PEDIATRICS

Karina Luise Glaser,MD

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Hemolytic Uremic Syndrome



The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in infants and young children, and an important cause of cronic renal failure and shock during youth. It is estimated that 90% of cases are preceded by a prodrome of bloody diarrhea. The syndrome may also follow the use of some drugs, malignancy, pregnancy, glomerulopathies, or it may be idiopathic.

Diagnosis

The classic diagnostic criteria are microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure, following an acute episode of bloody diarrhea. There may be incomplete syndromes, when the diagnosis becomes unclear.

The differential diagnosis include disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), bilateral renal vein thrombosis and lupus. In DIC, partial thromboplastin time and prothrombin time are prolonged, and the patient may be septic. TTP is common in adults, specially young women, with central nervous system involvement, fever and cutaneous manifestations, and tends to occur as a relapsing illness. The enlargement of kidneys and angiography help distinguish bilateral renal vein thrombosis from the hemolytic uremic syndrome.

Epidemiology

The most common microorganisms associated to the post-diarrhea hemolytic uremic syndrome are Escherichia coli (0157:H7 strain) and type 1 Shigella dysenteriae. The enterohemorrhagic E. coli produces a toxin called verotoxin, which is thought to be involved in the pathogenesis of the syndrome.

The majority of cases has been reported in Buenos Aires (Argentina). Children under 5 years old are most commonly affected. Some studies suggest that white children are more susceptible than black children. The syndrome is more common during the warm months.

The reservoir of the E. coli is the intestinal tract of domestic animals. It is usually transmitted by undercooked meat or unpasteurized milk. Outbreaks have followed ingestion of contaminated apple cider and bathing in a contaminated swimming pool. Direct person to person dissemination has been reported (in institutions for mentally retarded people, day care centers and in a small Canadian community).

Risk Factors Of Progression From Colitis To HUS

  • Young age
  • Infection with the toxin-producing E. coli strain
  • Administration of anti-peristaltic agents

    Pathogenesis

    Only a small inoculation of the enterohemorrhagic E. coli is necessary for colonization of the small intestine (distal ileus) and colon. The production of potent cytotoxins causes the hemorrhagic colitis, characterized by a thrombotic microangiopathy. Once the toxin reaches the circulation, almost any organ can be damaged, although the kidneys are most commonly affected. The damage is dependent on the presence of a specific receptor on the cells’ surface, the GB3 receptor. Once the toxin binds to the GB3 receptor, it reaches the cells’ cytoplasm via endocytosis, causing protein synthesis inhibition, cell injury or cell death.

    The primary event in pathogenesis of the syndrome appears to be endothelial cell injury. Capillary and arteriolar endothelial injury in the kidneys leads to localized clotting. The microangiopathic anemia results from mechanical damage to the red blood cells as they pass to the altered vasculature. Thrombocytopenia is due to intrarenal platelet adhesion or damage.

    Clinical Manifestations

    The onset is usually preceded by gastroenteritis (prodrome). The diarrhea is initially aqueous, soon becoming a bloody diarrhea. Abdominal pain, fever and vomiting may be present. This is followed in a week (it may vary from 1 to 14 days) by the sudden onset of irritability, pallor, weakness, lethargy and oliguria or anuria. Other signs and symptoms may include jaundice, convulsions, dehydration, edema, petechiae, hepatosplenomegaly.

    In 10% of cases rectal prolapse may occur, and 2% of patients may need surgery because of gangrene. Oliguria lasts for about 1 week in 60% of patients; half of patients are anuric for 3 days. Mild hypertension is present in the majority of patients, and resolves easily. When central nervous system involvement is present, patients appear with altered consciousness, changes in muscular tonus and posture, convulsions. Pancreatitis and diabetes may result from pancreatic involvement. Liver, heart, lungs, skin are rarely involved.

    Laboratory Exams

    The hemoglobin is commonly in the range of 5-9 g/dL. The blood film reveals helmet cells, burr cells and fragmented red blood cells. The reticulocyte count is moderately elevated; the Coombs test is negative. The white blood cell count may rise to 30.000/mm3 (the magnitude of white blood cell elevation is related to severity and prognosis of the syndrome). Thrombocytopenia (20.000 - 100.000/mm3) occurs in more than 90% of patients. Findings on urinalysis consist of microscopic hematuria and proteinuria. The severity of renal involvement vary from mild renal insufficiency to acute renal failure requiring dialysis. Complications include acidosis, hyperkalemia, hypocalcemia, hyperphosphatemia, dilutional hyponatremia, fluid overload, congestive heart failure and uremia. Liver enzymes levels may rise, serum albumin level is low and serum uric acid and triglycerides levels are high.

    Barium contrast roentgenograms reveal colonic spasm and transient early filling defects. Subsequent intestinal stenosis is a rare sequela.

    Prognosis and Treatment

    The aim of therapy is to maintain adequate fluid and electrolyte balance, nutritional requirements, treatment of anemia, hypertension, convulsions and uremia. With aggressive management, more than 90% of patients survive the acute phase, and the majority of these recover normal renal function.

    Red blood cells transfusions are necessary in cases of severe anemia. Platelet transfusions are indicated in cases of bleeding, when surgery or invasive procedures are indicated. Hypertension is best managed with calcium channel blockers.

    Some authors suggest that early dialysis offer the best chances of recovery. Peritoneal dialysis not only controls the manifestations of the uremic state, but also promotes recovery by removing an inhibitor of fibrinolysis (plasminogen activates inhibitor-1), thus allowing endogenous fibrinolytic mechanisms to dissolve vascular thrombi, which is believed to improve prognosis. Long term observation is necessary to watch for late development of hypertension or chronic kidney disease.

    Bibliography

    1. Nelson, Waldo E.; Behrman, Richard E.; Kliegman, Robert M.; Arvin, Ann M.; Textbook of Pediatrics; 15th edition; 1996; W. B. Saunders Company.

    2. Siegler, Richard L.: Hemolytic-Uremic Syndrome. Pediatric Clinics of North America - Nephrology.

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