Hepatorenal syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Hepatorenal syndrome (HRS) refers to acute renal failure that occurs in the setting of cirrhosis or fulminant liver failure associated with portal hypertension, usually in the absence of other disease of the kidney . It is a direct result of changes in the splanchnic and systemic circulation from cirrhosis or fulminant hepatic failure. It is usually secondary to trigger events which cause multi-system organ failure.

Historically, the hepatorenal syndrome was first defined as acute renal failure that occurred in the setting of biliary surgery. The syndrome was soon associated with advanced liver disease. It was determined that kidneys transplanted from patients with hepatorenal syndrome were functional, leading to the hypothesis that hepatorenal syndrome was a systemic process as opposed to renal disease, which affects the renal function.

The classification of hepatorenal syndrome is based on the deteriorating function of kidney.

The major pathophysiologic mechanism responsible for the clinical manifestation of hepatorenal syndrome is renal vasoconstriction. The hemodynamic disturbances include increased cardiac output, systemic vasodilatation and low arterial blood pressure. Thus, renal vasoconstriction occurs even with a normal blood volume and increased cardiac output.

The cause of Hepatorenal syndrome (HS) is deteriorating function of liver.

Many other diseases of the kidney are associated with liver disease and must be excluded before making a diagnosis of hepatorenal syndrome. 

Hepatorenal syndrome (HRS) is common in cirrhotic patients.

Hepatorenal syndrome (HRS) develops on the background of advanced liver disease. HRS may occur spontaneously mostly in type 2 HRS and may be precipitated in >70% of cases of type 1 HRS.

There are predictors for patients suffering from liver disease to view chances of development of hepatorenal syndrome (HRS).

Hepatorenal syndrome progresses from pre-ascitic stage to frank ascites. Multiorgan system failure, infections and chronic renal failure are the most common complication of HPS. Type I HPS carries poorer prognosis compared to type II HPS.

There is no specific marker or imaging test to diagnose patients with hepatorenal syndrome (HRS). For that reason the diagnosis of HRS is based on criteria for excluding other causes of renal impairment which are seen along with cirrhosis.

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies

HRS may develop in two clinical types as an acute and rapidly progressive renal failure (AKI-HRS) or as chronic and not progressive renal failure (CKD-HRS) which can be managed with medications but the end treatment depends on liver transplant.

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Historically, the hepatorenal syndrome was first defined as acute renal failure that occurred in the setting of biliary surgery. The syndrome was soon associated with advanced liver disease. It was determined that kidneys transplanted from patients with hepatorenal syndrome were functional, leading to the hypothesis that hepatorenal syndrome was a systemic process as opposed to renal disease, which affects the renal function.

Historically, the hepatorenal syndrome was first defined as acute renal failure that occurred in the setting of biliary surgery. The syndrome was soon associated with advanced liver disease. It was determined that kidneys transplanted from patients with hepatorenal syndrome were functional, leading to the hypothesis that hepatorenal syndrome was a systemic process as opposed to renal disease, which affects the renal function.^[1][2]

• In 1861, Frerichs noted an association among advanced liver disease, ascites, and oliguric renal failure in the absence of significant renal histologic changes.^[3]
• In 1863, Flint noted relation between ascites and renal failure.
• In 1956, Hecker and Sherlock published article to explain the pathogensis of renal failure in presence of liver failure.^[4]
• In 1965, 1965, Shear demonstrated that acute tubular necrosis (ATN) may also supervene.^[5]
• In 1969, Koppel MH published article regarding normalization of kidney function after it is transplanted to an healthy liver functioning body.^[6]
• In 1970, Epstein M experimentally showed that splanchnic and systemic vasodilation in combination of renal vasoconstriction is the pathogensis behind hepatorenal syndrome.^[7]
• In 1972, Vesin P explained that the prognosis is very poor in patient with renal failure together with of liver failure and named it is “terminal functional renal failure”^[8]
• In 1978, European symposium gathered to decide diagnostic criteria for hepatorenal syndrome.
• In 1980, in conclusion of European symposium Lancet published paper naming and diagnostic outlines of the condition as hepatorenal syndrome or hepatic nephropathy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Sunny Kumar MD [3]

The major pathophysiologic mechanism responsible for the clinical manifestation of hepatorenal syndrome is renal vasoconstriction. The hemodynamic disturbances include increased cardiac output, systemic vasodilatation and low arterial blood pressure. Thus, renal vasoconstriction occurs even with a normal blood volume and increased cardiac output.

