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

• Thrombotic Thrombocytopenia Purpura
• IgA Nephropathy
• "HUS-Like" Disorder

Hemolytic-Uremic Syndrome (HUS) is a very rare disorder that most commonly affects young children between the ages of one and 10 years, particularly those under the age of four years. In most cases, the onset of Hemolytic-Uremic Syndrome is preceded by a flu-like illness (gastroenteritis) that is characterized by vomiting, abdominal pain, fever, and diarrhea, which, in some cases, may be bloody. In some rare cases, the onset of Hemolytic-Uremic Syndrome may follow an upper respiratory tract infection.

In most cases of Hemolytic-Uremic Syndrome, initial symptoms usually become apparent three to 10 days after the development of gastroenteritis. Affected children may become increasingly irritable and have abnormally pale skin color (pallor), weakness, lack of energy (lethargy), and/or diminished excretion of urine (oliguria). In some severe cases, affected children may be unable to produce and pass urine (anuria). Many children also develop more severe symptoms associated with dysfunction of the kidneys and the cardiovascular and nervous (neurological) systems. In some cases, affected individuals may have an abnormally enlarged liver and/or spleen (hepatosplenomegaly).

Although rare, Hemolytic-Uremic Syndrome is the most common cause of acute kidney (renal) failure in young children. Acute renal failure is characterized by an inability of the kidneys to process waste products from the blood and excrete them in the urine, regulate the balance of salt and water in the body, and perform other vital functions. Acute renal failure may result in diminished amounts of excreted urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. Most individuals with Hemolytic-Uremic Syndrome experience recovery from renal failure. However, in approximately 10 percent of cases, affected individuals may develop chronic renal failure although having previously recovered from Hemolytic-Uremic Syndrome. Others may have permanent kidney damage and may experience progressive loss of kidney function during the following five to 10 years.

In many cases of Hemolytic-Uremic Syndrome, affected individuals have low levels of functioning red blood cells (erythrocytes) due to destruction of erythrocytes as they pass through injured blood vessels (microangiopathic hemolytic anemia). (For more information on this process, see the Causes section of this report.) Since red blood cells carry oxygen throughout the body, such anemia may cause dizziness, weakness, fatigue, headaches, breathing difficulties (dyspnea), and/or, upon exertion, chest pain (angina pectoris) and heart palpitations. In rare cases, affected individuals may also exhibit persistent yellowing of the skin, mucous membranes, and whites of the eyes due to such red blood cell destruction (hemolytic jaundice).

In addition, affected individuals have abnormally low levels of circulating blood platelets (thrombocytopenia) and platelets accumulate abnormally within damaged blood vessels, causing the formation of small blood clots (microthrombi) and compromising blood flow to certain organs of the body, particularly the kidneys. Such compromised blood flow may result in multiple organ dysfunction or failure (e.g., of the pancreas, heart, colon, etc.). Resulting abnormalities may include the sudden onset of diabetes (pancreatic dysfunction), impaired ability of the heart to pump blood effectively (heart failure), and/or inflammation of the colon (colitis). In addition, abnormally low levels of circulating blood platelets (thrombocytopenia) may result in a variety of symptoms including the development of purple bruises on the skin, blood in the urine (hematuria), and/or small red or purple spots on the skin and/or mucous membranes (petechiae).

In addition, in some cases, abnormalities of the central nervous system (i.e., brain and spinal cord) may also occur, which may be due, in part, to the formation of small blood clots (microthrombi) causing insufficient blood supply (ischemia) to certain areas of the brain (cerebral infarction). Such abnormalities may include disorientation and confusion, marked irritability, seizures (e.g., partial or generalized), and/or double vision (diplopia). Affected children may also experience hallucinations and abnormal rigidity of certain muscles, causing the muscles to become fixed in abnormal positions (dystonic posturing). In some severe cases, affected children may experience temporary or permanent paralysis of one side of the body (hemiparesis); blindness; altered consciousness; and/or loss of consciousness (coma). Neurological abnormalities may be present at the onset of Hemolytic-Uremic Syndrome or occur at any point during the disorder's progression. In most cases, such neurological symptoms may recede. According to the medical literature, individuals with neurological abnormalities may be at increased risk for severe kidney dysfunction.

