HUS is a thrombotic microangiopathy defined by the triad of non-immune microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI). Approximately 90% of cases are infection-induced (most commonly STEC), with atypical HUS (complement-mediated) comprising ~5–10%. [1-3] It is the most common cause of AKI in children. [4]
The following figure illustrates the diagnostic classification framework for thrombotic microangiopathies, including the distinction between STEC-HUS, aHUS, and TTP:
1. History
- Key HPI questions: Onset and character of diarrhea (watery → bloody), abdominal pain, decreased urine output, pallor, fatigue, edema, altered mental status
- Symptom characterization: Profuse bloody diarrhea (hemorrhagic colitis) occurs in ~90% of STEC-HUS patients 3–8 days after ingestion of contaminated food; HUS develops ~7 days later as diarrhea is resolving [1]
- Timing/triggers: Recent consumption of undercooked ground beef, unpasteurized milk/juice, contaminated produce, contact with farm animals, daycare exposure, swimming in contaminated water [3][6]
- Progression: Watery diarrhea → bloody diarrhea → pallor/oliguria/edema (the "diarrhea-positive" prodrome); aHUS may lack a diarrheal prodrome or follow a URI/other trigger [1]
- Important negatives: Absence of diarrhea should raise suspicion for aHUS or TTP; ask about prior episodes (relapsing course suggests aHUS), pregnancy, medications, autoimmune disease [1-2]
2. Alarm Features
- Anuria or severe oliguria — indicates severe AKI, likely need for dialysis [1]
- Neurological symptoms: Irritability, altered consciousness, seizures, focal deficits — seen in 10–25% of STEC-HUS; associated with worse severity and higher mortality [1]
- Hypertensive emergency — poor kidney outcomes, especially in aHUS [1]
- Severe abdominal distension — toxic megacolon, colonic perforation, or transmural necrosis [1]
- Cardiac symptoms — myocardial involvement (identified in ~7% of pediatric aHUS) [1]
- Rapidly progressive thrombocytopenia — sentinel hematologic abnormality heralding HUS [7]
- Disproportionate rise in creatinine relative to hematocrit drop — predicts severe HUS [7]
3. Medications
Contraindicated / Avoid
- Antibiotics — multiple studies show association with increased HUS risk in STEC infection; avoid empirical antibiotics in immunocompetent patients with bloody diarrhea [1][7]
- Antimotility agents (loperamide, diphenoxylate, opioids) — reduce colonic excretion of STEC, increase risk of HUS and neurologic complications [1][7]
- NSAIDs — can worsen AKI during GI infection [7]
- Multiple-dose ondansetron / IV ondansetron — no added benefit, may increase diarrhea frequency and prolong QT [7]
Treatments
- STEC-HUS: Supportive care only (IV isotonic fluids, RBC transfusions, dialysis as needed) [1]
- aHUS: Eculizumab (anti-C5 monoclonal antibody) or ravulizumab (longer-acting C5 inhibitor) — first-line for complement-mediated aHUS; plasma exchange if complement inhibitors are unavailable [1][8-9]
- Meningococcal vaccination is mandatory before initiating complement inhibitors (increased risk of Neisseria meningitidis infection) [8]
Drug-induced HUS triggers to consider: Calcineurin inhibitors, quinine, gemcitabine, oral contraceptives [1][10]
4. Diet
- Acute phase: NPO or clear liquids if severe GI involvement; advance as tolerated
- Hydration is critical: Early aggressive isotonic IV hydration from onset of bloody diarrhea reduces adverse outcomes [1]
- Avoid unpasteurized dairy, undercooked ground beef — primary prevention [3]
- Long-term: If residual CKD develops, dietary modifications per CKD stage (sodium, potassium, phosphorus restriction)
5. Review of Systems
- GI: Diarrhea (bloody vs. watery), abdominal pain, vomiting, rectal bleeding
- Renal: Urine output (oliguria/anuria), hematuria, tea-colored urine, edema
- Neuro: Headache, irritability, lethargy, seizures, vision changes, focal deficits
- Heme: Pallor, petechiae, bruising, fatigue
- Cardiac: Chest pain, dyspnea (fluid overload vs. myocardial involvement)
- Pancreatic: Nausea, vomiting (elevated amylase/lipase in up to two-thirds of STEC-HUS) [1]
- Ophthalmologic: Visual changes (retinal hemorrhage, optic disc edema in aHUS) [1]
6. Collateral History and Family History
- Collateral: Daycare/school outbreaks, sick contacts with diarrheal illness, shared food exposures, travel history
- Family history: Prior episodes of HUS in family members strongly suggest complement-mediated aHUS; ask about consanguinity, unexplained renal failure, or recurrent TMA in relatives [1][4]
- Social context: Water source, food preparation practices, farm/animal exposure
