What complement tests are recommended for patients with C3 glomerulopathy?

Complement Testing for C3 Glomerulopathy

For patients with C3 glomerulopathy, a comprehensive complement analysis is necessary, including serum complement levels (C3, C4, CH50), specialized complement regulatory protein testing, genetic testing, and autoantibody evaluation to identify underlying complement dysregulation. 1, 2

Essential Complement Tests

• Serum complement levels: C3, C4, and CH50 should be measured to evaluate complement consumption (low C3 with normal C4 is a common finding in C3G) 2, 3

• Specialized complement regulatory protein testing:

  • Factor H levels and function 1, 2
  • Factor I levels 2
  • Membrane cofactor protein (MCP/CD46) expression 2
  • Factor B levels 2

• Autoantibody evaluation:

  • C3 nephritic factor (C3NeF) - found in approximately 80% of patients with dense deposit disease (DDD) and 45% of patients with C3 glomerulonephritis (C3GN) 3, 4
  • C4 nephritic factor (C4NeF) - present in a small percentage of C3G patients 5
  • Anti-Factor H autoantibodies 2, 4
  • Anti-C3b autoantibodies 2

• Genetic testing for mutations in complement regulatory genes:

  • CFH (Factor H) 2, 3
  • CFI (Factor I) 3
  • C3 3
  • CFHR5 (Complement Factor H Related Protein 5) 3
  • MCP (Membrane Cofactor Protein) 3

Additional Essential Testing

• Evaluation for monoclonal gammopathy (especially in patients ≥50 years):

  • Serum and urine protein electrophoresis 1
  • Serum and urine immunofixation 1
  • Serum free light chain analysis 1

• Infectious disease workup:

  • Rule out active or prior infections (bacterial, viral, parasitic) 1, 6
  • Hepatitis B and C serology 6, 2
  • Blood cultures if endocarditis is suspected 6, 2

Specialized Laboratory Considerations

• Many specialized complement tests are not routinely available in commercial laboratories and may require sending samples to specialized reference laboratories 1
• Proper collection and storage of samples for specialized complement tests is critical - consultation with the clinical laboratory is recommended 1
• Immunofluorescence studies on protease-digested, paraffin-embedded tissue sections (paraffin IF) should be performed in all cases of apparent C3 glomerulopathy with a circulating monoclonal immunoglobulin to detect masked monoclonal immunoglobulin deposits 1

Clinical Pearls and Pitfalls

• Low serum C3 with normal C4 is characteristic of alternative complement pathway dysregulation but is not present in all cases 3, 4
• Evaluation for monoclonal gammopathy is essential in all adults with C3G, particularly those ≥50 years of age, as 60-80% of these patients have a monoclonal gammopathy at diagnosis 1, 7
• Comprehensive complement analysis should be performed even in the absence of hypocomplementemia 1
• Failure to screen for monoclonal gammopathy, especially in patients over 50 years old, may lead to inappropriate treatment selection 7
• Approximately 5-10% of patients with monoclonal gammopathy and findings consistent with C3G on standard immunofluorescence may actually have membranoproliferative glomerulonephritis with masked monoclonal deposits, requiring additional immunofluorescence studies 1

By performing this comprehensive complement evaluation, clinicians can identify the specific mechanisms of complement dysregulation in C3G patients, which is essential for guiding appropriate treatment strategies and improving outcomes 4, 8.