Management of Hemolytic Uremic Syndrome (HUS)
Immediate Recognition and Emergency Treatment
HUS must be treated as a medical emergency requiring immediate supportive care, with atypical HUS (aHUS) specifically requiring urgent complement inhibitor therapy to prevent irreversible organ damage and death. 1, 2
Initial Diagnostic Workup
When any patient presents with anemia plus thrombocytopenia in the emergency setting, immediately order the following laboratory tests 2:
- Complete blood count with peripheral blood smear for schistocytes
- Haptoglobin, LDH, and indirect bilirubin levels
- Direct Coombs test (must be negative for HUS diagnosis)
- ADAMTS13 activity
- Stool testing for verocytotoxin-producing E. coli (VTEC/STEC)
- Creatinine and urinalysis for hematuria and proteinuria
Critical timing note: Do not delay treatment while awaiting confirmatory testing—aHUS is a medical emergency requiring immediate intervention. 2
Differential Diagnosis Algorithm
The key to management is rapidly distinguishing between HUS subtypes 2:
- STEC-HUS (typical): Positive stool VTEC testing AND diarrhea onset 4-5 days before HUS symptoms 2
- aHUS (atypical): Negative VTEC testing OR short diarrhea period OR simultaneous onset of diarrhea and HUS 2
- TTP: ADAMTS13 activity <10 IU/dL 2
If diarrhea and HUS appear simultaneously or with shorter interval than 4-5 days, suspect aHUS rather than STEC-HUS. 2
Management by HUS Subtype
STEC-HUS (Typical HUS) Management
STEC-HUS is managed with supportive care only—there is no specific treatment. 3, 4
Supportive measures include 3:
- Careful management of electrolyte and water imbalance
- Treatment of anemia (transfusion as needed)
- Control of hypertension
- Renal replacement therapy if indicated
Critical pitfall: Avoid antibiotics, antimotility agents, narcotics, and NSAIDs during the acute phase as these may worsen outcomes. 5
Parenteral volume expansion should be initiated early to counteract thrombotic processes before full HUS development and attenuate renal injury. 5
Atypical HUS (aHUS) Management
Complement inhibitors (eculizumab or ravulizumab) are the standard of care for aHUS and must be initiated urgently. 1, 6
Eculizumab Dosing for aHUS
For adults (≥18 years) 6:
- 900 mg weekly for 4 weeks
- 1200 mg for the fifth dose (1 week later)
- 1200 mg every 2 weeks thereafter
For pediatric patients, dosing is weight-based 6:
- 40 kg and over: 900 mg weekly × 4 doses, then 1200 mg at week 5, then 1200 mg every 2 weeks
- 30 kg to <40 kg: 600 mg weekly × 2 doses, then 900 mg at week 3, then 900 mg every 2 weeks
- 20 kg to <30 kg: 600 mg weekly × 2 doses, then 600 mg at week 3, then 600 mg every 2 weeks
- 10 kg to <20 kg: 600 mg weekly × 1 dose, then 300 mg at week 2, then 300 mg every 2 weeks
- 5 kg to <10 kg: 300 mg weekly × 1 dose, then 300 mg at week 2, then 300 mg every 3 weeks
Mandatory Meningococcal Prophylaxis
All patients receiving complement inhibitors must be vaccinated against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to initiating therapy. 6
If urgent therapy is required before vaccination can be completed, provide antibacterial prophylaxis and administer vaccines as soon as possible. 6
Critical warning: Complement inhibitors increase the risk of life-threatening meningococcal infections, which can become rapidly fatal if not recognized early. 6
Plasma Therapy Considerations
Before the availability of complement inhibitors, plasma exchange or fresh frozen plasma infusion was the mainstay of aHUS treatment 7, 4. However, complement inhibitors have now replaced plasma therapy as first-line treatment due to superior outcomes. 1, 3
If plasmapheresis, plasma exchange, or fresh frozen plasma infusion is performed concurrently with complement inhibitor therapy, supplemental dosing is required. 6
Special Populations and Considerations
Pediatric Patients
In pediatric patients, particularly newborns, HUS may be present even if one of the three diagnostic parameters (thrombocytopenia, anemia, or elevated creatinine) is absent. 1, 2
In infants <1 year old with aHUS, test for complement-unrelated genes (DGKE, WT1) and consider methylmalonic acidemia with homocystinuria (MMACHC) causing cobalamin deficiency. 8, 2, 9
Pregnancy-Associated aHUS
Women with pregnancy-triggered aHUS benefit from C5 inhibitors, which are instrumental in resolving thrombotic microangiopathy. 1
Renal Transplant Recipients
Renal transplantation may trigger aHUS recurrence or de novo disease in the renal graft. 8, 1
Following renal transplant, the absence of marked thrombocytopenia or significant anemia should not exclude a TMA diagnosis. 8
Prophylactic administration of eculizumab should be considered to prevent recurrent disease in the allograft. 3
Genetic Considerations
Genetic testing should be performed through next-generation sequencing of complement genes (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB). 8
Once diagnosis is confirmed, patients should receive genetic counseling due to possible genetic transmission. 8, 1
Multidisciplinary Team Approach
aHUS management requires a multidisciplinary team including specialists from hematology, nephrology, and other relevant fields. 8, 1
Patients should be referred to rare disease reference centers for optimal management. 8
Monitoring and Long-Term Management
Monitor patients with aHUS for signs of relapse using clinical presentation, laboratory data (haptoglobin, LDH, indirect bilirubin), appearance of glomerular proteinuria, and microhematuria. 8, 1
Discontinuing complement inhibitor treatment in patients with aHUS carries significant risk of disease recurrence and renal failure (relapse rates 10-20%), requiring thorough assessment of risk factors before discontinuation. 1
Neurological Complications
If neurological symptoms develop (occurs in 10-20% of aHUS cases), obtain neurology consultation, perform EEG, and brain MRI with FLAIR and T2-weighted sequences. 2
Look for bilateral symmetric hyperintensities in basal ganglia, cerebral peduncles, caudate nuclei, putamen, thalami, hippocampi, insulae, or brainstem 2.
Critical Pitfall: STEC-HUS Misdiagnosis
The most important pitfall is failing to distinguish aHUS from STEC-HUS, as this determines whether complement inhibitor therapy is indicated. 2, 6
Eculizumab is NOT indicated for STEC-HUS and should only be used for aHUS. 6