What is the management approach for a patient with abnormal C3 (complement component 3) levels?

Management Approach for Abnormal C3 Complement Levels

The management of abnormal C3 complement levels requires a systematic evaluation for underlying causes, with treatment directed at the specific etiology rather than the C3 abnormality itself. 1

Diagnostic Evaluation Algorithm

Step 1: Determine Pattern of Complement Abnormality

• Measure both CH50 (classical pathway) and AH50 (alternative pathway) assays 1
• Interpret results according to pattern:
  • Normal CH50/Normal AH50: Normal complement function
  • Normal CH50/Low AH50: Consider properdin defect
  • Normal CH50/Zero AH50: Consider factor B or D defect
  • Low CH50/Normal or low AH50: Likely complement consumption or regulatory component defect
  • Zero CH50/Normal AH50: Likely C1, C2, or C4 deficiency
  • Zero CH50/Zero AH50: Likely C3 or C5-C9 deficiency 1

Step 2: Rule Out Secondary Causes

• For low C3 levels:

  • Infections (bacterial, viral - especially HBV, HCV)
  • Autoimmune diseases (SLE, rheumatoid arthritis)
  • Glomerulonephritis patterns (MPGN, C3G)
  • Malignancies (especially hematologic)
  • Paraproteinemias in patients ≥50 years 1

• For elevated C3 levels:

  • Acute inflammatory states
  • Immune complex-mediated glomerulonephritis
  • Neurodegenerative disorders 2

Step 3: Specialized Testing Based on Clinical Presentation

• If glomerular disease pattern:

  • Kidney biopsy with immunofluorescence to identify C3-dominant patterns 1
  • Comprehensive complement analysis including C3 nephritic factors, factor H, factor I antibodies 3
  • Genetic testing for complement regulatory proteins if indicated 4

• If recurrent infections:

  • Evaluate both protein and polysaccharide antibody responses
  • Consider specialized complement functional assays 1

Treatment Approach

For C3 Glomerulopathy (C3G)

1. Supportive care:

   • RAS inhibition for patients with proteinuria <3.5 g/day and normal eGFR 1

2. For idiopathic immune complex GN with nephrotic syndrome and normal/near-normal creatinine:

   • Limited course of glucocorticoids as first-line therapy
   • Consider mycophenolate mofetil, anti-CD20 agents (rituximab), or cyclophosphamide if contraindications to steroids exist 1, 5
   • Avoid calcineurin inhibitors due to risk of thrombotic microangiopathy 1

3. For C3G with rapidly progressive course:

   • Consider eculizumab (anti-C5 monoclonal antibody) 5

For Primary Complement Deficiencies

• Manage according to specific deficiency identified
• Immunoglobulin replacement therapy for recurrent infections if antibody responses are impaired 1
• Antimicrobial prophylaxis for specific deficiencies with high infection risk 4

Monitoring

• Regular assessment of kidney function and proteinuria
• Serial measurements of complement levels to track disease activity 2
• Monitor for infections in patients with complement deficiencies

Special Considerations

• Complement samples should be placed on ice or refrigerated after drawing to prevent degradation 1
• Consider age-related differences in normal complement levels
• In patients ≥50 years with C3G, always evaluate for monoclonal proteins with serum and urine immunoelectrophoresis, immunofixation, and free light chain analysis 1
• Low C3 in ANCA-associated vasculitis may indicate more severe disease and poorer renal outcomes 6

Pitfalls to Avoid

• Do not interpret C3 levels in isolation; always consider clinical context 2
• Do not assume normal C3 levels exclude complement-mediated disease, as levels may be normal in some complement disorders 1
• Avoid labeling ICGN as idiopathic without thorough evaluation for genetic and immune complement dysregulation 1
• Do not miss underlying infections that can trigger complement abnormalities 1