The pathology involved in the development of hepatorenal syndrome is thought to be an alteration in blood flow and blood vessel tone in the circulation that supplies the intestines (the splanchnic circulation) and the circulation that supplies the kidney.^[1] It is usually indicative of an end-stage of perfusion, or blood flow to the kidney, due to deteriorating liver function. Patients with hepatorenal syndrome are very ill, and, if untreated, the condition is usually fatal.

• The characteristic fall in systemic vascular resistance and increase in renal vasoconstriction also occurs in other conditions like sepsis and anaphylaxis.
• Doppler studies have proved that the reduced blood pressure in the splanchnic circulation is primarily responsible for the drop in systemic vascular resistance.
• The renal failure in hepatorenal syndrome is believed to arise from abnormalities in blood vessel tone in the splanchnic circulation (which supplies the intestines).^[2]
• It is known that there is an overall decreased systemic vascular resistance in hepatorenal syndrome, but that the measured femoral and renal fractions of cardiac output are respectively increased and reduced, suggesting that splanchnic vasodilation is implicated in the renal failure.^[3]
• There is activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, and profound vasoconstriction of the kidneys.^[4]
• Many vasocontrictor chemicals have been hypothesized as being involved in this pathway, including vasopressin,^[5] prostacyclin, thromboxane A2,^[6] and endotoxin.^[1]
• The prostaglandins antagonize the effects of the vasoconstrictors and maintain the blood flow into the glomerulus.
• The dominant effect of vasoconstrictors over vasodilators is exaggerated in hepatorenal syndrome.

Splanchnic vasodilatation

The vasodilator NO is thought to be responsible for the fall in arterial resistance of the splanchnic circulation and under-filling of the capillary bed. This along with portal hypertension and pooling of a part of blood volume in the form of ascitic fluid results in activation of the renin – angiotensin system, aldosterone and vasopressin causing vasoconstriction of systemic vessels.

Systemic Vasoconstriction

All systemic arteries including those of the kidneys, brain and muscles constrict under the influence of vasoconstrictors. However, the splanchnic vessels remain resistant to the effect of vasoconstrictors because of over production of NO.

In early stages of cirrhosis and ascites, renal vasodilators maintain the inflow of blood into the glomerulus. As the disease progresses and splanchnic arterial pressure falls further, the effect of vasoconstrictors predominate and cause sodium and water retention with dilutional hyponatremia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

The cause of hepatorenal syndrome (HS) is deteriorating function of liver.

The cause of Hepatorenal syndrome (HS) is deteriorating function of liver.

It happens in following context:^[1][2][3]

• Liver function goes down which causes portal hypertension.
• Portal hypertension causes arterial vasodilatation in the splanchnic circulation.
• Arterial vasodilatation in the splanchnic circulation is due to nitirc oxide.
• Arterial vasodilatation in the splanchnic circulation causes decreased blood flow to renal tissue.
• Renal tissue is prone to the hypoxemia.

For causes of liver failure click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Hepatorenal syndrome (HRS) is common in cirrhotic patients.

Incidence:

• In 1993, incidance of HRS had an incidence of 180 in 100000 at one year and 390 in 100000 at five years in patients with cirrhosis and ascites.^[1]

• In 2010, The annual incidence of HRS was 760 in 100000.^[2]

Approximately 50% of the cirrhotic patients with ascites developed some type of functional renal failure during the follow-up period.

