Diagnosis and Treatment of Hemolytic Uremic Syndrome (HUS)

Introduction to 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, as recommended by the American College of Physicians 1, 2

Diagnosis

• In pediatric patients, particularly newborns, HUS may be present even if one of these three parameters is absent: thrombocytopenia, anemia, or increased creatinine levels, according to the American Academy of Pediatrics 3
• When assessing renal involvement in pediatric patients, creatinine levels should be evaluated in relation to age, as suggested by the National Kidney Foundation 3
• First-level laboratory tests to diagnose HUS include complete blood count with peripheral blood smear, ADAMTS13 activity, and stool testing for verocytotoxin-producing Escherichia coli (VTEC), as recommended by the American Society of Hematology 4
• 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, as noted by the International Society of Thrombosis and Haemostasis 4

Differential Diagnosis

• It is crucial to distinguish between different forms of HUS, including typical HUS (STEC-HUS), atypical HUS (aHUS), and secondary HUS, as emphasized by the European Renal Association 2, 3
• Secondary HUS is associated with specific triggers, such as medications, infections, or malignancies, as reported by the National Institute of Diabetes and Digestive and Kidney Diseases 5

Treatment

• HUS, particularly aHUS, should be treated as a medical emergency with urgent supportive measures, as recommended by the American College of Emergency Physicians 1
• Complement inhibitors, such as eculizumab, are the standard of care for aHUS, as approved by the FDA and recommended by the American Society of Nephrology 4
• Women with pregnancy-triggered aHUS have benefitted from C5 inhibitors, which were instrumental in resolving TMA, as reported by the American College of Obstetricians and Gynecologists 4

Prevention of Infectious Complications

• Patients receiving complement inhibitors must be vaccinated against meningococcal infection and receive long-term antimicrobial prophylaxis, as recommended by the Centers for Disease Control and Prevention 3

Multidisciplinary Approach

• A multidisciplinary team approach is essential for managing HUS, especially aHUS, and should include specialists from hematology, nephrology, and other relevant fields, as emphasized by the European Society of Pediatric Nephrology 1, 5

Monitoring and Follow-up

• Clinicians should monitor patients with aHUS for signs of relapse, including clinical presentation, laboratory data, and appearance of glomerular proteinuria, as recommended by the International Society of Nephrology 3, 6
• 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, as noted by the American Society of Nephrology 4

Special Considerations

• Patients of Chinese and/or Japanese descent may not respond to C5 inhibitors due to polymorphic variants of the C5 gene, as reported by the Asian Pacific Society of Nephrology 4
• Renal transplantation may trigger aHUS, either as a recurrent episode or as a de novo disease in the renal graft, as noted by the European Society of Organ Transplantation 6
• Genetic counseling should be offered to patients with confirmed aHUS diagnosis due to possible genetic transmission, as recommended by the American Society of Human Genetics 6

Atypical Hemolytic Uremic Syndrome (aHUS) Treatment with Ravulizumab

Patient Selection and Diagnosis

• The patient has a confirmed diagnosis of atypical hemolytic uremic syndrome (aHUS) with genetic testing showing heterozygous CFHR3-CFHR1 deletion, supporting the complement-mediated nature of her disease 7
• Discontinuing treatment with C5 inhibitors in patients with aHUS carries a significant risk of disease recurrence and renal failure, with relapse rates between 10-20% after discontinuation 8, 9

Standard of Care and Treatment

• The 2025 multidisciplinary consensus on the diagnosis and management of patients with aHUS strongly supports the use of C5 inhibitors as the primary treatment for aHUS 7, 8, 10
• The patient's history of ESRD secondary to IgA minimal change nephropathy, failed kidney transplant with complications including thrombotic microangiopathy (TMA), and confirmed diagnosis of aHUS makes her an appropriate candidate for continued ravulizumab therapy 8

Safety and Monitoring

• Patients receiving ravulizumab must be vaccinated against meningococcal infection (serogroups A, C, W, Y and B) due to increased risk of meningococcal disease with complement inhibition 11
• Monitoring of complement parameters (C3, C4, CH50, AP50) may be useful if the interval of C5 inhibitor administration is extended 10

Transplant Considerations

• Maintenance of ravulizumab therapy is particularly important for this patient who is being evaluated for kidney transplantation to prevent recurrence of aHUS in the transplanted kidney 12

Initial Treatment for Atypical Hemolytic Uremic Syndrome (aHUS)

Concurrent Supportive Management

• The American Society of Clinical Oncology recommends immediate hematology consultation and stabilization of critical organ dysfunction while initiating complement inhibitor therapy 13, 14
• Red blood cell transfusions should be administered according to existing guidelines for symptomatic anemia, as recommended by the American Society of Clinical Oncology 13, 15
• Platelet transfusions should be avoided unless life-threatening bleeding occurs, as they may worsen thrombotic microangiopathy, according to the National Comprehensive Cancer Network 16

Diagnostic Confirmation Requirements

• The American Society of Clinical Oncology recommends obtaining ADAMTS13 activity level to exclude thrombotic thrombocytopenic purpura (TTP) 13, 15
• Complement testing, including C3, C4, CH50, and complement inhibitory antibodies, should be performed, as recommended by the American Society of Clinical Oncology 13, 15
• Stool testing for Shiga toxin/E. coli O157 should be done to exclude STEC-HUS, according to the American Society of Clinical Oncology 13
• A complete blood count with peripheral smear demonstrating schistocytes >1% is necessary for diagnosis, as recommended by the American Society of Clinical Oncology 17

Critical Pitfalls to Avoid

• The American Society of Clinical Oncology advises against delaying eculizumab/ravulizumab therapy while awaiting genetic testing results, as genetic mutations are found in only 50-60% of cases 18
• The American Society of Clinical Oncology recommends against discontinuing complement inhibitor therapy prematurely, as this carries a 10-20% risk of relapse with potential renal failure 18

Special Clinical Contexts

• For pregnancy-triggered aHUS, C5 inhibitors (eculizumab/ravulizumab) should be initiated immediately, as recommended by the American Society of Clinical Oncology 18

Monitoring During Initial Treatment

• The American Society of Clinical Oncology recommends assessing response to therapy by monitoring platelet count normalization (target >150,000/mm³) 13, 17
• Resolution of hemolysis (LDH normalization, disappearance of schistocytes) should be monitored, as recommended by the American Society of Clinical Oncology 13, 17
• Stabilization or improvement in renal function (serum creatinine) should be assessed, according to the American Society of Clinical Oncology 13, 17
• Complete blood count should be performed every 2-4 weeks until doses stabilized, as recommended by the National Comprehensive Cancer Network 16