In rare cases, Hemolytic-Uremic Syndrome may affect adults.
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In most cases, Hemolytic-Uremic Syndrome (HUS) occurs in association with infection by a particular strain (O157:H7) of bacterium known as Escherichia coli (E. coli). The bacterium may reside in the intestinal tract of certain domestic animals and may be transmitted to humans through the consumption of unpasteurized milk or infected, undercooked meat or poultry. In addition, cases have been reported in which HUS resulted due to consumption of unpasteurized or otherwise untreated apple juice or cider. In some cases, transmission may be the result of person-to-person contact. Other related toxin-producing (i.e., Shiga-producing) bacteria, such as Shigella dysenteriae Type I, may also cause Hemolytic-Uremic Syndrome.

The O157:H7 strain of E. coli produces a poison known as Shiga toxin or verotoxin that is absorbed through the intestines. Verotoxin damages specific cells (e.g., endothelial cells) that line the inner walls of the blood vessels, particularly those of the kidneys. Damage to these blood vessels (microangiopathy) leads to complications such as anemia, thrombocytopenia, acute renal failure, and other symptoms and findings associated with Hemolytic-Uremic Syndrome. For example, microangiopathic hemolytic anemia occurs when red blood cells are destroyed or damaged as they pass through the small damaged blood vessels. Likewise, circulating platelets are also damaged due to passage through such blood vessels, ultimately resulting in thrombocytopenia and the abnormal accumulation of platelets within narrowed blood vessels, causing the formation of small blood clots (microthrombi). As a result, blood flow to several organs such as the kidneys, brain, and pancreas may be decreased, leading to multiple organ dysfunction or failure. Some researchers have suggested that absence or underproduction of prostacyclin contributes to the progression of Hemolytic-Uremic Syndrome. Prostacyclin, a substance that is produced by endothelial cells, helps prevent blood from clotting (platelet aggregation).

Laboratory studies have suggested that therapy with certain antibiotic medications may increase the release of verotoxin by O157:H7 and other strains of E. coli, potentially resulting in a higher risk of Hemolytic-Uremic Syndrome. In addition, according to researchers, a recent prospective study appears to support this theory. In a study of 71 children younger than age 10 with diarrhea due to E. coli O157:H7, Hemolytic-Uremic Syndrome developed in five of nine children (or in 56 percent) who received treatment with antibiotics (e.g., trimethoprim-sulfamethoxazole or beta-lactams). However, the syndrome developed in just five of 62 children (or eight percent) who did not undergo such antibiotic therapy. The researchers were unable to identify any features that differentiated the children who received antibiotic therapy from those who did not (i.e., to help confirm that the association was independent of "confounding" variables, such as severity of initial infection). Based upon such evidence, the study's investigators concluded that antibiotic therapy for children with E. coli O157:H7 infection increases the risk of Hemolytic-Uremic Syndrome.

Ten of the 71 children (or 14 percent) within the study developed Hemolytic-Uremic Syndrome, a statistic similar to that reported by other investigators. Thus, these findings also suggest that other factors in addition to antibiotic therapy are involved. Additional research is therefore necessary to learn more about the various factors that may cause progression of a gastrointestinal infection with E. coli O157:H7 to Hemolytic-Uremic Syndrome. However, because current evidence now indicates that antibiotic therapy plays an important role, experts recommend that such therapy should be avoided in children infected with E. coli (i.e., enterohemorrhagic strains, such as O157:H7).

