Definition, clinical features and diagnosis of HRS
The HRS can be loosely defined as impaired renal function that occurs in patients with chronic advanced or acute liver failure because of marked renal vasoconstriction and concomitant extrarenal vasodilatation. In 1990, the International Ascites Club (IAC) met in Florence, Italy to focus on research involving the mechanisms of circulatory and renal dysfunction in liver diseases and set forth major and minor diagnostic criteria of HRS that are now widely used (Table 2).35 Based on the IAC definition, the HRS ‘…is a clinical condition that occurs in patients with chronic liver disease, advanced hepatic failure, and portal hypertension characterized by impaired renal function and marked abnormalities in the arterial circulation and activity of the endogenous vasoactive systems. In the kidney, there is marked renal vasoconstriction that results in a low GFR. In the extrarenal circulation there is predominance of arterial vasodilation that results in reduction of total systemic vascular resistance and arterial hypotension’.
Table 2. Criteria proposed by the International Ascites Club (IAC) for the diagnosis of hepatorenal syndrome (HRS)
| Chronic or acute liver disease with advanced hepatic failure and portal hypertension|
| Low glomerular filtration rate (serum creatinine > 1.5 mg/dL or 24-h creatinine clearance <40 mL/min)|
| Absence of shock, ongoing bacterial infection, current or recent treatment with nephrotoxic drugs, excessive gastrointestinal or renal fluid losses|
| No sustained improvement in renal function following diuretic withdrawal and plasma volume expansion with 1.5 L isotonic saline|
| Proteinuria <500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal disease|
| Urine volume <500 mL/day|
| Urine sodium <10 mm|
| Urine osmolality greater than plasma osmolality|
| Urine red blood cells <50 per high power field|
| Serum sodium concentration <130 mm|
Predictors for the development of HRS have been suggested to include liver size, serum sodium concentration <133 mm, elevated plasma renin >3.5 ng/mL/h, and increased resistive index of renal arcuate and interlobar arteries >0.7 by Doppler ultrasound studies.36, 37 It should be noted that while Gines et al. found that neither the aetiology of liver failure nor the Child-Pugh score had any positive predictive value for the development of HRS36 Platt et al. reported that two major determinants of the Child-Pugh score including total bilirubin (P < 0.05) and prothrombin time (PT) (P < 0.05) are independent predictive indicators for HRS.37
The IAC further subtyped HRS into types I and II to facilitate successful multicentre trials. Whereas the former includes patients with rapidly progressive renal failure with doubling of the SCr to a level >2.5 mg/dL or CCr reduction of >50% within 2 weeks, the latter includes patients with a more moderate or stable reduction in renal function. Once patients develop HRS, spontaneous recovery of renal function is rare (3.5%) and the median survival is <2 weeks without therapeutic intervention.
Management of HRS
Before the availability of liver transplantation, HRS was regarded as universally fatal. Survival following the development of HRS (type I) without renal replacement therapy and OLT is generally 2–3 weeks.33, 41 Spontaneous recovery from HRS is rare unless there is an improvement in liver function.42, 43 Ideally OLT is the treatment of choice for patients with HRS and ESLD. However, due to the limited supply of deceased donor organs, management of HRS in OLT candidates is often restricted to preventive measures and supportive care.
As HRS may be precipitated by therapies directed at the complications of cirrhosis, any such therapy has to be closely monitored. The potential benefits of diuretics, lactulose, contrast dye exposure, nephrotoxic medications, NSAIDs and selective COX-2 inhibitors have to be carefully balanced against the risk of precipitating HRS. Large volume paracentesis in patients with severe hypoalbuminaemia or ascites without peripheral oedema are thought to be at increased risk for the development of acute volume depletion and potential HRS.44 In these cases, the use of plasma expanders has been advocated. In general, albumin is felt to be more effective than artificial plasma expanders in the prevention of circulatory dysfunction. Nevertheless, not all investigators agree that plasma expansion is necessary during large volume paracentesis or that paracentesis can precipitate HRS.44–47 The use of albumin infusion among cirrhotic patients with SBP, on the other hand, has been more recently suggested to reduce the risk of renal failure and mortality, especially among those who present with renal insufficiency and hyperbilirubinaemia at the time of diagnosis.48, 49
Non-transplant management of HRS may be dictated by the severity of liver failure and the availability of different treatment modalities.
Transjugular intrahepatic shunt placement (TIPS) has been designed to divert portal blood flow to the hepatic vein, thereby redistributing splanchnic and portal blood centrally and effectively improving both variceal bleed and renal perfusion.50 Clinically, TIPS has been shown to increase urinary sodium excretion51–53 and in some studies52 improvement of renal function and reduction in the de novo development of HRS or conversion from type II to type I.54 The limitations of TIPS placement, however, include worsening of liver function and hepatic encephalopathy.50 For these reasons, TIPS is generally reserved for patients with Child-Pugh class B or early C. Survival improvement with TIPS has only been reported in selected patients.
For patients with more advanced liver disease, medical therapies with various vasoactive agents have resulted in different degrees of success. Vasoactive agents used in the treatment of HRS include renal vasodilators such as saralasine, dopamine, misoprostol and endothelin (ET)-A antagonists and/or splanchnic vasoconstrictors such as octapressin, ornipressin, terlipressin and octreotide.
