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Key Points

  • Disease summary:

    • Hemolytic uremic syndrome (HUS) is a rare disease (1-2 cases per 100,000) characterized by the triad of thrombocytopenia, nonimmune hemolytic anemia, and acute renal impairment, due to a microangiopathic lesion affecting especially the glomerular endothelium.

    • Around 90% of HUS cases, referred to as typical or diarrhea-associated HUS, are traceable to gastrointestinal infection with Shiga toxin (Stx)-producing bacteria such as Escherichia coli serotype 0157:H7, are usually heralded by bloody diarrhea and mostly affect children under 5 years. Causes of other distinct forms of HUS include infection by neuramidase-producing Streptococcus pneumoniae, a rare inborn error in cobalamin metabolism and quinine-induced antibodies.

    • The remaining 10% of cases are classified as atypical HUS (aHUS) and can be further distinguished into familial (<20%) and sporadic cases. aHUS occurs at any age and often carries a poor prognosis.

  • Hereditary basis:

    • Genetic abnormalities have been identified in 50% to 60% of aHUS cases, both in familial and sporadic forms. Both autosomal recessive and dominant inheritance are possible; penetrance is incomplete and clinical expression variable.

    • All the genetic defects identified so far result in susceptibility to uncontrolled activation of the alternative pathway of the complement system on the surface of self cells.

  • Differential diagnosis:

    • HUS-like presentations can occur in other forms of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura (usually with predominant neurologic manifestations; very low levels of von Willebrand factor cleaving protease ADAMTS-13), disseminated intravascular coagulation (relevant prolongation of coagulation tests and fibrinogen consumption), scleroderma renal crisis, and malignant hypertension.

    • The diagnosis of aHUS is made by exclusion, in particular typical HUS must be ruled out on the basis of microbiologic findings (serologic or culture evidence of infection by bacteria-producing Stx, toxin assays), since up to 25% of Stx-associated HUS cases may not manifest diarrhea.

    • Among aHUS cases, genetic testing can distinguish between the seven main categories of genetic defects identified so far (Table 81-1); no genetic alteration is found in 30% to 40% of patients.

Table 81-1Genetic Abnormalities and Clinical Outcome in Patients With aHUS

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