressure (goal: increase by 10-15 mmHg)
• Heart rate (expect decrease of approximately 10 beats/minute with terlipressin)
• Central venous pressure (ideally) to guide fluid management and prevent volume overload
• Urine output (should increase with effective treatment)
• Serum sodium (should increase with effective treatment)
• Signs of pulmonary edema from albumin administration, especially in patients with cardiac dysfunction

Watch for cardiac/intestinal ischemia, pulmonary edema, and distal necrosis with terlipressin; continuous hemodynamic monitoring is required in ICU with norepinephrine. 3

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

TIPS is more applicable in Type 2 HRS (HRS-NAKI) than Type 1 HRS due to the more stable clinical condition, and has been shown to improve both renal function and ascites control. 1, 2, 3

TIPS is contraindicated in patients with: 1

• Severe hepatic dysfunction (serum bilirubin >5 mg/dL)
• High MELD score
• Significant kidney dysfunction
• Cardiac failure
• Clinically significant hepatic encephalopathy

Small studies suggest TIPS may improve kidney function in Type 1 HRS, but applicability is limited due to severe liver failure in most patients. 1, 3

Renal Replacement Therapy

Initiate RRT based on clinical grounds, not as stand-alone therapy, for: 1, 4

• Severe and/or refractory electrolyte or acid-base imbalance
• Severe or refractory volume overload
• Symptomatic azotemia
• Worsening kidney function despite vasoconstrictors

RRT should be considered primarily as a bridge to liver transplantation in patients unresponsive to vasoconstrictors. 1, 3 Published data on RRT in cirrhosis show controversial effects on survival, with very high mortality in critically ill cirrhotic patients requiring RRT independent of transplant options. 1

Definitive Treatment: Liver Transplantation

Liver transplantation is the only definitive treatment for HRS-AKI, with post-transplant survival rates of approximately 65%. 2, 3, 4 Patients with Type 1 HRS should receive expedited referral for transplantation due to high mortality while on the waiting list. 2, 3

Treatment of HRS with vasoconstrictors before transplantation may improve post-transplant outcomes, and HRS reverses in approximately 75% of patients after liver transplantation alone without combined liver-kidney transplant. 3

Combined Liver-Kidney Transplantation

There is no advantage in using combined liver-kidney transplantation versus liver transplantation alone, except in patients who have been under prolonged renal support therapy (>12 weeks), have underlying chronic kidney disease, or have hereditary renal conditions. 2, 6 The reduction in serum creatinine after vasoconstrictor treatment should not change the decision to perform liver transplantation, as prognosis after recovering from HRS remains poor. 3

Prevention Strategies

Spontaneous Bacterial Peritonitis

Administer albumin 1.5 g/kg at diagnosis of spontaneous bacterial peritonitis, then 1 g/kg on day 3, to reduce HRS incidence from 30% to 10% and mortality from 29% to 10%. 1, 3 Use antibiotic prophylaxis following gastrointestinal bleeding for 7 days. 1

Advanced Cirrhosis

Norfloxacin 400 mg/day reduces the incidence of HRS in patients with advanced cirrhosis and low ascitic fluid protein. 2, 3, 4

Large-Volume Paracentesis

Administer IV albumin (6-8 g/L of ascitic fluid removed) during large-volume paracentesis (>5 L) to prevent post-paracentesis circulatory dysfunction and HRS. 1, 3

Severe Alcoholic Hepatitis

Pentoxifylline 400 mg three times daily for 4 weeks prevents HRS development in patients with severe alcoholic hepatitis. 2, 3

Recurrent HRS

In cases of HRS-AKI recurrence upon treatment cessation, administer a repeat course of vasoconstrictor therapy. 1 Long-term terlipressin administration (ranging from 62 days to 8 months) may be considered in selected patients with recurrent HRS awaiting liver transplantation to prevent irreversible renal failure and the need for dialysis. 7

Vasoconstrictors and albumin are not recommended for HRS-NAKI (formerly Type 2 HRS) outside the criteria of AKI, as recurrence after treatment withdrawal is the norm and controversial data exists on long-term clinical outcome. 1

Common Pitfalls

• Do not delay treatment: Prompt initiation of vasoconstrictors after HRS-AKI diagnosis improves outcomes, particularly before progression to higher ACLF grade. 3, 8
• Do not use vasoconstrictors without albumin: Albumin is essential for both volume expansion and anti-inflammatory properties. 6
• Do not continue ineffective treatment: If serum creatinine fails to decrease by 25% after 3-4 days despite dose escalation, consider alternative vasoconstrictors or prepare for RRT and transplantation. 1, 5
• Do not overlook volume overload: Monitor closely for pulmonary edema, especially in patients with underlying cardiac dysfunction or cirrhotic cardiomyopathy. 3, 4
• Do not miss precipitating factors: Always rule out and treat spontaneous bacterial peritonitis, gastrointestinal bleeding, and remove nephrotoxic drugs. 1, 3