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Clin Biochem Rev. 2007 February; 28(1): 11–17.
PMCID: PMC1904420

Hepatorenal Syndrome

Abstract

Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis with critically poor prognosis. The pathophysiological hallmark is severe renal vasoconstriction, resulting from complex changes in splanchnic and general circulations as well as systemic and renal vasoconstrictors and vasodilators. Rapid diagnosis and management are important, since recent treatment modalities including vasoconstrictor therapy can improve short-term outcome and buy time for liver transplantation, which can result in complete recovery.

Introduction

HRS involves development of renal failure in patients with severe liver disease. It is a life-threatening condition with poor prognosis. The pathophysiology of this syndrome is still not completely understood. However, recent research developments have provided newer treatment modalities with improved prognosis. Now it is possible that a patient developing HRS can survive if it is quickly diagnosed, medical treatment is promptly given to control the renal failure, and liver transplantation is feasible and available for the patient.

History and Definition

The association between liver disease and renal failure had been known for more than a hundred years. Frerichs, the founder of modern liver pathology, reported the presence of oliguria in patients with ascites in 1877.1 Flint noted that in most cases of renal failure in cirrhosis, there were no significant histological changes in the kidneys at autopsy.2 In 1956, Hecker and Sherlock described renal failure in nine patients with liver disease characterised by progressive oliguria, very low urinary sodium excretion, hyponatraemia, but no proteinuria.3 It was later established that the renal failure was functional, since the kidneys of these patients could be successfully transplanted to other patients with chronic renal failure, and the renal failure was reversible after liver transplantation.4,5 Using clearance techniques, the hallmark of the HRS was found in 1967 to be severe renal vasoconstriction.6,7

The term “hepatorenal syndrome” was first used in 1939 to describe the occurrence of renal failure after biliary surgery or hepatic trauma.810 Later it was extended to other types of acute renal failure in liver diseases. In 1996, the International Ascites Club proposed a new definition and diagnostic criteria for HRS, since then this term has been generally accepted for the functional renal failure that develops in patients with advanced cirrhosis.11

The diagnostic criteria of HRS are listed in the Table. Low glomerular filtration rate (GFR) is a highly specific but not very sensitive marker. For those at risk, the GFR should be monitored frequently to detect progressive reduction. To exclude prerenal failure, renal function should be reevaluated after diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline. Most cases of HRS have urine sodium <10 mmol/L and urine osmolality above plasma osmolality because the tubular function is preserved. However, a minority of patients may have higher urine sodium and low urine osmolality, similar to values found in acute tubular necrosis.12 Conversely, some cirrhotic patients with acute tubular necrosis may have low urine sodium and high urine osmolality.13 So urinary indices are not considered major criteria for the diagnosis of HRS. Other causes of renal failure in cirrhosis include prerenal failure secondary to volume depletion, acute tubular necrosis, drug-induced nephrotoxicity (e.g. aminoglycoside antibiotics, non-steroidal anti-inflammatory drugs, and antiviral therapy), renal failure due to radiocontrast agents, obstructive uropathy and glomerulonephritis in patients with hepatitis B or C. Since only about 30% of patients with cirrhosis and renal failure will have HRS and there are no specific clinical findings, it is important to exclude other causes, e.g. by abdominal ultrasound.

Table
International Ascites Club’s Diagnostic Criteria of Hepatorenal Syndrome.(Adapted from reference 11.)

Clinically HRS can be divided into types 1 and 2.11 Type 1 HRS is characterised by a rapid and progressive impairment of renal function as defined by a doubling of the initial serum creatinine to a level higher than 221 μmol/L in less than 2 weeks. The GFR is usually below 20 mL/min. The median survival time is less than 2 weeks and practically all patients die within 8–10 weeks after the onset of renal failure. Type 2 HRS is characterised by a subtler course with initial serum creatinine levels less than 221 μmol/L. The main clinical consequence of type 2 HRS is diuretic-resistant ascites. Patients have a longer median survival time of approximately 6 months.

