What are the diagnosis and treatment options for Hemolytic Uremic Syndrome (HUS)?

Diagnosis and Treatment of Hemolytic Uremic Syndrome (HUS)

Hemolytic Uremic Syndrome (HUS) is a rare, life-threatening disease characterized by non-immune hemolytic anemia, thrombocytopenia, and renal involvement that requires prompt diagnosis and treatment to prevent irreversible organ damage or death. 1

Diagnosis

Clinical Presentation

• HUS presents as a clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury associated with endothelial cell damage 2, 3
• In pediatric patients, particularly newborns, HUS may be present even if one of these three parameters is absent: thrombocytopenia, anemia, or increased creatinine levels 1
• When assessing renal involvement in pediatric patients, creatinine levels should be evaluated in relation to age 1

Diagnostic Workup

• First-level laboratory tests to diagnose HUS include 1:

  • Complete blood count with peripheral blood smear (looking for schistocytes)
  • Lactate dehydrogenase (LDH)
  • Haptoglobin
  • Creatinine
  • ADAMTS13 activity (to distinguish from TTP)
  • Stool testing for verocytotoxin-producing Escherichia coli (VTEC)

• The presence of schistocytes >1% favors a diagnosis of thrombotic microangiopathy (TMA), but their absence should not exclude an early diagnosis of TMA due to the low sensitivity of this test 1

• If neurological involvement is suspected (occurs in 10-20% of aHUS patients), a neurological consultation, electroencephalogram (EEG), and brain MRI are recommended 1

Differential Diagnosis

• It is crucial to distinguish between different forms of HUS 1:

  • Typical HUS (STEC-HUS): Associated with Shiga toxin-producing E. coli
  • Atypical HUS (aHUS): Associated with complement dysregulation
  • Secondary HUS: Associated with specific triggers (medications, infections, malignancies)

• ADAMTS13 activity testing should be conducted urgently if there is evidence of TMA (severely deficient, measuring <10 IU/dL in TTP) 1

• For aHUS diagnosis, genetic testing should include next-generation sequencing of complement genes: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB 1

Treatment

Initial Management

• HUS, particularly aHUS, should be treated as a medical emergency with urgent supportive measures 1
• For optimal patient outcomes, early recognition and appropriate treatment are critical to reduce the risk of irreversible organ damage or death 1

Specific Treatment for aHUS

• Complement inhibitors (anti-C5 antibodies) are the standard of care for aHUS 4, 5:

  • Eculizumab (Soliris) is FDA-approved for aHUS to inhibit complement-mediated thrombotic microangiopathy 6
  • For adult patients: 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter 6
  • For pediatric patients: Dosing is based on body weight (see specific weight-based dosing guidelines) 6

• Women with pregnancy-triggered aHUS have benefitted from C5 inhibitors that were instrumental in resolving TMA 1

• Long-term therapy assessment should be done on a case-by-case basis, with treatment administered for at least 6 months and discontinued after a minimum of 3 months of stabilized/normalized renal function 1

Prevention of Infectious Complications

• All patients receiving complement inhibitors must be vaccinated against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to treatment initiation 6

• Due to increased risk of invasive meningococcal disease even after vaccination, patients should receive long-term antimicrobial prophylaxis with penicillin (or macrolides for penicillin-allergic patients) for the duration of complement inhibitor treatment 1

• Patients should be monitored for early signs and symptoms of meningococcal infections and evaluated immediately if infection is suspected 6

Multidisciplinary Approach

• A multidisciplinary team (MDT) approach is essential for managing HUS, especially aHUS 1

• For pediatric patients, the MDT should include a neurologist, emergency physician, psychologist, pediatrician, hematologist, family pediatrician, and nephrologist 1

• Centers of reference for aHUS should have core competencies in hematology, nephrology, internal medicine, and transfusion medicine, along with genetic and laboratory facilities 1

Monitoring and Follow-up

• Although no single laboratory test is sufficiently sensitive or specific for early diagnosis of aHUS relapses, clinicians should monitor 1:

  • Clinical presentation
  • Laboratory data suggestive of hemolysis
  • Appearance/increase of glomerular proteinuria
  • Appearance of microhematuria

• For patients on complement inhibitors with extended dosing intervals, monitoring parameters such as C3, C4, CH50, and AP50 is useful 1

• Discontinuing treatment with complement inhibitors in patients with aHUS carries risk of disease recurrence and renal failure, requiring thorough assessment of risk factors before discontinuation 1

Special Considerations

• Patients of Chinese and/or Japanese descent may not respond to C5 inhibitors due to polymorphic variants of the C5 gene 1

• Renal transplantation may trigger aHUS, either as a recurrent episode or as a de novo disease in the renal graft 1

• Genetic counseling should be offered to patients with confirmed aHUS diagnosis due to possible genetic transmission 1