Diagnosis of Hemolytic Uremic Syndrome (HUS)
HUS is diagnosed by the clinical triad of microangiopathic hemolytic anemia (non-immune), thrombocytopenia, and acute renal involvement, with immediate laboratory testing required to distinguish between atypical HUS (aHUS), STEC-HUS, and thrombotic thrombocytopenic purpura (TTP) to guide life-saving treatment. 1, 2
Core Diagnostic Criteria
The diagnosis requires all three components of the classic triad:
- Microangiopathic hemolytic anemia confirmed by negative direct Coombs test, elevated LDH, reduced haptoglobin, and elevated indirect bilirubin 1, 2
- Thrombocytopenia defined as platelet count <150,000/mm³ or a 25% reduction from baseline 1, 3
- Renal involvement evidenced by hematuria, proteinuria, and/or elevated creatinine levels 1, 2
Critical caveat: In pediatric patients, particularly newborns, HUS may be present even if one of these three parameters is absent in up to 50% of cases at disease onset 2, 3. The absence of marked thrombocytopenia or significant anemia should not exclude TMA diagnosis, especially post-renal transplant 1.
Immediate Laboratory Workup
When any patient presents with anemia plus thrombocytopenia in the emergency setting, immediately order: 1, 2
First-Level Tests (Urgent):
- Complete blood count with peripheral blood smear for schistocytes
- Haptoglobin, LDH, and indirect bilirubin levels 1
- Direct Coombs test (must be negative) 1
- ADAMTS13 activity (must be ordered urgently before plasma therapy) 1, 4
- Stool testing for verocytotoxin-producing E. coli (VTEC/STEC) 1, 2
- Creatinine (evaluated relative to age in pediatric patients) 2
- Urinalysis for hematuria and proteinuria 1
Important pitfall: Schistocytes >1% favor TMA diagnosis, but their absence should NOT exclude early TMA diagnosis due to low test sensitivity 1, 2, 3. Do not wait for schistocytes to appear before initiating workup.
Differential Diagnosis Algorithm
Once the triad is confirmed, distinguish between the major forms:
1. Rule out TTP first:
- ADAMTS13 activity <10 IU/dL indicates TTP 1, 4
- If ADAMTS13 is normal (>10 IU/dL), proceed to differentiate HUS subtypes 4
2. Distinguish STEC-HUS from aHUS:
- STEC-HUS: Positive stool VTEC testing AND diarrhea onset 4-5 days before HUS symptoms 1
- aHUS: Negative VTEC testing OR short diarrhea period OR simultaneous onset of diarrhea and HUS 1, 3
- Key timing distinction: STEC-HUS typically appears 4-5 days after diarrhea onset; if diarrhea and HUS appear simultaneously or with shorter interval, suspect aHUS 1
3. Consider secondary HUS:
- Evaluate for triggers: medications, infections (non-STEC), malignancies, transplantation, pregnancy 2, 4
Second-Level Testing for aHUS
Once aHUS is suspected, obtain: 1, 5
- Complement genetic testing (mutations in CFH, CFI, CFB, C3, MCP, THBD) 5, 6
- Anti-complement factor H antibodies 5, 6
- Complement levels (C3, C4, CH50, AP50) 2
Special pediatric considerations:
- In infants <1 year old, test for complement-unrelated genes (DGKE, WT1) 1
- Consider methylmalonic acidemia with homocystinuria (MMACHC) causing cobalamin deficiency 1
Neurological Assessment
If neurological symptoms present (occurs in 10-20% of aHUS cases): 1
- Obtain neurology consultation
- Perform electroencephalogram (EEG)
- Brain MRI with FLAIR and T2-weighted sequences 1
- Look for bilateral symmetric hyperintensities in basal ganglia, cerebral peduncles, caudate nuclei, putamen, thalami, hippocampi, insulae, or brainstem 1
Neurological manifestations to recognize: motor symptoms, generalized weakness, vision changes, seizures, encephalopathy 1
Critical Timing Considerations
Do not delay treatment while awaiting confirmatory testing - aHUS is a medical emergency requiring immediate intervention 2. ADAMTS13 testing should be conducted urgently but treatment decisions cannot wait for genetic results, which take weeks to months 4, 5. The diagnosis of aHUS remains primarily clinical, with genetic testing serving to confirm and guide long-term management 4, 6.