Hemolytic Uremic Syndrome (HUS)

Shiga toxin–mediated and complement-mediated thrombotic microangiopathy — distinguishing typical HUS from atypical HUS and the role of complement inhibition

Key Points

• HUS is a thrombotic microangiopathy defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury — with renal involvement dominating the picture.
• Typical HUS (STEC-HUS) follows Shiga toxin–producing E. coli (often O157:H7) gastroenteritis, usually in children with bloody diarrhea; management is primarily supportive.
• Atypical HUS (aHUS) is a complement-mediated TMA from dysregulation of the alternative complement pathway; it is treated with complement inhibitors (eculizumab or ravulizumab).
• HUS is distinguished from TTP by ADAMTS13 activity (>10% in HUS, <10% in TTP) and by the predominance of renal failure over neurologic disease.
• Antibiotics and antimotility agents are generally avoided in suspected STEC-HUS because they may increase toxin release and the risk of progression.
• Complement inhibition requires meningococcal vaccination (and often antibiotic prophylaxis) because it markedly increases the risk of Neisseria meningitidis infection.

Classification and Pathophysiology

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) in which microvascular platelet-fibrin thrombi — concentrated in the renal microvasculature — cause mechanical red-cell fragmentation (schistocytes), platelet consumption, and acute kidney injury. It is classified by mechanism: **Typical HUS (STEC-HUS / "diarrhea-positive" HUS):** The most common form, especially in children. It follows infection with Shiga toxin–producing bacteria — most often enterohemorrhagic Escherichia coli (EHEC), classically serotype O157:H7, and occasionally Shigella dysenteriae. Shiga toxin enters…

Diagnosis and Distinguishing HUS from TTP

The initial evaluation of any TMA (MAHA + thrombocytopenia) must rapidly triage among TTP, HUS, DIC, and secondary causes, because treatment differs fundamentally. **Core findings in HUS:** - **Microangiopathic hemolytic anemia:** schistocytes on smear, elevated LDH, low haptoglobin, elevated indirect bilirubin, negative direct antiglobulin test. - **Thrombocytopenia:** usually present, often less severe than in TTP. - **Acute kidney injury:** the hallmark — rising creatinine, hematuria, proteinuria, oliguria. Renal involvement is far more prominent than in TTP. **Key discriminators:** -…

Management of Typical (STEC) HUS

Treatment of STEC-HUS is predominantly **supportive**, because the syndrome is toxin-mediated and usually self-limited once the acute injury is weathered: - **Fluid and electrolyte management:** careful volume support (early isotonic fluids during the diarrheal phase may be renoprotective), and management of hyperkalemia, acidosis, and hyponatremia. - **Renal replacement therapy:** dialysis is needed in a substantial minority during the acute phase; most children recover renal function. - **Transfusion:** packed red cells for symptomatic anemia; platelet transfusion generally avoided unless…

Management of Atypical HUS — Complement Inhibition

Atypical HUS is driven by uncontrolled alternative-complement activation, and its management was transformed by terminal complement inhibition. **Complement inhibitors (C5 blockade):** - **Eculizumab** — a monoclonal antibody against complement C5 that blocks formation of the terminal membrane attack complex (C5b-9). It halts the TMA, improves platelet counts and renal function, and reduces the need for dialysis and plasma exchange. It is first-line for aHUS. - **Ravulizumab** — a long-acting C5 inhibitor engineered from eculizumab that allows every-8-week dosing (versus every-2-week…