aHUS

Atypical hemolytic-uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Unlike Shiga toxin–mediated HUS, aHUS is driven by dysregulation of the alternative complement pathway, leading to endothelial injury and microvascular thrombosis.

Most cases result from genetic mutations in complement regulatory genes or from autoantibodies against factor H. Common genetic causes include mutations in CFH, CFI, MCP (CD46), C3, and CFHR genes; autoantibodies to factor H may also occur. Triggers such as infections, pregnancy, or certain drugs can precipitate episodes in susceptible individuals.

Diagnosis relies on the clinical triad plus laboratory findings of hemolysis (schistocytes, elevated LDH, low haptoglobin) and thrombocytopenia, with evidence of kidney dysfunction. It is essential to exclude other thrombotic microangiopathies, particularly TTP (ADAMTS13 activity assessment) and Shiga toxin–producing infections. Complement testing can support the diagnosis but is not definitive; genetic testing for complement-related genes is typically pursued for confirmation and family counseling.

Treatment centers on controlling complement activation. Eculizumab or ravulizumab, monoclonal antibodies that inhibit terminal complement, are first-line therapies. Plasma exchange or plasma infusion may be used when the diagnosis is uncertain or before complement inhibition is initiated. Supportive care, including renal replacement therapy when needed, is important. Patients should receive meningococcal vaccination before starting complement inhibitors, with appropriate infection monitoring thereafter. The duration of therapy is individualized based on genetic findings and clinical response, though long-term therapy may be required in some cases. Kidney transplantation can be considered in those with end-stage renal disease, often with ongoing complement inhibition to prevent recurrence.

See also: thrombotic microangiopathy, STEC-HUS, TTP.