In some adults, Hemolytic-Uremic Syndrome has been linked to the prolonged use of oral contraceptives and chemotherapeutic agents; exposure to radiation; certain systemic conditions, such as systemic lupus erythematosus (lupus) or cancer; transplant rejection; pregnancy; and other factors. The development of Hemolytic-Uremic Syndrome in relation to these factors is not fully understood.

In addition, in a few sporadic cases, a familial pattern has been proposed, suggesting that hereditary factors may cause some individuals to have a genetic predisposition to Hemolytic-Uremic Syndrome.

Hemolytic-Uremic Syndrome is a very rare disorder that in theory affects males and females in equal numbers. Most cases occur in children between the ages of one and 10 years; however, individuals of any age may be affected. Each year in the United States, approximately 7,500 children are diagnosed with Hemolytic-Uremic Syndrome. Reports in the medical literature estimate between one and three cases yearly per 100,000 children. In one study, the incidence of Hemolytic-Uremic Syndrome was .97 in 100,000.

Most cases of Hemolytic-Uremic Syndrome tend to occur during warmer months of the year (i.e., April-October). Argentina, the Netherlands, South Africa, Canada, and the west coast of the United States are specific areas where Hemolytic-Uremic Syndrome may have a particularly high rate of occurrence (endemic).

According to the medical literature, females with Hemolytic-Uremic Syndrome appear to be at a greater risk for developing the neurological abnormalities associated with this disorder. The cause for such potentially increased risk is not known.
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Symptoms of the following disorders may be similar to those of Hemolytic-Uremic Syndrome. Comparisons may be useful for a differential diagnosis:

Thrombotic Thrombocytopenia Purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). There is considerable overlap between the physical findings of this disorder and those associated with Hemolytic-Uremic Syndrome, and many researchers have suggested that they may essentially represent the same disorder with variable, overlapping findings due to microangiopathy. According to the medical literature, whereas Hemolytic-Uremic Syndrome is most commonly recorded in children, Thrombotic Thrombocytopenia Purpura appears to occur most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with Thrombotic Thrombocytopenia Purpura may experience acute renal failure, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. The exact cause of Thrombotic Thrombocytopenia Purpura is not known. (For more information on this disorder, choose "Thrombotic Thrombocytopenia Purpura" as your search term in the Rare Disease Database.)

IgA (Immunoglobulin A) Nephropathy is a rare kidney disorder that typically becomes apparent during childhood or young adulthood. The disorder usually follows a viral infection of the upper respiratory tract, flu-like illness, or inflammation of the stomach and intestines (gastroenteritis). The major finding associated with this disorder is blood in the urine (hematuria). There may be associated pain in the lower back and, in rare cases, high blood pressure (hypertension) and/or an abnormal accumulation of fluid between layers of tissue under the skin (edema). Approximately 50 percent of individuals with IgA Nephropathy experience progressive loss of kidney (renal) function. The exact cause of IgA Nephropathy is not known. (For more information on this disorder, choose "IgA Nephropathy" as your search term in the Rare Disease Database.)

A "HUS-Like" disorder that has symptoms and physical findings similar to Hemolytic-Uremic Syndrome has been reported in the medical literature. This "HUS-Like" disorder often occurs in association with Systemic Lupus Erythematosus and is characterized by abnormally high blood pressure (hypertension) and inability of the kidneys to process waste products from the blood and excrete them in the urine, regulate the balance of salt and water in the body, and perform other vital functions (renal failure).
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Diagnosis
The diagnosis of Hemolytic-Uremic Syndrome may be suspected based upon identification of characteristic findings (e.g., acute kidney failure, thrombocytopenia, hemolytic anemia). Hemolytic-Uremic Syndrome should be suspected in young children who experience a sudden development of acute renal failure.