Prevalence:

• The prevalence of HRS was from 13000 to 45800 in 100000 n patients with cirrhosis and ascites.^[3]

Age:

• Most patients with HRS are in their sixth or seventh decade.^[4]

Gender:

• Male are more affected population.^[5]

Etiology of Cirrhosis:

•  Alcohol (type 1 HRS 46.1%; type 2 HRS 55%).^[6][7]
• Viral (type 1 HRS 31.6%; type 2 HRS 40%).
• Alcohol and viral causes (type 1 HRS 10.5%; type 2 HRS 2.5%).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Hepatorenal syndrome (HRS) develops on the background of advanced liver disease. HRS may occur spontaneously mostly in type 2 HRS and may be precipitated in >70% of cases of type 1 HRS.

HRS may occur spontaneously mostly in type 2 HRS and may be precipitated in >70% of cases of type 1 HRS.^[1]

Risk factors include:

• Blood pressure that falls when a person rises or suddenly changes position (orthostatic hypotension),
• Use of medicines called diuretics (“water pill“),
• Gastrointestinal bleeding,
• Infection,
• Large volume abdominal fluid tap (paracentesis), ^[2]
• Fulminant hepatic failure,
• Severe acute alcohol-related hepatitis,
• Spontaneous bacterial peritonitis (SBP), ^[3]
• Oxidative stress,
• Fluid loss.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

There are predictors for patients suffering from liver disease to view chances of development of hepatorenal syndrome (HRS).

There are predictors for patients suffering from liver disease to view chances of development of hepatorenal syndrome (HRS).^[1][2]

Following are variables that should taken in consideration to predict HRS:^[3][4]

• Hepatomegaly
• Esophageal varices
• History of ascites
• Nutritional status
• GFR
• Blood urea nitrogen
• Serum sodium and potassium
• Plasma renin activity
• Plasma noradrenaline
• Serum and urinary osmolality
• Urinary sodium excretion
• Free water clearance after a water load
• Mean arterial pressure 

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Many other diseases of the kidney are associated with liver disease and must be excluded before making a diagnosis of hepatorenal syndrome. 

Many other diseases of the kidney are associated with liver disease and must be excluded before making a diagnosis of hepatorenal syndrome. They include the following:^{[1][2][3][4][5]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

Hepatorenal syndrome progresses from pre-ascitic stage to frank ascites. Multiorgan system failure, infections and chronic renal failure are the most common complication of HPS. Type I HPS carries poorer prognosis compared to type II HPS.

Systemic vasodilatation causes kidneys to retain sodium and water, thereby overcoming the compensatory renal vasoconstriction. This prevents the drop in glomerular filtration rate and subsequent vasoconstriction of renal arterioles.^[1][2]

As the systemic vasodilatation worsens further, the kidney’s are unable to compensate and renal arterioles undergo vasoconstriction. As a result, there is sodium and water retention from the renal tubules resulting in ascites. This ascites is responsive to diuretics. Further increase in renal sodium retention causes the ascites to become resistant to treatment with diuretics.^[3][4][5]

Once the ascites progresses to a point where it is unresponsive to diuretics, even repeated paracentesis does not prevent progression to hepatorenal syndrome type I or II.^[6][7]

Hepatorenal syndrome complications include:

• Bleeding
• Multiorgan system failure
• End-stage kidney disease
• Fluid overload with congestive heart failure or pulmonary edema
• Hepatic coma
• Secondary infections
• Death

• Type I HRS carries a very poor prognosis, usually of less than 50% over one month. Patients with type I hepatorenal syndrome are usually ill, may have low blood pressures, and may require therapy with inotropes, or intravenous drugs to maintain blood pressure.^[8]

• It is typically associated with ascites that is unresponsive to diuretic medications, and also carries a poor, if somewhat longer (median survival ~6 months) outlook,^[9] unless the patient undergoes liver transplantation.

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