What is Hemolytic Uremic Syndrome (HUS)?

What is Hemolytic Uremic Syndrome (HUS)?

HUS is a rare, life-threatening disease defined by the simultaneous occurrence of three features: non-immune hemolytic anemia (microangiopathic), thrombocytopenia, and acute renal involvement. 1

Core Pathophysiology

HUS results from endothelial cell injury and platelet activation leading to thrombotic microangiopathy, which predominantly affects the kidneys but can involve multiple organ systems. 2 The underlying mechanisms differ based on the type of HUS, making accurate classification critical for appropriate management. 1

Two Main Types of HUS

Typical HUS (STEC-HUS)

• Caused by Shiga toxin-producing Escherichia coli (STEC), most commonly E. coli O157:H7. 3, 4
• Represents approximately 90% of HUS cases in children. 3
• Diarrhea precedes HUS symptoms by 4-5 days - this timing is the key diagnostic clue. 5, 3
• Transmitted through contaminated ground beef, unpasteurized milk, or contaminated water. 6
• Treatment is primarily supportive with no specific therapy to reverse the disease process. 3, 6

Atypical HUS (aHUS)

• A complement-mediated disease caused by genetic mutations or acquired abnormalities (anti-CFH antibodies) affecting the alternative complement pathway. 1, 3
• Represents only 5% of HUS cases but carries significantly worse prognosis. 6
• Requires environmental triggers (infections, pregnancy) to unmask the disease due to incomplete penetrance of complement gene mutations. 1
• Genetic mutations found in approximately 60% of cases involving complement factor H (20-30%), MCP (10-15%), factor I (4-10%), C3 (5-10%), factor B (1-2%), or anti-factor H antibodies (6%). 1, 7
• Treated as a medical emergency with complement inhibitors (eculizumab or ravulizumab) - treatment must begin immediately without waiting for genetic confirmation. 8, 3

Clinical Presentation

Laboratory Triad (Required for Diagnosis)

• Microangiopathic hemolytic anemia: Negative direct Coombs test, elevated LDH, reduced haptoglobin, elevated indirect bilirubin, with or without schistocytes on peripheral smear. 1, 5
• Thrombocytopenia: Platelet count <150,000/mm³ or 25% reduction from baseline. 1, 5
• Renal involvement: Hematuria, proteinuria, and/or elevated creatinine. 1, 5

Common Clinical Features

• Gastrointestinal symptoms: Diarrhea (often bloody in STEC-HUS), abdominal pain, vomiting. 9
• Bleeding manifestations: Melena, purpura due to thrombocytopenia. 9
• Renal manifestations: Oliguria, hypertension, hematuria, edema. 9
• Neurological involvement (occurs in 10-20% of aHUS cases): Altered sensorium, seizures, encephalopathy, motor symptoms, vision changes, generalized weakness. 1, 9

Critical Diagnostic Distinctions

When you see anemia plus thrombocytopenia in the emergency department, immediately order: complete blood count with peripheral smear, haptoglobin, LDH, indirect bilirubin, direct Coombs test, ADAMTS13 activity, stool testing for STEC, creatinine, and urinalysis. 5

Distinguishing Between Types

• STEC-HUS: Positive stool VTEC testing AND diarrhea onset 4-5 days before HUS symptoms. 5
• aHUS: Negative VTEC testing OR short diarrhea period OR simultaneous onset of diarrhea and HUS. 5
• TTP (not HUS): ADAMTS13 activity <10 IU/dL. 5

Critical timing pitfall: If diarrhea and HUS appear simultaneously or with a shorter interval than 4-5 days, suspect aHUS rather than STEC-HUS. 1, 5

Special Populations

Pediatric Considerations

• In newborns and young children, HUS may be present even if one of the three diagnostic parameters is absent in up to 50% of cases at disease onset. 8, 5
• Age under 3 years is a risk factor for developing HUS from STEC infection (OR 2.4) and predicts poor renal outcome. 4
• In infants <1 year old, consider complement-unrelated genes (DGKE, WT1) and methylmalonic acidemia with homocystinuria (MMACHC). 1, 5

Transplant Setting

• Renal transplantation can trigger aHUS recurrence or de novo disease. 1
• 13% of transplant patients with TMA do not show significant platelet reduction and 38% lack significant anemia or thrombocytopenia - absence of these findings should not exclude TMA diagnosis post-transplant. 1

Prognosis and Outcomes

STEC-HUS

• Immediate outcome often favorable with supportive care. 6
• Long-term renal sequelae are frequent due to nephron loss. 6
• In one cohort, 63% required dialysis but 66% achieved complete renal recovery after median 4 years follow-up. 4

aHUS

• More than half of untreated patients either die or progress to end-stage renal failure. 6
• Higher mortality rates in children than adults, with prognosis strongly dependent on genetic background. 1
• Risk of recurrence after discontinuing complement inhibitors is 10-20% with potential for renal failure. 8, 3
• High risk of post-transplant recurrence in all genetic groups except MCP-HUS. 7

Management Principles

STEC-HUS

• Supportive care only. 3
• Platelet transfusions are contraindicated as they worsen microangiopathic thrombosis. 8, 3
• Red blood cell transfusions for symptomatic anemia per standard guidelines. 8

aHUS

• Immediate initiation of complement inhibitors (eculizumab or ravulizumab) without waiting for genetic testing results. 8, 3
• Treatment duration minimum 6 months. 3
• Mandatory meningococcal vaccination (serogroups A, C, W, Y, and B) plus long-term antimicrobial prophylaxis due to increased infection risk with complement inhibition. 8, 3
• Multidisciplinary team approach essential. 8