Epidemiology and Clinical Manifestations

HRS occurs in about 4% of patients admitted with decompensated cirrhosis, with a cumulative probability of 18% at 1 year and 39% at 5 years.14 Patients with spontaneous bacterial peritonitis will have a one-in-three chance of developing HRS.15

Mostly HRS develops in patients with advanced cirrhosis so they will usually have jaundice and other stigmata of chronic liver disease such as finger clubbing, palmar erythema and spider naevi. Other clinical features include splenomegaly, bleeding tendency, hepatic encephalopathy, oedema and ascites. Patients will usually have low arterial blood pressure, wider pulse pressure and bounding pulses. The urine output will be drastically reduced, particularly in type 1 HRS. Only rarely will HRS occur in patients with early well-compensated disease. Patients with refractory ascites, defined as a lack of response to high doses of diuretics (400 mg of spironolactone per day plus 160 mg of furosemide per day) will have an increased risk of HRS.11

Pathophysiology

The pathophysiology of HRS is complex and not completely understood. There are recent reviews with detailed descriptions on various physiological aspects of HRS.16,17 The hallmark of HRS is renal vasoconstriction. In contrast, there is severe arterial underfilling in the systemic circulation due to pronounced arterial vasodilatation in the splanchnic circulation, which is related to the portal hypertension. The following postulates contribute to the pathogenesis of HRS as schematically represented in the Figure.

Figure
Pathogenesis of HRS (adapted from References 16 and 17).

Hepatorenal Reflex

In dogs, increases in intrahepatic pressure resulted in increased renal sympathoadrenal activity with decreases in renal blood flow and GFR, and increases in tubular reabsorption of sodium and water.18 In another experiment, hepatic denervation postponed sodium and water retention and ascites formation in dogs.19 These studies support the existence of a hepatorenal reflex, which may be activated via adenosine receptors as in animals, and administration of an adenosine receptor antagonist prevented an increase in sodium and water retention following a reduction in portal venous blood flow.20 However, it is still debatable whether hepatorenal reflex is present in humans.

Arterial Vasodilatation Theory

The pathophysiology that best fits with the observed changes in renal and circulatory function in HRS is arterial vasodilatation.21 It is postulated that HRS is the result of the action of vasoconstrictor systems on the renal circulation activated as a homeostatic response to improve the extreme underfilling of the arterial circulation. As a result of this increased activity of the vasoconstrictor systems, renal perfusion and GFR are greatly reduced but tubular function is preserved.

Activation of the vasoconstrictor systems leads to the retention of sodium (renin-angiotensin-aldosterone system and sympathetic nervous system) and free water (arginine vasopressin) that occurs in advanced cirrhosis.22 Most available data suggest that the arterial underfilling is due to vasodilatation of the splanchnic circulation related to increased splanchnic production of various vasodilator substances with nitric oxide being the most studied.23 Renal excretion of nitrates and nitrites is increased in cirrhotic rats and acute nitric oxide synthase activity inhibition improves their excretory functions. Chronic inhibition of nitric oxide synthase activity also improves sodium and water excretion. Other vasodilators included tumour necrosis factor (TNF), calcitonin gene-related peptide, plasma substance P, adrenomedullin and endocannabinoids.2429 The HRS patients are also noted to have decreased cardiac output in the settings of severe arterial dilation.30

Renal Vasoconstriction

In the early phases of decompensated cirrhosis, renal perfusion is maintained within the normal range because of increased synthesis of vasodilating factors (mainly prostaglandins).3133 In the later phases, renal perfusion cannot be maintained because the extreme arterial underfilling causes maximum activation of vasoconstrictor systems together with decreased production of renal vasodilator factors, and HRS develops. The splanchnic area escapes the effect of vasoconstrictors probably because of the greatly increased local production of vasodilators.

Endothelins

Endothelins are a group of three related peptides of 21 amino acids with two receptor subtypes, ETA and ETB. In vascular smooth muscle both receptor subtypes are expressed which mediate vasoconstriction. ETB receptors are also found on endothelial cells where they cause vasodilatation through a nitric oxide dependent mechanism.34 Endothelin 1 (ET-1) was first isolated from porcine endothelial cells.35 Increased circulating ET-1 concentrations and hepatic release have been found in cirrhosis with highest levels in patients with ascites and HRS, and ET-1 may mediate renal vasoconstriction.36,37 However, the mechanisms leading to increased ET-1 synthesis in HRS are still unknown.

Management

Until recently, HRS, particularly type 1, has been considered a rapid and fatal complication of end-stage liver disease unless liver transplantation can be immediately performed. Fortunately with increased knowledge in pathogenesis, new pharmacological treatments have been devised to improve short-term outcome and enhance the feasibility of performing liver transplantation for patients with HRS.

