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 haemodynamic 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 intra-hepatic 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 hypovolaemia.[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 pre-renal azotaemia and allows for early volume expansion.[25] Expansion should be monitored closely to avoid overexpansion.[29] If renal failure is due to hypovolaemia (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] Non-selective 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 fulfil 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 analogue 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, noradrenaline (norepinephrine) should be administered. In general, terlipressin may be given on medical wards, whereas noradrenaline is preferably administered in the intensive care unit. If neither terlipressin nor noradrenaline 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 noradrenaline.[33] Both terlipressin and noradrenaline 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 diarrhoea/abdominal pain, peripheral cyanosis, minor cardiovascular events, and respiratory failure.

The European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK recommend several safety measures when using terlipressin, following a safety review based on the findings of one large randomised controlled trial in patients with HRS-AKI.[37][39][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. Unless the benefits outweigh the risks, the EMA recommends avoiding terlipressin in patients who have advanced renal dysfunction (serum creatinine ≥442 micromol/L [5 mg/dL]), and in patients who have acute-on-chronic liver disease grade 3 and/or a model for end-stage liver disease (MELD) score ≥39.[39] Any new onset or worsening respiratory symptoms should be treated and stabilised before starting terlipressin, and patients monitored during and after treatment. If respiratory symptoms develop during treatment, a dose reduction of human albumin should be considered, and terlipressin should be discontinued if respiratory symptoms are severe or do not resolve. Patients should also be monitored for symptoms of infection. Continuous infusion of terlipressin can be considered as an alternative to bolus injection as it may reduce the risk of severe adverse events.[39] In addition, the MHRA recommends counselling patients on the benefits and risks of terlipressin, preferably before treatment. Patients can also be counselled after terlipressin treatment under certain circumstances.[40] The MHRA further states that these recommendations are not relevant when terlipressin is used for treating bleeding oesophageal varices. Suspected adverse reactions associated with terlipressin should be reported.[40]

Terlipressin is approved and available in many countries, and has now been approved in the US by the Food and Drug Administration (FDA).[41] The FDA approval of terlipressin for patients with HRS-AKI also 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. They recommend assessing oxygen saturation 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 ischaemia and should be discontinued in any patients showing signs or symptoms of an ischaemic adverse reaction.[41]

Noradrenaline 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 noradrenaline dose should be titrated to achieve a 10 mmHg increase in mean arterial pressure from baseline.

Response to terlipressin or noradrenaline is defined by creatinine decrease to <133 micromol/L (<1.5 mg/dL), or a return to within 26.5 micromol/L (0.3 mg/dL) of baseline over a maximum of 14 days. In patients who maintain a creatinine level at or above the pre-treatment level over 4 days, with the maximum tolerated doses of the vasoconstrictor, therapy may be discontinued.[2]

Midodrine (an alfa-1 receptor agonist) plus octreotide (a somatostatin analogue which inhibits glucagon release) work synergistically to improve renal haemodynamics. 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 noradrenaline.[42]

Prior to initiating vasopressor therapy, the patient's risk of ischaemic 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 ischaemic complications and pulmonary oedema.[2]

Renal replacement therapy (RRT)

RRT may be indicated in patients with HRS-AKI unresponsive to pharmacotherapy and with volume overload/pulmonary oedema, severe metabolic acidosis, uraemia, or electrolyte derangements.[5][21][29] RRT can provide patients with a bridge to liver transplantation with >70% survival at 1 year post-transplant.[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 co-morbidities, 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 hyponatraemia.

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

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

Immunisation 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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