What are the primary causes of Hemolytic Uremic Syndrome (HUS)?

Primary Causes of Hemolytic Uremic Syndrome

Hemolytic Uremic Syndrome is primarily caused by Shiga toxin-producing Escherichia coli (STEC), particularly E. coli O157:H7, which accounts for the majority of typical HUS cases, while atypical HUS results from complement dysregulation due to genetic mutations or autoantibodies. 1

Typical (Post-Diarrheal) HUS - STEC-Associated

The dominant cause of HUS is infection with Shiga toxin-producing bacteria:

• E. coli O157:H7 is the most common causative organism in the United States, with approximately 8% of infected persons developing HUS 1
• Non-O157 STEC strains (particularly serogroups O26, O45, O103, O111, O121, and O145) also cause HUS, though less frequently 1
• Shigella dysenteriae type 1 can produce Shiga toxin and cause HUS, especially in travelers to endemic areas 1

Mechanism of STEC-HUS

• Shiga toxins (Stx1 and Stx2) directly damage endothelial cells, particularly in the kidney, leading to the characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure 2, 3
• Stx2-producing strains are more virulent and more frequently associated with HUS progression than Stx1-only or mixed toxin producers 1
• The toxins cause endothelial injury and platelet activation, resulting in platelet-rich thrombi that occlude the microcirculation and trap red blood cells in fibrin networks, causing mechanical hemolysis 4

Transmission Routes

STEC transmission occurs through:

• Consumption of undercooked ground beef, unpasteurized juice, raw milk, and raw produce (lettuce, spinach, alfalfa sprouts) 1
• Ingestion of contaminated water 1
• Direct contact with animals or their environment 1
• Person-to-person transmission, particularly in child-care settings 1
• The infectious dose is remarkably low (<100 organisms for O157 and O111 strains) 1

Atypical HUS (aHUS) - Complement-Mediated

Atypical HUS represents approximately 5-10% of all HUS cases and has a distinct pathophysiology:

• Genetic mutations in complement regulatory proteins of the alternative pathway are found in approximately 60% of aHUS cases 5, 6
• Autoantibodies against complement regulatory proteins can cause complement dysregulation 4, 5
• aHUS occurs without preceding diarrheal illness or has evidence of complement dysregulation despite diarrhea 7

Key Distinguishing Features

• aHUS has a relapsing course with more than 50% of patients progressing to chronic renal dysfunction and 10% mortality 5, 6
• Recurrence after renal transplantation is frequent in aHUS 2, 6
• In pediatric patients, simultaneous onset of diarrhea and HUS or very short diarrheal prodrome suggests aHUS rather than STEC-HUS 7

High-Risk Populations

Certain groups face elevated risk for HUS development:

• Children under 5 years have the highest incidence of STEC infection and greatest risk for HUS progression 1
• Young children represent the primary demographic for typical HUS, as it is the most common cause of acute renal failure requiring dialysis in this age group 5, 6, 8
• Adults can develop HUS but may present asymptomatically or with atypical features 8

Clinical Pitfalls and Diagnostic Considerations

Critical points for accurate diagnosis:

• Typical HUS onset occurs within 3 weeks after acute or bloody diarrhea, with approximately one week between diarrhea onset and HUS development 7, 8
• Up to 50% of aHUS cases may not clearly present with all three diagnostic features (hemolytic anemia, thrombocytopenia, renal involvement) at disease onset 7
• Antibiotic therapy in STEC infections may worsen outcomes and potentially increase HUS risk, making prompt diagnosis essential to avoid inappropriate treatment 1
• If platelet count obtained within 7 days after gastrointestinal illness onset is not below 150,000/mm³, consider alternative diagnoses 7

Secondary Causes of HUS-Like Syndromes

Other conditions can produce similar thrombotic microangiopathy:

• Systemic Lupus Erythematosus and lupus nephritis with monoclonal immunoglobulins acting as autoantibodies against complement regulatory proteins 4
• Antiphospholipid syndrome causing antiphospholipid syndrome nephropathy through inhibition of prostacyclin formation or protein C activation 4
• Chronic hemolytic anemias (sickle cell disease, thalassemia, hereditary spherocytosis) resulting in TMA due to high nitric oxide consumption 4