Hepatorenal syndrome

“Hepatorenal syndrome (HRS) is defined as the occurrence of renal failure in a patient with advanced liver disease in the absence of an identifiable cause of renal failure. Thus, the diagnosis is essentially one of exclusion of other causes of renal failure” - EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis (2010).

Classification and diagnosis

There are two different types of hepatorenal syndrome (HRS). HRS-AKI (HRS-Acute Kidney Injury), previously known as Type 1 HRS, which is defined as an increase in serum creatinine of ≥26.5 micromol/L within 48 hours, or ≥1.5 times baseline. HRS-NAKI (HRS-Non-Acute Kidney Injury), previously known as Type 2 HRS, encompasses kidney dysfunction not meeting HRS-AKI criteria. HRS-NAKI is further divided into HRS-AKD (HRS-Acute Kidney Disease) and HRS-CKD (HRS-Chronic Kidney Disease). HRS-AKD is characterised by an eGFR below 60 mL/min for less than three months while HRS-CKD is defined by an eGFR below 60 mL/min for more than three months.

Diagnosis of HRS-AKI requires all of the following International Club of Ascites (ICA) criteria to be met:

• Cirrhosis with ascites.

• Serum creatinine meeting HRS-AKI criteria.

• No response to diuretic withdrawal and 2 day fluid challenge with 1g/kg/day of Human Albumin Solution (HAS) 20%.

• Absence of shock.

• No current or recent nephrotoxic medication use e.g. NSAIDs, contrast dye, etc.

• No structural kidney disease:

  • normal ultrasound.

  • absence of proteinuria <500 mg/day.

  • absence haematuria <50 red cells per high power field.

Pathophysiology

Advanced liver cirrhosis leads to portal hypertension due to scarring of the liver. Portal hypertension promotes bacterial translocation across the gut wall and increased stress on splanchnic vessels, which upregulates endothelial nitric oxide synthase and drives splanchnic nitric oxide production. This causes splanchnic vasodilation and increased blood flow to the splanchnic organs, reducing the effective arterial blood volume (EABV).

Cardiac output is increased to help compensate for this. However, despite this elevated cardiac output, the EABV remains insufficient, triggering the renin-angiotensin-aldosterone system (RAAS) and other vasoconstrictor systems. These systems attempt to compensate by constricting blood vessels elsewhere in the body, including the renal blood vessels. This renal vasoconstriction reduces renal blood flow and glomerular filtration rate (GFR), impairing kidney function and ultimately leading to HRS.

As cirrhosis progresses, cardiac output decreases, and this contributes to the reduction in EABV.

Bacterial infection, particularly spontaneous bacterial peritonitis (SBP), and advanced liver disease are associated with persistent systemic inflammation. Even in the absence of overt infection, chronic bacterial translocation across the gut wall sustains ongoing immune activation. Inflammatory mediators such as cytokines (including TNF-α and IL-6) and pathogen-associated molecular patterns (PAMPs) further upregulate systemic vasodilators, worsening the existing circulatory dysfunction and precipitating HRS.

Risk factors and prevention

Risk factors for HRS in patients with advanced liver disease include infection (particularly SBP), gastrointestinal bleeding, overdiuresis, large volume paracentesis without adequate albumin cover, severe alcoholic hepatitis, and the use of nephrotoxic drugs such as NSAIDs.

Prevention of HRS requires a comprehensive approach, including avoiding nephrotoxic medications, careful use of diuretics to avoid overdiuresis, administering albumin with large volume paracentesis, and long-term antibiotic prophylaxis (e.g. co-trimoxazole or ciprofloxacin) in high-risk patients to prevent SBP.

When SBP is confirmed or being treated empirically, prompt antibiotic therapy in line with local antimicrobial guidelines should be initiated alongside HAS 20% at a dose of 1.5 g/kg on the day of diagnosis and 1 g/kg on day 3. This albumin regimen has been shown to significantly reduce the incidence of HRS and improve survival in this setting.

Medical management

Liver Transplantation

Liver transplantation remains the best therapeutic option for patients with HRS. Renal function frequently improves or recovers following transplantation in HRS. However, several studies have shown that serum creatinine after liver transplantation is higher in patients transplanted with HRS compared to those without HRS at the time of transplant, and the presence of HRS at the time of transplantation has a negative impact on post-transplant survival.

Human Albumin Solution

Human Albumin Solution (HAS) is an intravenous colloid solution derived from human plasma, serum, or normal placentas. In the context of HRS, the primary mechanism of albumin is expansion of the EABV, which reduces activation of the RAAS and sympathetic nervous system, thereby relieving renal vasoconstriction and improving renal perfusion. In addition to its volume-expanding properties, albumin has antioxidant and anti-inflammatory properties that may give additional benefit in the context of the systemic inflammation that drives HRS.

Terlipressin

Terlipressin is a synthetic vasopressin analogue and V1 receptor agonist. It works by causing splanchnic vasoconstriction, which reduces splanchnic pooling and improves EABV. This reduces activation of the RAAS and sympathetic nervous system, relieving renal vasoconstriction and improving renal perfusion.

The combination of terlipressin and albumin has been shown to be more effective than terlipressin alone in reversing HRS-AKI. Response rates (complete or partial) range from 64 to 76%, with complete response rates of 46 to 56%, where a complete response is defined as a return of serum creatinine to within 26.5 micromol/L of the pre-AKI baseline value. Terlipressin improves renal function and HRS reversal rates and may have a short-term survival benefit.

