Hepatorenal syndrome

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Renal recovery rarely occurs in the absence of hepatic recovery. The goal of treatment is to support the patient and reverse the hemodynamic changes until the precipitating causes of renal failure are corrected or the hepatic exacerbation (e.g., decompensation due to alcohol excess) is overcome, or liver transplant is available. Transjugular intrahepatic portosystemic shunts should not be used as a specific treatment of HRS-AKI and cannot currently be advised for the specific treatment of HRS-AKI in the absence of data supporting their use.

Initial therapy

Intravascular volume expansion with albumin is recommended to manage hypovolemia.[25][29] Patients with suspected HRS should receive a fluid challenge with intravenous albumin for 2 days, and diuretics should be held. This helps rule out prerenal azotemia and allows for early volume expansion.[25] Expansion should be monitored closely to avoid overexpansion.[29] If renal failure is due to hypovolemia (half the cases of AKI in cirrhosis), it will improve after albumin challenge and discontinuation of diuretics. No improvement will occur in patients with HRS-AKI.[20]

Diuretics should be held.[15] Nonselective beta-blockers should also be temporarily discontinued to avoid a reduction in cardiac output due to their negative inotropic effect.[30]

Diagnostic paracentesis should be performed within 12 hours of presentation to rule out spontaneous bacterial peritonitis.[1]

Spontaneous bacterial peritonitis: prevention of hepatorenal syndrome-acute kidney injury (HRS-AKI)

Cefotaxime is the preferred antibiotic to treat SBP.[2] It is given according to the serum creatinine level and continued for 5 days. However, in one third of patients with SBP, renal impairment develops despite treatment.

Combined treatment with albumin and antibiotics reduces the incidence of renal impairment and death.[2][22][23]

Patients who fulfill diagnostic criteria for HRS-AKI

Combined therapy with a vasoconstrictor plus albumin is the recommended treatment for HRS-AKI. The updated diagnostic criteria, with the removal of minimum serum creatinine concentration, allows for immediate drug therapy after an unsuccessful fluid challenge (compared to the previous criteria). Earlier treatment likely results in higher reversal rates and better outcomes given that response to vasoconstrictors is dependent on the serum creatinine concentration at the start of treatment.[2][8][29][31][32]

The preferred vasoconstrictor is terlipressin, a vasopressin analog with increased selectivity for the V1 receptor administered either as a continuous intravenous infusion or as an intravenous bolus. Although intravenous bolus administration is the method approved in the US, a continuous infusion may be considered to reduce the risk of adverse events.[2] If terlipressin is not available, norepinephrine (noradrenaline) plus albumin should be administered. In general, terlipressin may be given on medical wards, whereas norepinephrine is preferably administered in the intensive care unit. If neither terlipressin nor norepinephrine are available, a trial of oral midodrine in combination with octreotide may be considered, but it is less effective.[2]

One meta-analysis of 16 studies reported no significant differences in HRS reversal, serious adverse events, and liver transplantation-free patient survival with terlipressin compared with norepinephrine.[33] Both terlipressin and norepinephrine were found to be superior to the combination of midodrine plus octreotide in HRS reversal.[33]

Evidence suggests that terlipressin may reduce the incidence of persistent HRS, compared with alternative vasoactive pharmacotherapy, and may improve renal function in patients with HRS-AKI.[34][35][36][37][38] [ ] However, terlipressin is more commonly associated with adverse effects, such as diarrhea/abdominal pain, peripheral cyanosis, minor cardiovascular events, and respiratory failure.

The Food and Drug Administration (FDA) has approved terlipressin to improve kidney function in adults with HRS with rapid reduction in kidney function.[39] The approval includes safety recommendations regarding the potential for serious or fatal respiratory failure, particularly for patients with volume overload or acute-on-chronic liver failure grade 3. Oxygen saturation should be assessed via pulse oximetry before starting terlipressin. Treatment is contraindicated in patients with hypoxia (SpO₂ <90%) until their oxygenation levels improve, or if they have respiratory symptoms that are worsening. Continuous pulse oximetry should be used to monitor patients during treatment, and treatment stopped if hypoxia or increased respiratory symptoms develop. Intravascular volume overload should be managed by discontinuing albumin and/or other fluids with the use of intravenous furosemide; terlipressin should be paused, reduced, or stopped until volume status has improved. Treatment is also contraindicated in patients with ongoing coronary, peripheral, or mesenteric ischemia and should be discontinued in any patients showing signs or symptoms of an ischemic adverse reaction. Patients with a serum creatinine >5 mg/dL are unlikely to experience benefit with terlipressin.[39]

