What is the appropriate management and treatment for a patient with low complement C3 and C4 levels, potentially indicating an autoimmune disease, infection, or immune complex disease?

Management of Low Complement C3 and C4 Levels

When both C3 and C4 are low, immediately evaluate for immune complex-mediated disease (particularly systemic lupus erythematosus), infection-related glomerulonephritis, or cryoglobulinemia, as this pattern indicates classical pathway activation requiring urgent diagnostic workup and treatment of the underlying cause. 1, 2

Understanding the Complement Pattern

Low C3 with low C4 specifically indicates classical pathway activation, distinguishing this from alternative pathway disorders where C4 remains normal. 2, 3 This pattern narrows your differential diagnosis considerably and demands specific investigations.

The dual depression of both complement components signals one of three primary mechanisms:

• Immune complex consumption (most common in autoimmune disease) 4
• Infectious triggers activating the classical pathway 5, 6
• Acquired complement deficiency from consumption or inhibition 1

Immediate Diagnostic Workup

Essential Laboratory Tests

Obtain these tests immediately to establish the diagnosis:

• Complete blood count with differential to detect lupus-associated cytopenias, eosinophilia from parasitic infections, or leukopenia suggesting SLE 1
• Erythrocyte sedimentation rate which is typically elevated in urticarial vasculitis and autoimmune syndromes but may be normal in uncomplicated immune complex disease 1
• Comprehensive metabolic panel including creatinine and BUN to assess renal involvement 2
• Urinalysis with microscopy looking specifically for dysmorphic red blood cells, red cell casts, and proteinuria indicating glomerulonephritis 2
• 24-hour urine protein quantification (significant if >500 mg/day) 2

Autoimmune Disease Screening

Since complement deficiency strongly predisposes to SLE (5.9% of SLE patients have inherited complement deficiency), perform: 6

• Antinuclear antibody (ANA) as the primary screening test 1
• Anti-double stranded DNA antibodies if ANA is positive 1
• Thyroid autoantibodies and thyroid function tests, especially given the autoimmune clustering 1

Infection Evaluation

Bacterial infections, particularly invasive pneumococcal disease and endocarditis, can simultaneously cause low C3 and C4 through classical pathway activation. 2, 5 Obtain:

• Blood cultures if fever or systemic signs present 2
• Hepatitis B and C serology as chronic viral hepatitis activates complement 7
• Chest radiograph if respiratory symptoms suggest pneumococcal infection 6

Monoclonal Gammopathy Assessment

In patients over 50 years old, monoclonal gammopathy is the leading cause when low complement accompanies renal dysfunction. 2 The same monoclonal protein can trigger complement dysregulation through immune complex formation. 2

Immediately order:

• Serum protein electrophoresis with immunofixation 2
• Urine protein electrophoresis with immunofixation 2
• Serum free light chain analysis 2

Cryoglobulin Testing

If vasculitic symptoms (palpable purpura, arthralgias, neuropathy) are present, obtain cryoglobulin levels as cryoglobulinemia classically presents with low C3 and C4. 1

Kidney Biopsy Indications

Proceed to kidney biopsy if any of the following are present: 2

• Proteinuria >500 mg/day with active urinary sediment
• Rising creatinine without alternative explanation
• Clinical suspicion for glomerulonephritis based on the constellation of low complements, hematuria, and proteinuria

The biopsy must include: 2

• Light microscopy with Congo red staining to detect amyloid
• Immunofluorescence for IgG, IgM, IgA, C1q, C3, and κ and λ light chains
• Electron microscopy to characterize deposit location and ultrastructure
• Pronase digestion of paraffin-embedded tissue if monoclonal gammopathy is detected, as standard immunofluorescence misses masked monoclonal deposits in 5-10% of cases 2

Management Based on Etiology

Systemic Lupus Erythematosus

If SLE is confirmed, treatment depends on organ involvement:

• For lupus nephritis with nephrotic syndrome and declining kidney function: Consider oral cyclophosphamide or mycophenolate mofetil plus low-dose corticosteroids (therapy limited to <6 months) 3
• For non-renal SLE manifestations: Follow disease-specific guidelines from the American College of Rheumatology 8

Infection-Related Glomerulonephritis

Treat the underlying infection with appropriate antimicrobial therapy as the cornerstone of management. 8 Post-infectious glomerulonephritis classically presents with low C3 that normalizes by 8-12 weeks. 2

Critical pitfall: If C3 remains low beyond 12 weeks, this mandates evaluation for C3 glomerulopathy or monoclonal gammopathy rather than infection-related disease. 2

Monoclonal Gammopathy of Renal Significance

If monoclonal protein is identified with renal involvement:

• Obtain hematology consultation for clone-directed therapy 8
• Do not delay treatment, as early diagnosis of MGRS-related lesions is critical for targeted therapy 2

Cryoglobulinemia

For cryoglobulin-associated vasculitis, treat the underlying cause (typically hepatitis C) and consider immunosuppression for severe manifestations. 1

Monitoring Strategy

Repeat C3 and C4 levels every 2-4 weeks initially to distinguish acute from chronic processes and assess response to treatment. 8

For patients with renal involvement, monitor: 8

• Serum creatinine at each visit
• Urine protein-to-creatinine ratio monthly until stable
• Urinalysis to track resolution of active sediment

Critical Pitfalls to Avoid

• Do not assume infection-related disease if C3 remains low beyond 12 weeks—this pattern demands evaluation for primary complement disorders or monoclonal gammopathy 2
• Do not rely solely on standard immunofluorescence in patients over 50—60-80% may have monoclonal gammopathy requiring pronase digestion to detect masked deposits 2
• Do not overlook active infections as triggers for complement dysregulation in genetically susceptible patients; treat the infection before labeling as primary autoimmune disease 2
• Do not delay kidney biopsy in the setting of declining renal function, as early histologic diagnosis directs specific therapy 2
• Ensure proper specimen handling for complement testing, as complement components degrade with time and warming, potentially causing falsely low results 8