What is the significance of C3 (Complement 3) and C4 (Complement 4) levels in patients with Hemolytic Uremic Syndrome (HUS), particularly those with atypical HUS (aHUS)?

C3 and C4 Levels in Hemolytic Uremic Syndrome

C3 and C4 levels are essential diagnostic and monitoring tools in atypical HUS (aHUS), with low C3 levels indicating alternative pathway activation and consumption, while C4 typically remains normal, helping distinguish complement-mediated aHUS from other thrombotic microangiopathies. 1, 2

Diagnostic Significance of Complement Levels

C3 Levels in aHUS

• Low C3 levels are a hallmark finding in many aHUS patients, reflecting consumption through alternative pathway dysregulation 3, 4
• Persistently low serum C3 levels have been documented in patients with C3 gene mutations, establishing C3 as a susceptibility factor for aHUS 5
• Severe activation and consumption of complement components, particularly C3, correlates with poor prognosis and rapid disease progression 3
• In approximately 50% of aHUS cases, mutations occur in complement regulatory proteins (factor H, factor I, MCP) that normally inactivate C3b, leading to uncontrolled C3 consumption 6

C4 Levels in aHUS

• C4 levels typically remain normal in aHUS because the disease primarily involves alternative pathway activation rather than classical pathway activation 4
• Normal C4 with low C3 helps distinguish aHUS from classical pathway-mediated conditions like lupus-associated TMA 4

Clinical Application and Monitoring

Initial Diagnostic Workup

• When aHUS is suspected, measure C3, C4, CH50 (classical pathway hemolytic activity), and AP50 (alternative pathway hemolytic activity) as part of the comprehensive complement assessment 1, 2
• These complement parameters should be obtained alongside the core diagnostic triad: microangiopathic hemolytic anemia (negative Coombs, elevated LDH, reduced haptoglobin), thrombocytopenia (<150,000/mm³), and renal involvement (hematuria, proteinuria, elevated creatinine) 2, 7

Monitoring During Treatment

• Monitoring C3, C4, CH50, and AP50 is particularly useful when extending the interval of C5 inhibitor (eculizumab/ravulizumab) administration 1
• Serial complement measurements help assess disease activity and guide treatment decisions, though no single laboratory test is sufficiently sensitive for detecting early aHUS relapses 1

Genetic and Pathophysiologic Context

Complement Mutations and C3 Levels

• Nine novel C3 mutations have been identified in aHUS patients with persistently low serum C3, with five being gain-of-function mutations and two being inactivating mutations 5
• Genetic testing should include next-generation sequencing of complement genes: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB 1, 2
• Approximately 40-50% of aHUS patients have no identifiable mutation, yet can still be diagnosed with aHUS based on clinical and laboratory criteria 1, 8

Complement Regulatory Protein Deficiency

• Screening for factor H and factor I deficiency through antigenic testing, combined with flow cytometry for MCP (CD46) expression levels, provides a practical approach when comprehensive genetic testing is not immediately available 6
• Factor H mutations carry approximately 80% recurrence risk in renal transplants, while MCP deficiency can be partially corrected by renal allograft 6

Critical Clinical Pitfalls

Common Diagnostic Errors

• Do not exclude aHUS based on normal C3 levels alone - approximately 50% of patients have normal complement levels despite having the disease 4, 8
• Never delay treatment while awaiting complement testing results - aHUS is a medical emergency requiring immediate intervention with eculizumab if suspected 7, 3
• In pediatric patients presenting with severe complement consumption and rapid progression, plasma therapy may be insufficient, and immediate eculizumab should be considered as first-line therapy 3

Special Populations

• In post-transplant patients, complement levels should be interpreted cautiously as 13% lack significant platelet reduction and 38% lack significant anemia or thrombocytopenia despite active TMA 1
• When aHUS presents in infants <1 year old, test for complement-unrelated genes (DGKE, WT1) and cobalamin metabolism defects (MMACHC), as these may present with different complement profiles 1, 2

Integration with Other Diagnostic Tests

• Complement testing must be combined with ADAMTS13 activity measurement (severely deficient <10 IU/dL indicates TTP, not aHUS) 2, 7
• Stool testing for verocytotoxin-producing E. coli (VTEC/STEC) is mandatory to distinguish STEC-HUS from aHUS 2, 7
• The pattern of low C3 with normal C4 and reduced AP50 with normal CH50 strongly suggests alternative pathway-mediated aHUS 1, 2