7. Risk Factors
For developing HUS after STEC infection
- Age <5 years [1]
- Elevated WBC count during diarrheal illness [1]
- Specific STEC strains: O157:H7, O104:H4, O126 [1]
- Infection with Stx2-producing organisms [1]
- Antibiotic use during STEC infection [1][7]
- Antimotility agent use [7]
- Dehydration [1]
For aHUS
- Complement gene mutations (CFH, CFI, MCP/CD46, C3, CFB) [4]
- Anti-factor H autoantibodies (~10% of pediatric aHUS) [2]
- Complement-amplifying conditions: pregnancy, SLE, transplantation, malignancy [1]
8. Differential Diagnosis
- Thrombotic thrombocytopenic purpura (TTP): Distinguished by ADAMTS13 activity <10%; typically more severe thrombocytopenia (platelets <30 × 10⁹/L) with relatively mild renal dysfunction (creatinine <2 mg/dL); more neurologic involvement [1][11]
- Disseminated intravascular coagulation (DIC): Prolonged PT/PTT, low fibrinogen, elevated D-dimer — coagulation studies are normal in HUS [1]
- HELLP syndrome: In pregnant patients, second/third trimester; elevated liver enzymes [11]
- Drug-induced TMA: Quinine, gemcitabine, calcineurin inhibitors — temporal association with drug exposure [10]
- Malignant hypertension with TMA [1]
- Autoimmune conditions: SLE, antiphospholipid syndrome, scleroderma renal crisis [1]
- Severe vitamin B12 deficiency: Can mimic MAHA; elevated MCV, very high LDH, low reticulocyte count [11]
- Evans syndrome: Autoimmune hemolytic anemia + ITP — positive direct Coombs test distinguishes from HUS [1]
9. Past Medical History
- Prior episodes of TMA/HUS (relapsing course → aHUS) [3]
- History of transplantation (solid organ or stem cell) [1]
- Autoimmune disease (SLE, APS)
- Chronic kidney disease
- Pregnancy or postpartum state
- Malignancy or chemotherapy exposure
- Known complement gene mutations or family history of complement disorders
10. Physical Exam
Vital signs
- Hypertension (may be severe/malignant)
- Tachycardia
- Fever (variable)
Focused exam
- General: Pallor, fatigue, irritability
- Skin: Petechiae, purpura, peripheral edema, jaundice; rarely peripheral gangrene or cutaneous rash (aHUS) [1]
- Abdomen: Tenderness (especially RLQ/right colon), distension, guarding (concern for perforation/toxic megacolon) [1]
- Neuro: Mental status changes, seizures, focal deficits, cranial nerve palsies [1]
- Fundoscopy: Flame-shaped hemorrhages, optic disc edema (aHUS) [1]
- Cardiovascular: Signs of fluid overload (JVD, crackles, S3)
11. Lab Studies
Initial workup
- CBC with peripheral smear: Anemia (Hgb <10 g/dL), thrombocytopenia (platelets <150,000), schistocytes ≥2% [1]
- Reticulocyte count: Elevated (appropriate response to hemolysis)
- LDH: Elevated — may be the earliest marker of progression to HUS [6-7]
- Haptoglobin: Low or undetectable [1]
- Direct Coombs test: Negative (critical to exclude immune-mediated hemolysis) [1]
- BMP: Elevated BUN/creatinine, electrolyte derangements (hyperkalemia, metabolic acidosis)
- Coagulation studies (PT/PTT, fibrinogen, D-dimer): Normal in HUS; abnormal suggests DIC [1]
- Urinalysis: Hematuria, proteinuria, hemoglobinuria
To determine etiology
- Stool culture and Shiga toxin assay (PCR preferred) [12]
- ADAMTS13 activity: To exclude TTP (<10% diagnostic of TTP) [1][13]
- Complement studies: C3, C4, factor H, factor I, anti-factor H antibodies (for aHUS workup) [9][14]
- Amylase/lipase: Pancreatic involvement in up to two-thirds of STEC-HUS [1]
Monitoring: Serial CBC, reticulocyte count, LDH, creatinine, electrolytes every 12–24 hours during acute phase [7]
12. Imaging
- Renal ultrasound: First-line; assess kidney size, echogenicity, and perfusion; rule out obstruction
- Brain MRI: If neurological symptoms present — may show posterior reversible encephalopathy syndrome (PRES) or TMA-specific findings (hyperintense lesions in posterior white matter, thalami, brainstem, basal ganglia) [1]
- Abdominal CT: If concern for toxic megacolon, colonic perforation, or surgical abdomen [1]
- Echocardiogram: If cardiac symptoms or signs of fluid overload/myocardial involvement [1]
- Routine imaging is not required in uncomplicated cases
13. Special Tests
- PLASMIC score or French score: Clinical prediction tools to risk-stratify for TTP vs. HUS at presentation while awaiting ADAMTS13 results [1][13]
- Complement genetic testing: Panel for CFH, CFI, MCP, C3, CFB, THBD, DGKE mutations — essential for aHUS classification and transplant planning [4][9]
- Anti-factor H antibody testing [2]
- Cobalamin C studies: In infants/neonates with HUS [14]
- Renal biopsy: Not routinely required; considered in atypical presentations or diagnostic uncertainty — shows thrombotic microangiopathy with fibrin thrombi [1]
