Information on the following diseases can be found in the Related Disorders section of this report:

• None

Individuals with hepatorenal syndrome will have a variety of nonspecific symptoms including fatigue, abdominal pain, and a general feeling of ill health (malaise). Affected individuals also have symptoms related to advanced liver disease including the accumulation of fluid in the abdomen (ascites), yellowing of the skin and the whites of the eyes (jaundice), an enlarged spleen (splenomegaly) and an enlarged, extremely tender liver (hepatomegaly).

Hepatorenal syndrome type I is characterized by a rapid decrease in kidney function. The kidneys act as a filtration system removing unwanted substances and excess fluid from the body. Symptoms of decreasing renal function include the accumulation of excess watery fluid in the spaces between the tissues and organs causing swelling of these areas (edema), dramatically decreased urination, and the presence of increased nitrogenous waste products such as creatinine in the blood (azotemia). Hepatorenal syndrome type I can progress to life-threatening renal failure within weeks.

Individuals with hepatorenal syndrome type I are more likely to develop hepatic encephalopathy, a condition that occurs when the liver fails to breakdown (metabolize) certain substances in the body. These substances travel through the bloodstream to the brain with toxic effects. Hepatic encephalopathy may cause confusion, drowsiness, recognizable changes in judgment and other intellectual processes, and other psychological alterations.

Hepatorenal syndrome type II causes renal dysfunction that generally progresses much slower than it does in type I. Affected individuals are less likely to develop jaundice and usually do not develop hepatic encephalopathy. Individuals with hepatorenal syndrome type II often develop accumulation of fluid in the abdomen (ascites) does not respond to treatment with diuretics, which are drugs that help remove excess fluid from the body. This finding is referred to as diuretic-resistant ascites.

The exact cause of hepatorenal syndrome is unknown. It occurs in individuals with advanced liver disease, especially individuals who have scarring and dysfunction of the liver (cirrhosis). The characteristic finding in individuals with hepatorenal syndrome is narrowing (constriction) of the blood vessels that feed the kidneys (renal vasoconstriction), which results in decreased blood flow to the kidneys, eventually impairing kidney function.

The reason that renal vasoconstriction occurs is unknown. Researchers believe that the complex interaction of several different factors is involved including high blood pressure of the main blood vessels of the liver (portal hypertension), abnormalities in the physical factors that govern blood flow (systemic hemodynamics), the activation of substances that cause blood vessels to narrow (vasoconstrictors) and suppression of substances that cause blood vessels to widen (vasodilators).

Researchers have also determined that cirrhotic cardiomyopathy may also contribute to the development of hepatorenal syndrome in some individuals. Cirrhotic cardiomyopathy refers to the abnormal functioning of the heart in individuals with scarring of the liver (cirrhosis). Cirrhotic cardiomyopathy results in decreased cardiac outflow and abnormal widening of certain arteries in the body.

In some individuals with hepatorenal syndrome, certain 'triggers' can be identified that make it more likely for individuals with liver disease to developed impaired kidney function (hepatorenal syndrome). There triggers are called precipitating factors. The most common precipitating factor is spontaneous bacterial peritonitis (SBP), an infection of the thin membrane (peritoneum) that lines the abdominal cavity. SBP is a known complication in individuals with ascites and cirrhosis.

Hepatorenal syndrome affects males and females in equal numbers. The exact incidence of hepatorenal syndrome is unknown. It is estimated to occur in approximately 8-10 percent of individuals with the accumulation of fluid in the abdomen (ascites) and cirrhosis. Although it is most common in individuals with advanced cirrhosis and ascites, hepatorenal syndrome has also occurs in individuals with other forms of liver disease including fulminant hepatic failure.

Symptoms of the following disorders can be similar to those of hepatorenal syndrome. Comparisons may be useful for a differential diagnosis.

There are many causes of acute kidney failure: abnormalities of the blood vessels of or leading to the kidney; abnormalities of the glomeruli of the kidneys due to infections or diseases such as Goodpasture syndrome, polycystic kidney disease, or Wegener's granulomatosis; acute interstitial nephritis (inflammation of the kidney) commonly related to drugs or infections; intratubular obstruction; or acute tubular necrosis. An underlying problem in the kidney distinguishes these disorders from the hepatorenal syndrome. (For more information on these disorders, choose 'Goodpasture', 'Polycystic Kidney', or 'Wegener' as your search terms in the Rare Disease Database.)

Diagnosis
A diagnosis of hepatorenal syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. The International Ascites Club, an organization dedicated to encouraging scientific research into advanced cirrhosis, has established criteria for a diagnosis of hepatorenal syndrome.

