What is the management approach for a patient with low Complement 3 (C3) levels, normal Complement 4 (C4) levels, and a normal Anti-Streptolysin O (ASO) titre?

Management of Low C3 with Normal C4 and Normal ASO Titre

The pattern of isolated low C3 with normal C4 indicates alternative complement pathway activation or consumption, requiring immediate evaluation for alternative pathway-mediated glomerulonephritis, C3 nephritic factor, infection (particularly meningococcal), or rare genetic C3 deficiency. 1

Understanding the Complement Pattern

The combination of low C3 with normal C4 specifically excludes classical pathway activation, which would lower both components simultaneously. 1 This pattern points to:

• Alternative pathway consumption from ongoing disease processes 1
• C3 nephritic factor causing persistent C3 consumption 2
• Primary C3 deficiency (rare genetic disorder) 2
• Infection-mediated alternative pathway activation without classical pathway involvement 1

The normal ASO titre effectively excludes post-streptococcal glomerulonephritis, which typically presents with both low C3 and elevated ASO. 3

Immediate Diagnostic Workup

Assess for Renal Involvement (Critical First Step)

• Obtain urinalysis with microscopy looking for dysmorphic red blood cells, red cell casts, and proteinuria indicating glomerulonephritis. 1
• Measure serum creatinine and BUN to assess kidney function. 1
• Quantify 24-hour urine protein if urinalysis shows proteinuria; >500 mg/day is significant. 1

Screen for Infection

• Obtain blood cultures if fever or systemic signs are present, as bacterial infections (particularly invasive pneumococcal disease and meningococcal infection) can cause isolated low C3. 1, 2
• Consider meningococcal screening even without active meningitis, as isolated C3 deficiency predisposes to recurrent meningococcal infections. 2

Evaluate for C3 Nephritic Factor

• Measure C3 nephritic factor (C3 Nef) if membranoproliferative glomerulonephritis is suspected, as this autoantibody stabilizes the alternative pathway C3 convertase causing persistent C3 consumption. 2

Rule Out Monoclonal Gammopathy

• Perform serum protein electrophoresis with immunofixation in patients over 50 years old. 1
• Obtain urine protein electrophoresis with immunofixation and serum free light chain analysis if renal dysfunction is present. 1

Repeat Complement Testing with Proper Handling

• Place blood specimens on ice or refrigerate immediately after drawing to prevent complement degradation, as complement proteins are highly unstable. 4
• Repeat C3 and C4 levels to confirm the pattern and exclude laboratory error. 4

Management Based on Etiology

If Glomerulonephritis is Confirmed

• Perform kidney biopsy if proteinuria >500 mg/day with active urinary sediment, rising creatinine without alternative explanation, or clinical suspicion for glomerulonephritis. 1
• Consider oral cyclophosphamide or mycophenolate mofetil plus low-dose corticosteroids for progressive immune complex-mediated glomerulonephritis with nephrotic syndrome and declining kidney function. 1

If Infection is Identified

• Treat with appropriate antimicrobial therapy as the cornerstone of management for infection-related complement consumption. 1

If Monoclonal Protein is Found

• Obtain hematology consultation for clone-directed therapy if monoclonal gammopathy is identified with renal involvement. 1

If Primary C3 Deficiency is Suspected

• Administer meningococcal vaccines to all patients with complement deficiency, as they face increased risk of invasive meningococcal disease. 4
• Consider daily prophylactic antibiotics for terminal pathway deficiencies despite vaccination, given the extreme infection risk. 4

Monitoring Strategy

• Repeat C3 and C4 levels every 2-4 weeks initially to distinguish acute from chronic processes and assess response to treatment. 1
• Monitor serum creatinine, urine protein-to-creatinine ratio, and urinalysis if renal involvement is present. 1

Critical Pitfalls to Avoid

• Do not assume normal C4 excludes all complement-mediated disease, as alternative pathway disorders specifically spare C4. 1
• Do not delay vaccination while awaiting complete diagnostic workup, as patients with complement deficiency are at immediate risk for life-threatening infections. 4
• Do not overlook the possibility of isolated C3 deficiency in patients with recurrent meningococcal infections, even without other immunological abnormalities. 2

When to Refer

• Consult nephrology if proteinuria, hematuria, or rising creatinine is present. 1
• Consult immunology or complement specialists for all confirmed complement deficiencies to ensure comprehensive evaluation, appropriate genetic testing, and optimal long-term management. 4