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Hepatorenal syndrome (HRS)

What is HRS?

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 caused by intrarenal vasoconstriction which occurs in patients with end-stage liver disease and circulatory dysfunction. Circulatory dysfunction is characterized by vasodilatation in the splanchnic circulation with a relatively low and insufficient cardiac output, leading to effective hypovolaemia. HRS may occur spontaneously with worsening liver function, or secondary to a precipitating event such as bacterial infection or large volume paracentesis without albumin administration.

What are the types of HRS?

There are two types of HRS.

Type-1 HRS is characterized by rapid progressive renal failure defined by doubling of the initial serum creatinine concentrations to a level greater than 226 mmol/l in less than 2 weeks.

Type-2 HRS is characterized by moderate renal failure (serum creatinine from 133 to 226 mmol/l), 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.

HRS means type -1 HRS, unless otherwise indicated.

How do you diagnose HRS?

New diagnostic hepatorenal syndrome criteria in cirrhosis

  1. Cirrhosis with ascites.
  2. Serum creatinine >133 mmol/l (1.5 mg/dl).
  3. No improvement of serum creatinine (decrease to a level of (133 mmol/l) after at least 2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day.
  4. Absence of shock.
  5. No current or recent treatment with nephrotoxic drugs.
  6. Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhaematuria (>50 red blood cells per high power field) and/or abnormal renal USS.

How do you treat HRS?

Terlipressin- It should be started at 0.5– 1 mg every 4–6 h.

  • If there is no early response (>25% decrease in creatinine levels after 2 days), the dose can be doubled every 2 days up to a max of 12 mg/day.
  • Treatment can be stopped if serum creatinine does not decrease by at least 50% after 7 days of the highest dose, or if there is no reduction after the first 3 days.
  • In patients with early response, treatment should be extended until reversal of HRS or for a maximum of 14 days.
  • Terlipressin may induce ischaemic side effects and arrhythmias requiring drug discontinuation. Severe side effects of the treatment are uncommon (5-10%)

Albumin-
In the absence of dose/effect studies, the dose of albumin recommended is 1 g/kg of body weight on the first day, up to a maximum of 100 g, followed by 20–40 g/day. Albumin may be discontinued if serum albumin concentration is >45 g/l.

Complete response (reversal of HRS): defined as decrease of serum creatinine to below 133 mmol/l occurs in 60% with the above regimen.

No response: defined as no decrease of serum creatinine or decrease to less than 50% of its pre-treatment value, with a final level above 133 mmol/l (1.5 mg/dl).

What are the options if the patient relapses after treatment?

Renal failure may recur after discontinuation of therapy (relapse- occurs in 20%), but retreatment is usually effective. In contrast, partial response is frequently followed by a severe and irreversible relapse of renal failure.

Do all patients with HRS need a central line for treatment?

Albumin may cause pulmonary oedema and should be withdrawn if this happens. Since this complication is uncommon, catheterization to monitor central venous pressure is not mandatory, but careful physical and radiological monitoring of the cardiopulmonary function is recommended.

Is TIPS effective in non responders?

Patients with partial or no response to vasoconstrictors may be treated with 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 more than 85.5 mmol/l (5 mg/dl), severe encephalopathy or history of recurrent encephalopathy, severe bacterial infection, and serious cardiac or pulmonary dysfunction or a Child–Pugh score more than 11.

What is the role of extracorporeal albumin dialysis (ECAD) in HRS treatment?

If there are contra-indications to TIPS, ECAD (could be used in the setting of prospective trials. ECAD decreases serum creatinine levels, but it is not definitively known whether or not this effect is due to a true improvement of renal function or simply to the filtration process.

What is the role of liver transplantation?

Liver transplantation 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. Patients with HRS who undergo liver transplantation tend to have more complications, spend more days in intensive care units and have higher in-hospital mortality rates than liver transplant patients without HRS. However, their 3-year probability of survival is acceptable (60% vs. 70–80% in liver transplant patients without HRS). The main limitation of liver transplantation is that due to the shortage of donor organs, and their extremely short survival, most patients with type-1 HRS die before transplantation.

Can HRS be prevented?

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. As type-1 HRS almost exclusively occurred in patients with serum bilirubin >68 mmol/l (4 mg/dl) and serum creatinine >88.4 mmol/l (1 mg/dl), the prophylactic use of albumin could probably be restricted to these patients, but trials need to be conducted so that the optimum dosage to be used can be defined more precisely. So, Albumin administration is clearly indicated for patients with SBP and serum bilirubin levels more than 68.4 mmol/l or serum creatinine levels more than 88.4 mmol/l.

Is Terlipressin and albumin regime effective for type 2 HRS?

There are no definite data to support the use of vasoconstrictors in type 2 HRS patients. TIPS can be used to improve refractory ascites, which is often associated with type-2 HRS. Data on the effect of TIPS on survival are still insufficient.

A patient with cirrhosis and ascites admitted with pneumonia develops renal failure in the absence of septic shock? Is it HRS?

Renal failure in the setting of ongoing bacterial infection, but in the absence of septic shock, is now considered HRS. This means treatment of HRS can be started without waiting for complete recovery from the infection.

Ref

  1. Salerno F et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310-1318.

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