Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a serious complication of end-stage liver disease, occurring mainly in patients with advanced cirrhosis and ascites, who have marked circulatory dysfunction, as well as in patients with acute liver failure. In spite of its functional nature, HRS is associated with a poor prognosis, and the only effective treatment is liver transplantation.

The definition and diagnostic criteria for HRS established in 1994 were based on the following three concepts: renal failure in HRS is functional and caused by marked intrarenal arteriolar vasoconstriction;  systemic circulatory dysfunction caused by extra-renal vasodilatation; plasma volume expansion does not improve renal failure.

New Definition

HRS is a potentially reversible syndrome that occurs in patients with cirrhosis, ascites and liver failure, as well as in patients with acute liver failure or alcoholic hepatitis. It is characterised by impaired renal function, marked alterations in cardiovascular function and overactivity of the sympathetic nervous and renin–angiotensin systems. There are two types of HRS.

Type-2 HRS is characterised by moderate renal failure (serum creatinine from 1.5 to 2.5 mg/dl), with a steady or slowly progressive course. It appears spontaneously, but can also follow a precipitating event. Type-2 HRS is typically associated with refractory ascites. Survival of patients with type-2 HRS is shorter than that of non-azotaemic cirrhotic patients with ascites but better than that of patients with type-1 HRS.

Type-1 HRS is characterised by rapid progressive renal failure defined by doubling of the initial serum creatinine concentrations to a level greater than 226 mmol/l (2.5 mg/dl) in less than 2 weeks. It may appear spontaneously, but often develops after a precipitating event, particularly SBP. Type-1 HRS usually occurs within the setting of an acute deterioration of circulatory function characterised by arterial hypotension and activation of endogenous vasoconstrictor systems, and may be associated with impaired cardiac and liver functions as well as encephalopathy.
The natural prognosis of type-1 HRS is very poor.

Prevention 

The incidence of HRS in patients with SBP may be reduced by albumin administration, prevention which was associated with improved survival. The suggested dose of albumin is 1.5 g/kg body weight on the first day and 1 g/kg body weight on the third day, up to a maximum of 150 and 100 g, respectively. Albumin administration is clearly indicated for patients with SBP and serum bilirubin levels 4 mg/dl or serum creatinine levels 1 mg/dl. Future studies are necessary to define better optimal doses of albumin and the subgroup of patients for whom treatment is highly indicated.

Treatment of HRS

Liver Transplantation 

This is the treatment of choice for both type-1 and type-2 HRS. Morbidity after liver transplantation is higher in patients with HRS than in those without HRS, although the long-term probability of survival is only slightly lower. Reversal of type-1 HRS by pharmacological treatment before liver transplantation may improve survival after transplantation. The reduction in serum creatinine levels after treatment and the related decrease in the MELD score should not change the decision to perform
liver transplantation since the prognosis after recovering from type-1 HRS is still very poor.

Vasoconstrictors and Albumin 

The use of an analogue of vasopressin to improve renal blood flow in cirrhotic patients was first proposed by Kew et al, 35 years ago. The mechanism by which vasoconstrictors and albumin improve the glomerular filtration rate (GFR) in patients with HRS is incompletely understood. Nevertheless, administration of terlipressin to patients with HRS increases blood pressure and leads to a significant decrease in PRA and increase in GFR, indirectly indicating correction of circulatory dysfunction.

It is conceivable that vasopressin analogues cause vasoconstriction of the splanchnic bed, thereby allowing redistribution of the blood volume to some of the extrasplanchnic organs including the central compartment and the kidneys. Filling of the central compartment will lead to the inhibition of the sympathetic nervous and renin–angiotensin systems, thereby shifting the autoregulatory curve to the left
and making renal blood flow and GFR more responsive to changes in blood pressure. Albumin is traditionally considered to improve circulatory function in cirrhosis by expanding central blood volume and increasing cardiac output.

TIPS 

The small amount of data on the use of TIPS in HRS shows that it improves renal function and eliminates ascites. In patients with type-1 HRS, TIPS may also improve survival, but this is debatable in patients with type-2 HRS. The major disadvantage
of TIPS is its low applicability. Indeed, it should not be used in patients with serum bilirubin levels 5 mg/dl, severe encephalopathy or history of recurrent encephalopathy, severe bacterial infection, serious cardiac or pulmonary dysfunction or a Child–Pugh score >11.

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