Arterial vasodilation appears to be the most plausible explanation for circulatory dysfunction that occurs in patients with cirrhosis and ascites (3). This involves two major mechanisms as follows: firstly, systemic circulatory disturbances and, secondly, activation of neurohumoral systems. Splanchnic vasodilatation, resulting from portal hypertension secondary to cirrhosis, leads to decreased systemic vascular resistance and subsequent reduction in effective blood volume, which is clinically mediated by an increased production of nitric oxide (NO), carbon monoxide and/or endogenous cannabinoids (3). In the early stages, the effective arterial blood volume and arterial pressure are maintained by increased cardiac output resulting in a hyperdynamic circulation. In later stages, the progressive splanchnic vasodilatation results in a decrease in effective arterial blood volume that can no longer be compensated by cardiac output. Moreover, the subsequent decrease in cardiac output may be due to cirrhotic cardiomyopathy, thereby contributing to further arterial underfilling and worsening of renal function (4).

In order to maintain arterial pressure, systemic vasoconstrictor systems, such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS) and the non-osmotic hypersecretion of arginine vasopressin (AVP), are activated leading to increased plasma renin activity and increased plasma norepinephrine levels. However, the activation of neurohumoral systems has harmful impacts on kidneys. Development of renal sodium and solute-free water retention leads to ascites and oedema, and hypervolemic hyponatremia, respectively. This results in significant renal vasoconstriction, which leads to a decrease in glomerular filtration rate and subsequently HRS (5).

Prostaglandins (PGs), specifically PGI₂ and PGE₂, induce renal vasodilation, thereby providing renal protective effects by compensating for the vasoconstrictor systems of RAAS, SNS and AVP. The levels of renal PGs are increased in patients with cirrhosis and ascites (6). NSAIDs are a common cause of kidney failure in patients with cirrhosis (6), illustrating the probable important role of PG production for maintaining renal function in patients with cirrhosis.

Systemic inflammation plays a role in the pathophysiology of HRS. Bacterial translocation has been implicated in the haemodynamic derangement of cirrhotic patients, thereby leading to HRS (4). In the clinical setting, increased levels of pro-inflammatory cytokines, such as tumour necrosis factor α (TNFα), interleukin-6 (IL-6) and NO, in the splanchnic area lead to reduced systemic vascular resistance and increased cardiac output (7).

The existence of sensor(s) in the hepatic circulation, which play a role in regulating extracellular fluid volume, is pathologically stimulated by hepatic haemodynamic irregularities. This may contribute to volume overload and ascites by activating renal sympathetic nerves to promote salt and water retention (8).

In patients with SBP, a meta-analysis of four randomised trials demonstrated that treatment with antibiotics and albumin was associated with a significant reduction in renal impairment (8% vs. 31%) and mortality (16% vs. 35%) compared with controls (12). Furthermore, another randomised controlled trial reported that primary prophylaxis with norfloxacin reduced the incidence of SBP, delayed the development of HRS and improved survival in patients with cirrhosis, ascites and either advanced liver failure or impaired renal function (13). The phosphodiesterase inhibitor, pentoxifylline, which has anti-inflammatory properties through inhibition of leukotriene and TNFα synthesis, was included in management for prevention of HRS. However, a recent randomised study demonstrated that pentoxifylline is not statistically equivalent to the efficacy of prednisolone in patients with severe alcoholic hepatitis (14).

Medical treatment for patients with suspected HRS usually consists of vasopressor and albumin infusion, with the aims of improving splanchnic arterial circulation and plasma volume expansion, respectively. Several vasopressor therapies have been trialled in HRS, including terlipressin, norepinephrine and midodrine plus octreotide. Terlipressin is not licensed for use in the United States nor is it on the Pharmaceutical Beneficial Scheme (PBS) in Australia, whilst midodrine is only available through Special Assess Scheme (SAS). A pooled analysis of 501 patients in 21 studies showed that an increase in mean arterial pressure of at least 5 mmHg correlated with improvement in renal function regardless of which vasopressor was used (15).

A systematic review and meta-analysis of randomised controlled trials of norepinephrine versus terlipressin in patients with Type 1 HRS found no significant difference in reversal of HRS, mortality at 30 days or recurrence of HRS (16). Furthermore, a recent study indicated that the efficacy of a midodrine plus octreotide regimen might not be as significant as previous studies suggested (17). In 2015, a randomised controlled trial of 49 patients comparing terlipressin with octreotide/midodrine illustrated a significantly higher rate of improvement in renal function with terlipressin (≥50% serum creatinine decrease, 70.4% vs. 28.6%, P = 0.01), although there was no significant difference in survival between the two groups (18). Terlipressin is a bridging option, despite its high cost, to liver transplantation in patients who are transplant candidates as it may improve both renal function and short-term survival for patients awaiting a liver transplant. Further clinical trials will be required to assess the indication, efficacy and duration of different vasopressors under the new ICA-AKI criteria and management algorithm.

Although limited studies have suggested that transjugular intrahepatic portosystemic shunt (TIPS) may lead to improvement of renal function in a well-selected group of patients (19), poor prognosis has been associated with patients with advanced liver disease undergoing TIPS procedure (20). TIPS aims to reduce portal pressure by inserting an intrahepatic stent, which shunts portal blood into the systemic circulation, and in theory may benefit some patients with HRS. However, many patients with HRS are ineligible for TIPS due to contraindications including severe hyperbilirubinaemia or Child-Pugh class C (e.g., Bilirubin >5 mg/dL, Child-Pugh score >11). Moreover, the risks associated with TIPS, namely hepatic encephalopathy, liver failure, cardiac failure and renal injury due to contrast, also need to considered (21).

Renal replacement therapy (RRT) has been shown to improve short-term survival in patients with AKI and may provide a bridge to liver transplantation for patients with HRS who are unresponsive to vasopressors and ineligible for TIPS (22). However, in the absence of an acute reversible component to the AKI or a plan for liver transplantation, initiation and/or continuation of RRT should be evaluated carefully, as these patients have a poor prognosis and are unlikely to recover with RRT alone (22).

Molecular absorbent recirculating system (MARS) removes albumin-bound and water-soluble substances, including NO and TNF, which are involved in pathogenesis of HRS. MARS has been shown to improve neurological function and coagulation parameters although a randomised trial of 189 patients reported no beneficial effect on survival of MARS therapy in patients with acute or chronic liver failure (23).

The definitive treatment for Type 1 HRS is liver transplantation, as this will reverse both portal hypertension and liver failure, the two main factors leading to systemic circulatory disturbances in HRS. A case-control study suggested that patients with HRS treated with vasopressin before transplantation had similar outcomes compared with patients transplanted with normal renal function (24). However, other studies have demonstrated that vasopressors, regardless of the agent used, had no significant impact on survival (1, 25). Simultaneous liver–kidney transplantation is not necessary for patients with isolated HRS and should only be considered in selected patients at high risk for non-recovery of renal function, such as patients with heavy proteinuria and other evidence of advanced primary renal disease.