In glomerulonephritis, what diagnoses are suggested by low complement component 3 (C3) and complement component 4 (C4), isolated low complement component 4 (C4), and isolated low complement component 3 (C3), and what appropriate work‑up should be performed for each pattern?

Complement Patterns in Glomerulonephritis: Diagnostic Approach

Direct Answer to the Question

The complement patterns you've outlined are generally correct, but require important refinements based on current guidelines: Low C3 and C4 together strongly suggest lupus nephritis or cryoglobulinemia; isolated low C4 is characteristic of lupus nephritis and cryoglobulinemia; isolated low C3 indicates post-infectious GN, MPGN (now reclassified as C3 glomerulopathy), or infection-related immune complex disease. 1

Detailed Complement Pattern Analysis

Pattern 1: Low C3 AND Low C4

Primary Differential Diagnoses:

• Lupus nephritis is the most common cause, with C4 typically more profoundly and persistently depressed than C3 2, 3
• In lupus nephritis, C4 depression is the most consistent finding and may indicate occult disease activity even when other markers normalize 2
• Cryoglobulinemia (particularly HCV-associated mixed cryoglobulinemia) also presents with both C3 and C4 depression 1
• Post-streptococcal GN may show transient C4 depression during the initial phase only, with C4 normalizing while C3 remains low 2, 3

Workup for Low C3 and C4:

• ANA, anti-dsDNA, anti-Smith antibodies, complete lupus serologies 4
• Cryoglobulins, rheumatoid factor, hepatitis C serology 1
• Serum and urine protein electrophoresis with immunofixation to exclude monoclonal gammopathy 5
• Kidney biopsy with immunofluorescence looking for "full house" pattern (IgG, IgM, IgA, C3, C1q) which strongly indicates lupus nephritis even without positive serology 4

Pattern 2: Isolated Low C4 (Normal C3)

This pattern is uncommon and suggests:

• Early or mild lupus nephritis where C4 depression precedes C3 consumption 2, 3
• Hereditary angioedema (C1 esterase inhibitor deficiency) - though this rarely causes glomerulonephritis 5
• Cryoglobulinemia in early stages 1

Workup for Isolated Low C4:

• Complete lupus serologies (ANA, anti-dsDNA, complement levels including C1q) 4, 5
• Cryoglobulins and hepatitis C testing 1
• C1 esterase inhibitor level and function if angioedema history present 5
• Consider kidney biopsy if proteinuria or hematuria present 4

Pattern 3: Isolated Low C3 (Normal C4)

This pattern strongly suggests alternative complement pathway activation:

• Post-infectious glomerulonephritis (particularly post-streptococcal) with C3 depression lasting 8-12 weeks 6, 3, 7
• C3 glomerulopathy (formerly MPGN type II/dense deposit disease) with persistently low C3 beyond 12 weeks 1, 5
• Membranoproliferative pattern with complement dysregulation 1
• Infection-related glomerulonephritis from non-streptococcal organisms (especially staphylococcus in adults) 6

Critical Workup for Isolated Low C3:

Immediate evaluation:

• Streptococcal serology: ASO, anti-DNAse B, anti-hyaluronidase antibodies (ASO may be normal in skin infections) 6
• Recent infection history: pharyngitis (1-2 weeks prior) or impetigo (4-6 weeks prior) 6
• Blood and throat cultures if active infection suspected 6
• Urinalysis with microscopy for RBC casts, dysmorphic RBCs 5, 6

If C3 remains low beyond 8-12 weeks:

• Kidney biopsy is mandatory to distinguish post-infectious GN from C3 glomerulopathy 5, 6
• Comprehensive complement workup including C3 nephritic factor (C3NeF), factor H, factor I, factor B antibodies 5, 8
• Serum and urine protein electrophoresis with immunofixation (60-80% of adults >50 years with C3G have monoclonal gammopathy) 5
• Pronase digestion immunofluorescence on kidney biopsy if monoclonal protein detected, to unmask hidden monoclonal deposits 1, 5

Critical Diagnostic Pitfalls

Timing is Essential:

• In post-streptococcal GN, C3 normalizes by 8-12 weeks; persistent depression beyond this indicates C3 glomerulopathy requiring different management 6, 3
• Early return of C4 to normal in post-streptococcal GN (while C3 remains low) is a favorable prognostic sign 2

Age-Related Considerations:

• Adults >50 years with apparent C3 glomerulopathy require aggressive monoclonal gammopathy screening 5
• IgA-dominant infection-related GN (not classic post-streptococcal) is increasingly common in older adults with staphylococcal infections 6

Biopsy Interpretation:

• Apparent C3 glomerulopathy on standard immunofluorescence may actually be MPGN with masked monoclonal deposits requiring pronase digestion 1, 5
• "Full house" immunofluorescence pattern (IgG, IgM, IgA, C3, C1q) indicates lupus nephritis even with negative serology 4

Infection Screening:

• Always exclude hepatitis B, hepatitis C, HIV, and endocarditis before diagnosing idiopathic immune complex GN 1
• Complement abnormalities can be triggered by infections in genetically susceptible patients 5

Algorithmic Approach to Low Complement in GN

Step 1: Measure both C3 and C4 simultaneously 5, 3

Step 2: Pattern recognition:

• Both low → Lupus workup first, then cryoglobulin/HCV testing 4, 2
• C4 low only → Lupus workup, consider early disease 2
• C3 low only → Infection history, streptococcal serology, plan for repeat C3 at 8-12 weeks 6, 3

Step 3: If isolated low C3, timeline determines next step:

• <8 weeks: Treat as post-infectious, supportive care, antibiotics to reduce antigenic load 6

• 12 weeks: Kidney biopsy mandatory plus comprehensive complement workup 5, 6

Step 4: Kidney biopsy interpretation guides therapy:

• Immunofluorescence pattern (Ig-positive vs complement-dominant vs negative) determines underlying mechanism 1
• If monoclonal protein present, perform pronase digestion to detect masked deposits 1, 5