The major criteria are: the presence advanced liver failure with portal hypertension; high levels of creatine (an organic acid); the absence of other causes of renal failure such as bacterial infection, shock, and the use of drugs that are toxic to the kidneys; no improvement in renal function with the withdrawal of diuretics and expansion of plasma with saline; and low levels of protein in the urine with no evidence of a disease of the urinary disease (uropathy) or parenchymal renal disease.

Treatment
The only curative therapy for individuals with hepatorenal syndrome is a liver transplant, which corrects both the liver disease and associated impaired renal function. However, due to a limited amount of donors and long waiting lists, a liver transplant is not always feasible. For patients who develop hepatorenal syndrome with acute liver failure and not cirrhosis, recovery from hepatorenal syndrome can occur if the liver recovers.

Individuals with liver disease and the hepatorenal syndrome who receive a liver transplant have a lower success rate than in individuals with liver disease and normal kidney function who receive a liver transplant. Therefore, many of the therapies used to treat hepatorenal syndrome are done to improve kidney function in individuals eligible for a liver transplant.

For individuals awaiting a transplant, several therapies to maintain kidney function may be used. Paracentesis is a surgical procedure that removes the excess fluid from the abdomen (ascites). Under carefully controlled conditions, this procedure may benefit some affected individuals. In addition, avoiding diuretics (which can worsen kidney function), maintaining electrolyte balance, and promptly treating infection may also be necessary.

Several therapies for hepatorenal syndrome have been explored in recent years including drug therapy, a transjugular intrahepatic portosystemic shunt (TIPS), and renal replacement therapy.

A class of drugs known as systemic vasocontrictors (drugs that cause the blood vessels to narrow) has been studied to treat individuals with hepatorenal syndrome. These drugs include terlipressin, ornipressin, midodrine, octreotide, and norepinephrine. Terlipressin has been studied the most for individuals with hepatorenal syndrome and early results have shown improved renal function in affected individuals who have taken the terlipressin along with albumin. Albumin is a protein made by the liver. However, more research is necessary to determine the long-term safety and effectiveness of vasocontrictive agents such as terlipressin for the treatment of individuals with hepatorenal syndrome.

A non-surgical procedure known as transhepatic portosystemic shunts or TIPS has been used to treat several individuals with hepatorenal syndrome. During this procedure, a small metal device called a stent is placed into the liver to improve blood flow. The procedure has been successful in reversing kidney dysfunction in individuals with hepatorenal syndrome. TIPS can lower elevated blood pressure within the portal veins (portal hypertension) – a finding that researchers believe plays a key role in the development of the kidney dysfunction in individuals with liver disease. More research including proper clinical study is necessary to determine the long-term safety and effectiveness of TIPS for the treatment of individuals with hepatorenal syndrome.

Hemodialysis and continuous renal replacement therapy have also been reported as potential treatment options for individuals with hepatorenal syndrome. However, these therapies are only supportive and not curative. More research is necessary to determine the safety, effectiveness and feasibility of these potential therapies for individuals with hepatorenal syndrome.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

TEXTBOOKS
Marrero J A. Hepatorenal Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:344-345.

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:795-796.

Yamada T, Alpers DH, Kaplowitz N, Laine L, et al. Eds. Textbook for Gastroenterology. 4th ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2003:967-969.

JOURNAL ARTICLES
Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008;134:1360-1368.

Wong F. Hepatorenal syndrome: current management. Curr Gastroenterol Rep. 2008;10:22-9.

McCormick PA, Donnelly C. Management of hepatorenal syndrome. Pharmacol Ther. 2008;Epub.

Turban S, Thuluvath PJ, Atta MG. Hepatorenal syndrome. World J Gastroenterol. 2007;13:4046-4055.

Betrosian AP, Agarwal B, Douzinas EE. Acute renal dysfunction in liver diseases. World J Gastroenterol. 2007;13:5552-5559.

Ng CK, Chan MH, Tai MH, Lam CW. Hepatorenal syndrome. Clin Biochem Rev. 2007;28:11-17.

Wadei HM, Mai ML, Ahsan N, Gonwa TA. Hepatorenal syndrome: pathophysiology and management. Clin J Am Soc Nephrol. 2006;1:1066-1079.

Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology. 2005;42:439-447.

FROM THE INTERNET
Bunn AD, Symons JM, Stock A. Hepatorenal Syndrome. Emedicine Journal, September 21 2006. Available at: http://www.emedicine.com/ped/TOPIC985.HTM Accessed on: June 19, 2008.

Bunn AD, Symons JM, Stock A. Hepatorenal Syndrome. Emedicine Journal, September 21 2006. Available at: http://www.emedicine.com/ped/TOPIC985.HTM Accessed on: June 19, 2008.