The European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK also recommend several safety measures when using terlipressin.[37][40][41] Safety recommendations follow a safety review based on the findings of one large randomized controlled trial in patients with HRS-AKI.[37][40] The trial results suggest that patients treated with terlipressin are more likely to experience, and die from, respiratory disorders (e.g., respiratory failure) within 90 days of the first dose, compared with placebo, and identified a previously unreported risk of sepsis.[37] Respiratory disorders are a known risk of terlipressin; however, the frequency of respiratory failure seen in this study (11%) was higher than that previously reported.

Norepinephrine plus albumin is an alternative to terlipressin. It was associated with HRS reversal in one network meta-analysis, and may be associated with fewer adverse effects than terlipressin plus albumin.[34][35] [ ] The norepinephrine dose should be titrated to achieve a 10 mmHg increase in mean arterial pressure from baseline.

Response to terlipressin or norepinephrine is defined by creatinine decrease to <1.5 mg/dL, or a return to within 0.3 mg/dL of baseline over a maximum of 14 days. In patients who maintain a creatinine level at, or above, the pretreatment level over 4 days, with the maximum tolerated doses of the vasoconstrictor, therapy may be discontinued.[2]

Midodrine (an alpha-1 receptor agonist) plus octreotide (a somatostatin analog which inhibits glucagon release) work synergistically to improve renal hemodynamics. While well-tolerated, the combination of midodrine plus octreotide is significantly less effective than terlipressin and should be reserved for patients with contraindications to both terlipressin and norepinephrine.[42]

Prior to initiating vasopressor therapy, the patient's risk of ischemic or cardiovascular events should be evaluated. This should include an electrocardiogram.[8] During vasopressor treatment, patients should be closely monitored for the possible development of adverse effects of vasoconstrictors and albumin, including ischemic complications and pulmonary edema.[2]

Renal replacement therapy (RRT)

RRT may be indicated in patients with HRS-AKI unresponsive to pharmacotherapy and with volume overload/pulmonary edema, severe metabolic acidosis, uremia, or electrolyte derangements.[5][21][29] RRT can provide patients with a bridge to liver transplantation with >70% survival at 1 year posttransplant.[43] However, patients requiring RRT generally have a poor prognosis, and the American Gastroenterological Association (AGA) does not recommend this measure in patients ineligible for liver transplantation.[21][44]

Whether the candidate requires liver transplantation or simultaneous liver-kidney transplantation can be decided based on the duration of kidney injury. Structural and irreversible kidney injury is anticipated for patients requiring dialysis for more than 6-8 weeks.[29]

Liver transplantation

Liver transplantation is the optimal treatment for HRS-AKI, with RRT as a bridge.[2][5][21] The decision for transplantation of a limited resource is complex and involves severity of illness and likely prognosis. Advanced age, severe comorbidities, alcohol use disorder, and infection might represent barriers to liver transplantation.[20]

Simultaneous liver-kidney transplantation may be an option in select cases and is recommended for patients with prolonged AKI, underlying chronic kidney disease, or with hereditary renal conditions.[5][8] The transplant team will evaluate the suitability of the individual patient.

Supportive therapies

Patients should have their fluid status, urine output, and serum electrolytes monitored closely. In particular, it is important to prevent patients from developing severe hyponatremia.

Therapeutic paracentesis is indicated if there is a symptomatic accumulation of ascites.

Patients may need continuous hemofiltration for complications of renal failure, such as severe electrolyte disturbances, volume overload, or metabolic acidosis.[8]

Immunization with influenza, COVID-19, and pneumococcal vaccines is important, as these patients are immunocompromised.

Extracorporeal liver support has been investigated in patients with HRS-AKI but did not show survival benefit.[45]

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