An early study involving saralasine, an angiotensinogen antagonist, only led to worsening of systemic hypotension and did not improve renal function.55 Renal dose dopamine previously used for acute renal failure in critically ill patients failed to significantly improve renal function in patients with HRS.56, 57 Reports on the benefit of combination administration of dopamine and vasopressors in HRS have been inconsistent.57 As ET-1 has been proposed to play a role in both renal and hepatic vasoconstriction in HRS, the use of ET antagonist has also been suggested to ameliorate HRS. In an anecdotal report involving three patients, Soper et al. documented a dose-dependent renal improvement during treatment with the ET-A antagonist BQ123, but unfortunately, all patients subsequently died.58 Low doses of misoprostol, a synthetic prostaglandin E1 analogue, are vasodilatory, natriuretic and diuretic, and are therefore, potentially beneficial in HRS. Nevertheless, none of the HRS studies involving misoprostol therapy revealed substantial and/or conclusive benefit.59–62
The rationale for the use of splanchnic vasoconstrictors is the reduction in splanchnic organ blood flow and resultant reduction of portal blood flow and pressure. Splanchnic vasoconstrictors used in the management of HRS include the vasopressin synthetic analogues octapressin, ornipressin and terlipressin. Octapressin, when infused at low doses (0.004–0.002 units/min) produced an increase in renal blood flow with an associated decrease in renal vascular resistance. At higher doses, however, renal vascular resistance increased significantly, and changes in renal blood flow diminished. In an earlier study involving 11 patients, only four of five patients who had a systemic improvement in blood pressure >5 mmHg, had improvement of renal perfusion. The drug only appeared to work for hypotensive patients who responded with increased blood pressure. Despite temporary improvement in renal haemodynamics and function, all patients eventually died.63
Ornipressin has been shown to confer minimal improvement in renal function with or without the addition of dopamine, unless the medication was administered as a continuous and prolonged infusion. Unfortunately, with prolonged infusion, complications including intestinal and tongue infarctions and arrhythmias were reported.64–66
To date, the most widely studied splanchnic vasoconstrictor and perhaps most promising medical therapy in the treatment of HRS is terlipressin with or without albumin infusion. Unlike ornipressin, terlipressin has a longer biological half-life, which allows for administration as a 4 h bolus. In 1995, Hadengue et al. first reported the success of 10 patients who had improvement in renal function and diuresis following a low-dose administration of terlipressin at 1 mg q 12 h over a 48-h period.67 In 1996, Ganne-Carrie et al. reported the successful use of long-term treatment with terlipressin as a bridge to liver transplantation.68 Based on the favourable outcomes of these reports, a series of studies on the effect of terlipressin in patients with HRS were performed using different protocols including variations in dosages, duration of terlipressin infusion and addition of albumin. Most of these studies were prospective open studies involving mostly type I HRS patients. Overall, there was an improvement in renal function and a significant improvement in survival compared with that reported by Gines et al.69–74 Unlike previous vasopressin analogues, side-effects of terlipressin have been reported to be minimal and reversible with dose reduction or discontinuation. More recently, a randomized placebo-controlled clinical trial similarly confirmed that terlipressin administered at 1 mg intravenously at 12-h intervals over a study period of 15 days significantly improved renal function and systemic haemodynamics, and a trend towards better clinical outcome.75 Another potentially beneficial approach to the use of terlipressin is the addition of albumin infusion. Although inconclusive, available data appear to suggest that the addition of albumin may be beneficial in terms of better response rates and greater reduction in SCr.69, 74
Anecdotal reports and smaller studies of therapies that may benefit patients with HRS include noradrenaline plus albumin,76N-acetylcysteine77 and the combination of octreotide, midodrine and albumin.78
In patients with complete renal failure, various renal replacement therapies including intermittent haemodialysis (HD), continuous renal replacement therapy and molecular adsorbent recirculating system (MARS; Teraklin, AG, Rostock, Germany) may be performed as a bridge to liver transplantation. The choice of intermittent HD vs. continuous renal replacement therapy is often based on the clinical condition of the patient. In patients with severe liver disease and significant hypotension, intermittent HD may worsen the haemodynamic status.79 Slow continuous correction of volumes and solutes with continuous renal replacement therapy (CRRT) [preferably in the form of continuous venovenous haemodialysis (CVVHD)] is preferred. It is speculated that the removal of inflammatory cytokines such as tumour necrosis factor, interleukin (IL)-6, IL-8 and IL-10 may partly explain the better cardiovascular stability seen in patients treated with CRRT compared to those treated with intermittent HD.80 More recently it has been suggested that the MARS might offer survival advantage over dialysis therapy in type I HRS patients awaiting liver transplantation. MARS is based on the concept that kidney dialysis removes only water-soluble toxins, while the liver removes albumin-bound toxins. In Teraklin's MARS system, blood is cleansed in an extracorporeal circuit designed as a combination of both kidney and ‘liver dialysis’. For this reason, in addition to a conventional kidney dialysis, MARS uses human albumin in a second closed loop circuit to cleanse the blood of albumin-bound toxins, hence mimicking the detoxification function of the liver. Additional toxins that may be dialysed by the Teraklin's MARS system include bilirubin, bile acids, phenols, mercaptans, dioxin-like substances, tryptophan, ammonia, copper and iron. Although MARS has shown promising results in some reports,81,82 its use is not without criticisms. In addition to its limited availability and data involving large randomized-controlled trials and costs, MARS has been reported to induce coagulopathy,83 non-cardiogenic pulmonary oedema84 and hypoglycaemia in non-diabetic patients.85
Although liver transplantation is the ultimate life-saving procedure, bridging therapies including TIPS, the use of vasoconstrictors, and MARS have been shown to have marginal to moderate improvement in short-term survival. A recent review of pooled data to evaluate the impact of TIPS and vasoconstrictors on survival in patients with HRS suggests that both TIPS and vasoconstrictors do improve short-term survival compared to the traditional treatment with paracentesis with or without the addition of dopamine.86 Nevertheless, it should be noted that TIPS placement is only appropriate in selected patients with lower Child-Pugh scores while vasopressors may be used in patients with more advanced liver disease. Finally, MARS remains to be proven a viable option for patients with the most advanced liver failure.