The diagnosis of Hemolytic-Uremic Syndrome may be confirmed by a thorough clinical evaluation, a detailed patient history, and laboratory tests, particularly blood and urine tests. Blood tests may reveal low levels of circulating red blood cells, platelets, and/or certain white blood cells (reticulocytes); damaged or distorted red blood cells (fragmented cells, known as microangiopathic changes); abnormally high levels of potassium (hyperkalemia); and/or the presence of urea or other nitrogen waste products in the blood (azotemia). In addition, testing of the urine (urinalysis) may reveal blood (hematuria) and/or protein (proteinuria) in the urine. Other features may include elevated bilirubin levels. In some cases, additional diagnostic tests may include microscopic examination (i.e., electron microscopy) of samples of kidney tissue (renal biopsy) and electroencephalography (EEG). During electron microscopy, examination of tissue from the structures that filter the blood passing through the kidneys (glomeruli) may reveal characteristic changes that may occur in association with Hemolytic-Uremic Syndrome (e.g., narrowing of the glomerular capillaries and arterioles, formation of microthrombi, necrosis). During an EEG, the brain's electrical impulses are recorded and may reveal brain wave patterns that are characteristic of certain types of seizure activity.

Treatment
The treatment of Hemolytic-Uremic Syndrome is symptomatic and supportive. Early diagnosis is essential for appropriate acute, aggressive care. The main focus of treating Hemolytic-Uremic Syndrome is restoring normal kidney function. During acute renal failure, treatment typically involves using a special medical procedure to remove wastes from the blood (dialysis) until the kidneys can recover and function on their own.

Physicians may prescribe medication to control high blood pressure (hypertension). In addition, in many cases, treatment of seizures with anticonvulsant drugs such as diazepam or phenytoin has proven beneficial.

Most infants and young children with Hemolytic-Uremic Syndrome tend to recover quickly with immediate, appropriate, aggressive supportive therapy. Recovery time may be longer in affected adults, since kidney complications tend to be more extensive. Long-term follow-up and observation are usually recommended to monitor for potential chronic kidney disease and hypertension.

As mentioned above, experts indicate that antibiotic therapy should be avoided in children with E. coli infection (i.e., enterohemorrhagic strains, such as O157:H7). (For further information, please see the "Causes" section of this report above.)

The U.S. Food and Drug Administration has issued emergency approval (August 2000) of an experimental drug to reduce the severity of symptoms from E. coli 0157:H7 infection. If taken early in the course of an infection, the drug may reduce the chance of developing hemolytic uremic syndrome. Called SYNSORB Pk, it is manufactured by Synsorb Biotech Inc. of Canada. In phase II of an FDA-sponsored clinical trial involving 152 children, seven percent of the children who got the drug within two days of onset came down with HUS, compared to 17 percent of those who got only a placebo. Additional research is needed to determine the long-term safety and effectiveness of this drug.

Plasmapheresis may be of benefit in some cases of Hemolytic-Uremic Syndrome. This procedure is a method for removing potentially harmful substances (toxins, metabolic substances, and plasma parts) from the blood. Blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individual.

Fresh frozen plasma transfusions have also been used (alone or in conjunction with plasmapheresis) for treatment of Hemolytic-Uremic Syndrome, in some cases. However, both of these therapies are still under investigation to analyze side effects and effectiveness. More research is needed before plasmapheresis or fresh frozen plasma transfusions can be recommended for use in all but the most severe cases of Hemolytic-Uremic Syndrome.

Scientists are studying whether an agent that binds to shiga-like toxins, SYNSORB PK, may be beneficial in treating individuals with Hemolytic Uremic Syndrome associated with Escherichia coli. For more information on this study, contact:

Howard Trachtman or Erica Christen
Schneider Children's Hospital
Division of Nephrology, Rm. 365
269-01 76th Ave
New Hyde Park, NY 11040-1432
Phone: (718) 470-3491
Fax: (718) 470-0887
e-mail: <trachtman@lij.edu>

NORD does not promote, endorse, or encourage the participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders. NORD recommends that anyone interested in participating in a clinical research program seek the advice or counsel of his or her own personal physician(s).
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