14. ECG
- Indications: Hyperkalemia, cardiac symptoms, fluid overload
- Findings to watch for:
- Peaked T waves, widened QRS, sine wave pattern (hyperkalemia)
- ST changes suggesting myocardial ischemia/injury (rare, TMA-related cardiac involvement)
- QT prolongation (if multiple-dose ondansetron was administered) [7]
15. Assessment
HUS is a medical emergency requiring rapid recognition and etiologic classification. The clinical triad of MAHA + thrombocytopenia + AKI following a bloody diarrheal prodrome in a young child is the classic presentation of STEC-HUS. [1] Key severity stratifiers include:
- Mild: Anemia and thrombocytopenia with preserved urine output and stable creatinine
- Moderate: Oliguria, rising creatinine, need for transfusion (~70% require RBC transfusion) [1]
- Severe: Anuria requiring dialysis (30–60%), neurological involvement (10–25%), multiorgan dysfunction [1]
Atypical presentations include aHUS without diarrheal prodrome, relapsing course, or onset in adults. Mortality in STEC-HUS is 1–5% in children; aHUS carries worse prognosis with 50% progressing to ESKD without complement inhibition. [3-4]
16. Treatment Plan
STEC-HUS (supportive care)
- IV isotonic fluids — early aggressive hydration from onset of bloody diarrhea [1]
- RBC transfusion for symptomatic anemia (avoid platelet transfusion unless active life-threatening bleeding — may worsen microthrombosis) [1]
- Blood pressure management — antihypertensives as needed
- Renal replacement therapy — peritoneal dialysis or hemodialysis for severe AKI (anuria, refractory hyperkalemia, fluid overload, uremia); continuous RRT for hemodynamically unstable patients [7]
- Nutritional support — enteral preferred when feasible
- Avoid: Antibiotics, antimotility agents, NSAIDs [1][7]
Atypical HUS (complement-mediated)
- Eculizumab — first-line; should be initiated as soon as aHUS is suspected; requires meningococcal vaccination ≥2 weeks prior (or antibiotic prophylaxis if urgent) [8-9]
- Ravulizumab — longer-acting alternative with reduced dosing frequency [2][8]
- Plasma exchange — initiate while awaiting complement inhibitor access or ADAMTS13 results; remains first-line where eculizumab is unavailable [1][9]
- Anti-factor H antibody-associated aHUS: Plasma exchange + immunosuppression is a satisfactory initial approach, particularly in resource-limited settings [15]
17. Disposition
Admission criteria (essentially all confirmed HUS cases)
- All patients with confirmed HUS require inpatient management
- ICU admission: Anuria/need for dialysis, neurological involvement, hemodynamic instability, multiorgan dysfunction, need for continuous RRT [7]
Observation
Specialist consultation triggers
- Nephrology: All cases — for dialysis planning and complement workup
- Hematology: TMA workup, ADAMTS13 testing, differentiation from TTP
- Pediatric intensivist: Severe disease, neurological involvement
- Infectious disease: Outbreak investigation, atypical organisms
18. Follow Up / Return Precautions
Follow-up timing
- Post-discharge: Weekly labs (CBC, reticulocyte count, LDH, creatinine) until normalization
- Long-term nephrology follow-up: Blood pressure, proteinuria, and GFR monitoring — residual renal dysfunction occurs in ~25% of STEC-HUS; >50% of aHUS patients progress to ESKD without complement inhibition [3-4]
- aHUS patients on complement inhibitors require ongoing monitoring for optimal complement blockade and meningococcal infection surveillance [1]
Return precautions (counsel families)
- Decreased urine output, blood in urine, new swelling/edema
- Severe abdominal pain, bloody stools
- Confusion, seizures, severe headache, vision changes
- Persistent vomiting, inability to tolerate fluids
- Fever (especially in patients on complement inhibitors — risk of meningococcal disease)
Expected recovery
- STEC-HUS: Most children recover renal function; neurological outcomes are generally satisfactory with complete recovery in most [1]
- aHUS: Relapsing course without complement inhibition; duration of therapy remains an area of active study [1]
The following figure illustrates the spectrum of HUS subtypes along axes of genetic susceptibility and endothelial stressor intensity, highlighting the role of complement dysregulation across different forms:
References
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15. A Systematic Review of Short-Term Outcomes in Patients With Anti-Factor H Associated Atypical HUS Managed With Plasma Exchanges Versus Eculizumab. — Sinha A, Bindal T, Zotta F, et al. Pediatric Nephrology. 2026.
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