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  Disease summary:

  
  
  
  
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    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.

    
    
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    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.

    
    
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    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.

  
  
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  Hereditary basis:

  
  
  
  
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    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.

    
    
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    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.

  
  
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  Differential diagnosis:

  
  
  
  
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    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.

    
    
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    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.

    
    
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    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.

Diagnostic Criteria for Genetic aHUS

aHUS is considered to have a genetic basis when at least one of the following conditions is present:

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  Two or more members of the same family are affected by the disease at least 6 months apart and exposure to a common triggering infectious agent has been excluded.

  
  
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  A disease-causing mutation is identified in one of the genes in which mutations are known to be associated with aHUS, irrespective of familial history.

Nonetheless, it is possible that at least a subset of the cases not fulfilling the above criteria carry yet to be identified genetic defects.

Clinical Characteristics

About 60% to 70% of patients with genetic aHUS have childhood onset. A variety of triggering conditions have been described, including infections, pregnancy (10%-15% of aHUS cases in females manifest in pregnancy or postpartum), malignancies, transplantation, antiphospholipid syndrome, and use of drugs (calcineurin inhibitors, chemotherapy agents, oral contraceptives, interferon). No triggers are identifiable in about 50% of cases (idiopathic aHUS).

During acute episodes, key clinical findings are thrombocytopenia (often severe, below 60,000/mm³), microangiopathic hemolytic anemia with fragmented red blood cells—schistocytes—in peripheral blood smears, and acute kidney dysfunction (rise in serum creatinine, hypertension, oligoanuria, urinalysis abnormalities). Involvement of other organs, such as brain, heart, pancreas, and gastrointestinal tract, occurs in 20% of cases.

Typical renal histology findings affecting glomeruli and, in most severe cases, arterioles as well, comprise platelet-fibrin thrombi, narrowing of the capillary lumen and endothelial swelling, with detachment of endothelial cells from basal membrane and subendothelial deposition of electron-lucent fluffy material and cell debris.

Overall, renal prognosis is poor in most cases, with frequent relapses even after full recovery and progression to end-stage renal disease in 60% of patients.

Screening

At present, a genetic mutation can be identified in 50% to 60% of aHUS cases, with important implications for the patient and close relatives. All patients presenting with clinical features compatible with aHUS should be screened for genetic alterations, including cases of pregnancy-associated HUS, in whom complement abnormalities have been reported in as much as 86% cases.

No clinical feature can reliably distinguish between different genetic defects. Determination of plasma levels of complement components C3, factor H (FH), and factor I (FI), search for autoantibodies against FH and analysis of surface expression of MCP on peripheral leukocytes by flow cytometry, if altered, can provide hints of the genetic defect most likely involved and therefore guide genetic testing strategy. If no information emerges following this first survey, genetic testing can be undertaken in a stepwise fashion, starting from more prevalent mutations and proceeding to less frequent ones, as resumed in the diagnostic algorithm presented in Fig. 81-1.