What is the management approach for a patient with a positive C3 (complement component 3) test result?

Management of Positive C3 Complement Test Results

The management of a patient with positive C3 complement test results should include a thorough evaluation for underlying causes, with treatment directed at the specific etiology rather than the complement abnormality itself. 1

Diagnostic Approach

Step 1: Classify the Complement Pattern

• Determine if the pattern is:
  • Immune complex-mediated (immunoglobulin-positive with or without complement)
  • Complement dominant (immunoglobulin-negative, C3-positive)
  • Immunofluorescence-negative (immunoglobulin-negative, complement-negative) 2

Step 2: Evaluate for Underlying Causes

For immune complex-mediated MPGN (immunoglobulin-positive):

• Infectious causes:
  • Hepatitis B and C
  • Chronic microbial infections (fungal, parasitic, protozoal, mycobacterial)
• Autoimmune disorders:
  • Mixed cryoglobulinemia
  • Systemic lupus erythematosus
  • Sjögren syndrome
  • Rheumatoid arthritis
• Neoplasms:
  • Leukemia (chronic lymphocytic leukemia)
  • Lymphoma
  • Carcinoma
  • Plasma cell dyscrasia or monoclonal gammopathy 2

For C3 glomerulopathy (immunoglobulin-negative, C3-positive):

• Genetic testing:
  • C3, complement factors H, I, B
  • CD46 (membrane cofactor protein)
  • Complement factor H-related proteins (CFHR) 1-5
• Acquired causes:
  • Antibody to C3 convertase (C3 nephritic factor)
  • Anti-factor H antibody 2

Step 3: Rule Out Infection-Related GN

• Evaluate for active or prior infection before diagnosing C3 glomerulopathy 2
• Note that infection can trigger underlying complement abnormalities

Treatment Approach

For Idiopathic MPGN with Nephrotic Syndrome and Progressive Renal Decline:

1. First-line therapy:

   • Oral cyclophosphamide or mycophenolate mofetil (MMF)
   • Plus low-dose alternate-day or daily corticosteroids
   • Initial therapy limited to less than 6 months 2

2. If no significant reduction in proteinuria:

   • Taper and discontinue steroids 2

For C3 Glomerulopathy:

1. First-line therapy:

   • MMF plus glucocorticoids for moderate-to-severe disease 1

2. For refractory cases:

   • Consider eculizumab if MMF fails
   • For severe forms with crescents or rapidly progressive glomerulonephritis, consider aggressive immunosuppression similar to ANCA-associated vasculitis 1

For Patients with Proteinuria <3.5 g/day and Normal eGFR:

• Renin-angiotensin system (RAS) inhibition 1

For Patients with eGFR <30 ml/min/1.73m² without Active Necrotizing or Crescentic GN:

• Supportive care alone 1

Monitoring

• Monitor C3 levels over time to assess disease activity and treatment response
• Trends in C3 levels are more valuable than single measurements 1
• Follow renal function tests (serum creatinine, eGFR, urinalysis, urine protein/creatinine ratio)

Important Considerations

• The diagnosis of MPGN should be evaluated by nephropathologists experienced in interpretation of such biopsies 2
• Data regarding treatment of MPGN are exceptionally weak and consist mainly of uncontrolled observational, retrospective, or underpowered studies 2
• For patients with monoclonal immunoglobulin deposits, evaluation for hematologic malignancy is essential 2
• Before labeling ICGN (immune complex glomerulonephritis) as idiopathic, evaluate for both complement dysregulation and drivers of complement dysregulation, even in the absence of hypocomplementemia 2

Pitfalls to Avoid

1. Misdiagnosis: Don't rely solely on light microscopy and electron microscopy findings, as they lack specificity for underlying diagnosis. Immunofluorescence findings are crucial for classification 2

2. Incomplete evaluation: Ensure comprehensive testing for underlying causes before labeling as "idiopathic" MPGN, which is becoming increasingly rare as more pathophysiologic mechanisms are identified 2

3. Overlooking monoclonal gammopathies: Finding immunoglobulin subclass or light chain restriction warrants workup for paraprotein with serum and urine electrophoresis, immunofixation, and free light chain analysis 2

4. Inappropriate treatment duration: Limit initial immunosuppressive therapy to less than 6 months for idiopathic MPGN 2