As terlipressin causes splanchnic vasoconstriction and reduces the hyperdynamic circulation, it can decrease cardiac output. Albumin infusion helps to maintain cardiac output and EABV in this setting, reducing activation of the RAAS and sympathetic nervous system and thereby supporting renal perfusion. This complementary mechanism provides the rationale for combining the two agents.

The 2023 MHRA drug safety alert highlighted that in patients with HRS-AKI, terlipressin may cause serious or fatal respiratory failure at a frequency higher than previously recognised, and that it increases the risk of sepsis and septic shock. The following guidance was issued:

• Terlipressin should be avoided in those with cardiovascular ischaemic complications.

• Terlipressin should be avoided in those with advanced renal dysfunction (baseline serum creatinine at or above 442 micromol/L), unless the benefit is judged to outweigh the risks.

• Consider a reduction in albumin dose in patients with signs or symptoms of respiratory failure or fluid overload; discontinue terlipressin if symptoms are severe or do not resolve.

• Terlipressin can be administered as a continuous intravenous infusion as an alternative to bolus injection, as infusion may be associated with lower rates of severe adverse events.

Noradrenaline

Noradrenaline is an endogenous catecholamine that acts as both a neurotransmitter and a hormone. When used as a vasopressor in HRS, it acts primarily on alpha-1 receptors, causing systemic vasoconstriction and improving EABV. It also has beta-1 agonist activity, which leads to an increase in cardiac output.

Noradrenaline requires administration via a central venous line, which in most centres necessitates transfer to a Critical Care setting for close monitoring.

Noradrenaline is considered an alternative to terlipressin when terlipressin is contraindicated or unavailable, rather than an equivalent first-line agent, given the less robust evidence base. Small randomised studies and meta-analyses have demonstrated comparable efficacy to terlipressin in terms of improvement in mean arterial pressure, reversal of HRS-AKI, and one-month survival, with HRS reversal rates ranging from 39% to 70%. However, these findings should be interpreted with caution, given the limitations of the available evidence, including small sample sizes between studies.

Midodrine and Octreotide

Midodrine is a sympathomimetic agent that acts selectively on peripheral alpha-1 adrenergic receptors, increasing systemic vascular resistance and improving EABV. This reduction in RAAS and sympathetic nervous system activation secondarily relieves renal vasoconstriction. Although some splanchnic vasoconstriction occurs, the primary therapeutic mechanism in HRS is improvement of EABV rather than direct targeting of the splanchnic circulation.

Octreotide is a somatostatin analogue that inhibits the release of glucagon and other vasodilatory peptides, thereby reducing splanchnic vasodilation. It is usually administered subcutaneously.

Neither midodrine nor octreotide is effective as monotherapy in HRS. Octreotide monotherapy is limited by a progressive loss of effect over time, as local release of vasodilatory mediators, including nitric oxide, counteracts its action; combining it with midodrine, which acts via a complementary mechanism, mitigates this limitation.

The combination of midodrine, octreotide, and albumin has demonstrated potential benefit in HRS-AKI and is considered the standard of care in countries where terlipressin is not approved. However, a randomised controlled trial demonstrated that terlipressin and albumin were superior to the combination of midodrine, octreotide, and albumin in reversing HRS-AKI. As such, midodrine and octreotide in combination with albumin are positioned as a later-line option when terlipressin and noradrenaline are both contraindicated or unavailable.

Renal Replacement Therapy

Renal Replacement Therapy (RRT) can be considered in patients with HRS-AKI who have not responded to vasoconstrictor therapy. In this context, RRT should be viewed primarily as a bridge to liver transplantation rather than a definitive treatment. The decision to initiate RRT should be based on the individual severity of illness, taking into account the overall clinical trajectory and transplant eligibility. Evidence for RRT use in patients with cirrhosis remains limited, with controversial and uncertain effects on survival.

Response to treatment

Response to treatment in HRS-AKI is classified according to the following criteria, as defined by the ICA and found within the European Association for the Study of the Liver (EASL) guidance:

• Complete response: Return of serum creatinine to within 26.5 micromol/L of the pre-AKI baseline value, with creatinine stable or improving at the point of assessment.

• Partial response: Regression of at least one AKI stage with a final serum creatinine remaining more than 26.5 micromol/L above the pre-AKI baseline value.

• No response: Failure to meet criteria for either complete or partial response.

References

• Advances in the diagnosis and management of hepatorenal syndrome: insights into HRS-AKI and liver transplantation (2023). (http://dx.doi.org/10.1136/egastro-2023-100009)

• Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases (2021). (https://doi.org/10.1002/hep.31884)

• EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis (2010). (https://doi.org/10.1016/j.jhep.2010.05.004)

• EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis (2018). (https://doi.org/10.1016/j.jhep.2018.03.024)

• Hepatorenal syndrome (2018). (https://doi.org/10.1038/s41572-018-0022-7)

• Hepatorenal syndrome: pathophysiology, diagnosis, and management (2020). (https://doi.org/10.1136/bmj.m2687)

• MHRA Drug Safety Update - Terlipressin: new recommendations to reduce risks of respiratory failure and septic shock in patients with type 1 hepatorenal syndrome (https://www.gov.uk/drug-safety-update/terlipressin-new-recommendations-to-reduce-risks-of-respiratory-failure-and-septic-shock-in-patients-with-type-1-hepatorenal-syndrome)