General Management

Usually type 1 HRS develops in patients with advanced chronic liver disease but it can also occur in patients with acute liver failure. Frequent monitorings of fluid intake, blood chemistries and urine output are needed. In case of dilutional hyponatraemia, fluid restriction of 1 L per day is recommended.38 The use of diuretics in HRS requires very careful consideration due to the potential of worsening electrolytes (hyperkalaemia and hyponatraemia) and resistance to their actions. Patients with type 2 HRS are usually less sick and can be managed in an outpatient setting. Other causes which precipitate HRS should be excluded, e.g. diagnostic paracentesis for spontaneous bacterial peritonitis.

Vasoconstrictor Therapy

Many pharmacological interventions have been tried for treating HRS. Use of renal vasodilators (dopamine and prostaglandin analogues) was abandoned due to side effects and lack of adequate data confirming the benefits.39 Systemic vasoconstrictors with plasma expansion are now the best therapy since several uncontrolled studies have confirmed a beneficial role in HRS. They were first used in 1998 and their actions are to suppress the arterial splanchnic vasodilation and endogenous vasoconstrictor system activation with improvement of renal function.40

In most studies, vasoconstrictors were given in combination with albumin, with improved efficacy. Vasopressin analogues (ornipressin and terlipressin) have been used in the management of acute variceal bleeding in cirrhotic patients since they have a marked vasoconstrictor effect in the splanchnic circulation. Use of ornipressin was abandoned since it caused significant ischaemic side effects.40 Terlipressin has been shown to have the most successful outcomes of the vasoconstrictors studied.4144 Administration of terlipressin (0.5 2 mg/4–6h intravenously) is associated with an improvement in renal function in about 60% of the patients and the incidence of ischaemic side-effects is about 10%. The recurrence of HRS after treatment withdrawal is about 50%, and retreatment of recurrence is effective. Somatostatin analogues (octreotide), and alpha-adrenergic agonists (midodrine and noradrenaline) have also been used.4547 Midodrine (7.5–12.5 mg/8 hr orally) is found to be effective and is often used as a first-line treatment since the cost of terlipressin is high and it may not be available in some countries.

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

This is a non-surgical method of portal decompression previously used as an alternative therapy for cirrhotic patients bleeding from oesophageal or gastric varices who do not respond to endoscopic and medical treatment. An interventional radiologist will place a side-to-side portacaval shunt that connects the portal and hepatic veins within the hepatic parenchyma. TIPS reduces portal pressure and returns some of the volume of blood pooled in the splanchnic circulation to the systemic circulation. This suppresses the renin-angiotensin-aldosterone and sympathetic nervous systems activities and decreases their vasoconstrictor effect on the renal circulation.46,48 However there are also many complications associated with TIPS including transcapsular puncture, shunt dysfunction and encephalopathy, and it is contraindicated for patients with advanced Child C cirrhosis.46

Dialysis

Small uncontrolled studies using haemodialysis and peritoneal dialysis suggest that both are ineffective mainly due to a high incidence of severe side effects, including arterial hypotension, coagulopathy and gastrointestinal bleeding. However, haemodialysis may be useful in suitable liver transplant candidates as a bridge to transplantation when there is no response to vasoconstrictors or TIPS or patients develop severe volume overload, metabolic acidosis or refractory hyperkalemia. The beneficial effect of an extracorporeal albumin dialysis system was reported in patients with Child C cirrhosis and type 1 HRS.49

Liver transplantation

This is the definitive treatment for HRS. However, transplantation for type 1 HRS is limited by the fact that many patients die before the operation because they have a short survival against a prolonged waiting time in most centres. If liver transplantation can be performed, the 3-year survival probability after transplantation for HRS patients treated with terlipressin and albumin is similar to that of cirrhotic patients without HRS.50

Prevention

In patients with spontaneous bacterial peritonitis, the administration of albumin can prevent the circulatory dysfunction and subsequent development of HRS.51 The rationale is that it can prevent arterial underfilling and subsequent activation of vasoconstrictor systems during the infection. In patients with acute alcoholic hepatitis, the use of pentoxifylline, an inhibitor of TNF, had been shown to reduce the incidence of HRS and mortality compared to the control group.52

Concluding Remarks

HRS is a life threatening complication of liver cirrhosis. With increased knowledge regarding liver cirrhosis, portal hypertension, ascites as well as HRS, new pharmacological treatments such as administration of terlipressin and albumin have proven useful in improving the short-term outcome of HRS. Other medical treatments using different pharmacological principles such as endothelin antagonists, adenosine-receptor antagonists and N-acetylcysteine may also help in reducing renal vasoconstriction and improving renal function.5355 The future treatment of HRS will likely target the multiple aspects in the pathophysiological process.

Footnotes

Competing Interests: None declared.

References

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