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.
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.
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 |Favorite Table|Download (.pdf) Table 81-1 Genetic Abnormalities and Clinical Outcome in Patients With aHUS
|Gene ||Protein Affected ||% aHUS ||% Short-Term Remission With Plasma Therapya ||Rate of ESRD/Deathb ||Outcome of Kidney Transplantation |
|CFH (aHUS1) ||Factor H ||25%-30% ||50%-60% (plasma exchange superior to plasma infusion) ||70%-80% ||80%-90% recurrence |
|MCP (aHUS2) ||Membrane cofactor protein (CD46) ||10%-15% ||No definitive indication for therapy; 80%-90% complete remission independently on plasma therapy ||<20% ||15%-20% recurrence, long-term graft survival similar to graft recipients with other causes of ESRD |
|CFHR1, CFHR3, CFHR4 ||Deletion of factor H-related 1, 3, 4; formation of autoantibodies antifactor H ||6%-10% ||70%-80% (plasma exchange combined with immunosuppression) ||30%-40% ||20% recurrence |
|CFI (aHUS3) ||Factor I ||4%-10% ||25%-40% (larger quantities of plasma needed to achieve remission) ||60%-70% ||70%-80% recurrence |
|C3 (aHUS5) ||Complement C3 ||4%-10% ||50%-60% ||60%-70% ||40%-50% recurrence |
|THBD (aHUS6) ||Thrombomodulin ||5% ||50%-80% ||60% ||1 report of post-transplant recurrence |
|CFB (aHUS4) ||Factor B ||1%-2% ||30%-40% (few data available) ||70% ||Few data available (recurrence in one ...|
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