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A complication of end-stage liver disease which occurs in patients who have chronic liver dysfunction with cirrhosis and ascites and also in acute liver failure. In hepatorenal syndrome (HRS) there is impaired renal function which is often precipitated by events lowering blood pressure.
A number of factors can precipitate hepatorenal syndrome, including infections, alcoholic hepatitis and bleeding.
HRS is a common complication of end-stage liver disease. The incidence of HRS is unknown. However, it is estimated that 35-40% of patients with end-stage liver disease and ascites eventually develop HRS.
Diagnostic criteria for hepatorenal syndrome
HRS is essentially a diagnosis of exclusion - ie there is an absence of other identifiable causes of renal failure. The diagnostic criteria have been defined as follows:
- Cirrhosis with ascites.
- Serum creatinine >1.5 mg/dL (133 μmol/L).
- Absence of shock.
- Absence of hypovolaemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least two days of diuretic withdrawal (if on diuretics), and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day.
- No current or recent treatment with nephrotoxic drugs.
- Absence of parenchymal renal disease as defined by proteinuria <0.5 g/day, no micro-haematuria (<50 red cells/high-powered field), and normal renal ultrasonography.
HRS is probably the result of a combination of the following: splanchnic vasodilatation leading to systemic circulatory dysfunction, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, and changes in cardiac output (usually low but is always less than the patient's requirements). In addition there is enhanced release of vasoactive mediators - eg, thromboxane A2 and endothelin-1. The end result is intrarenal arteriolar vasoconstriction.
HRS has been divided into two types depending on rate of progression:
- Type 1 - defined as a doubling of serum creatinine to >221 μmol/L in less than two weeks, ie rapidly progressing. These patients have a very low glomerular filtration rate (GFR) (<20 ml/minute) and very poor prognosis. This is usually associated with a precipitating event - eg, variceal bleed, spontaneous bacterial peritonitis.
- Type 2 - defined as a more gradual decline in renal function, associated with sodium retention and refractory ascites.
Patients with type 2 HRS can go on to develop type 1 HRS following a precipitating event.
Patients with ascites and other signs of severe liver disease (jaundice, bleeding disorders, malnutrition, stigmata of chronic liver disease) develop renal failure (oligouria or just increasing serum creatinine levels). There is salt and water retention with increased ascites and peripheral oedema - although pulmonary oedema is uncommon. Hyponatraemia is almost universally present (dilutional hyponatraemia); hyperkalaemia is common (and should be aggressively treated).
- Spontaneous bacterial peritonitis - 30% will develop HRS.
- Gastrointestinal (GI) tract bleed.
- Superimposed infections - eg, pneumonia.
This is made after excluding other causes of renal failure in patients with liver failure:
- Pre-renal causes (eg, whether there is history of dehydration, over-diuresis, GI fluid loss).
- Any history of nephrotoxic drugs.
- Whether there is history of shock before renal failure (which would suggest acute tubular necrosis).
- Whether there is any proteinuria ± haematuria, suggesting a parenchymal renal disease (renal ultrasound scan may be helpful) - particularly, glomerulonephritis (associated with hepatitis B/hepatitis C or chronic alcoholism).
Type 1 HRS
- Admit to hospital - ideally to the high-dependency unit.
- Monitor fluid status closely - eg, urine output and CVP monitoring which will help guide fluid replacement.
- Restrict fluids if necessary.
- Treat any precipitating infections aggressively. If there is no clear focus of infection, patients should still be started on broad-spectrum antibiotics - and a full course completed.
- Avoid nephrotoxic drugs and stop diuretics.
- Start splanchnic vasoconstrictors - eg, terlipressin in combination with albumin replacement.
- Terlipressin leads to an increased blood pressure and GFR, through constriction of splanchnic blood vessels.
- Monitor closely for: ischaemic heart disease, arrhythmias, fluid overload and digital ischaemia.
- Alternatives include noradrenaline (norepinephrine) or midodrine (unlicensed in the UK) and octreotide, although at present there is little experience of using these drugs.
Transjugular intrahepatic portosystemic shunt (TIPS)
- TIPS is used to reduce ascites in patients with portal hypertension, in those who do not respond to medical treatment.
- It is contra-indicated in severe liver failure, which has limited its use.
- Studies have not reported TIPS to be associated with increased survival in type 2 HRS.
- The best chance of long-term survival would seem to be liver transplantation.
- Renal replacement therapy (RRT) may be necessary - eg, pulmonary oedema, severe hyperkalaemia or metabolic acidosis not responding to other treatment. Yet there are no data suggesting improvements in survival in HRS with RRT.
Type 2 HRS
- Patients who develop type 2 HRS may need to be admitted and treated as type 1 HRS.
- Some patients with type 2 HRS can be treated on an outpatient basis with sodium restriction and diuretics (eg, spironolactone - monitor for hyperkalaemia).
- Elective admissions with repeated paracentesis may be necessary to control gross ascites.
- TIPS can be used in refractory cases and may be more feasible than in type 1 HRS.
- Liver transplantation is the best option for both types 1 and 2 HRS (whether or not they respond to vasoconstrictors).
- Combined kidney and liver transplant may be needed in patients with HRS who require prolonged renal support (ie >3 months).
HRS is associated with low survival, with an average median survival rate of only three months for type 1 HRS and six months for type 2 HRS. Liver transplantation in both type 1 and type 2 HRS improves survival, with rates of 65% in type 1 HRS reported.
- It may be possible to reduce the incidence of HRS in patients by early administration of albumin (especially in patients with bacterial peritonitis).
- Pentoxifylline and norfloxacin may decrease the incidence of HRS in selected patients but further studies are needed.
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Further reading & references
- Gines P, Guevara M, Arroyo V, et al; Hepatorenal syndrome. Lancet. 2003 Nov 29 362(9398):1819-27.
- Egerod Israelsen M, Gluud LL, Krag A; Acute kidney injury and hepatorenal syndrome in cirrhosis. J Gastroenterol Hepatol. 2015 Feb 30(2):236-43. doi: 10.1111/jgh.12709.
- Al-Khafaji A, Nadim MK, Kellum JA; Hepatorenal Disorders. Chest. 2015 Mar 26. doi: 10.1378/chest.14-1925.
- Management of Ascites Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome in Cirrhosis; European Association for the Study of the Liver (2010)
- Salerno F, Gerbes A, Gines P, et al; Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007 Sep 56(9):1310-8. Epub 2007 Mar 27.
- Dundar HZ, Yilmazlar T; Management of hepatorenal syndrome. World J Nephrol. 2015 May 6 4(2):277-86. doi: 10.5527/wjn.v4.i2.277.
- Gines P, Uriz J, Calahorra B, et al; Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology. 2002 Dec 123(6):1839-47.
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