Why Order Serum C3 in Nephritis and Rheumatic Heart Disease
Serum C3 is essential in nephritis workup because it distinguishes alternative pathway activation (isolated low C3) from classical pathway activation (low C3 + low C4), directly guiding diagnosis between post-infectious glomerulonephritis, C3 glomerulopathy, lupus nephritis, and other immune-mediated kidney diseases. 1
Diagnostic Value of C3 in Glomerulonephritis
Pattern Recognition for Differential Diagnosis
Isolated low C3 with normal C4 indicates alternative pathway activation and narrows the differential to: 1
- Post-streptococcal glomerulonephritis (PSGN) – the classic presentation with profound C3 depression that typically normalizes within 8–12 weeks 2, 3, 4
- C3 glomerulopathy – persistent low C3 beyond 12 weeks mandates kidney biopsy to exclude this primary complement disorder 2, 1
- Infection-related glomerulonephritis – bacterial endocarditis, shunt nephritis, or visceral abscess can mimic PSGN 2
Low C3 plus low C4 signals classical pathway activation and points toward: 1, 4
- Lupus nephritis – occurs in >92% of active cases, with anti-dsDNA antibodies providing 98% specificity 5
- Cryoglobulinemic glomerulonephritis – particularly hepatitis C-associated mixed cryoglobulinemia 1
Temporal Dynamics Guide Management
In post-streptococcal glomerulonephritis, C3 depression precedes clinical nephritis by days – complement activation through the alternative pathway begins before hematuria or proteinuria appears. 3 Serial C3 measurements serve three critical functions:
- Confirm diagnosis – profound C3 reduction (often <30 mg/dL) with normal C4 in the acute phase 4, 6
- Monitor recovery – C3 normalizes within 8–12 weeks in uncomplicated PSGN 2, 4
- Trigger biopsy – persistently low C3 beyond 12 weeks indicates C3 glomerulopathy rather than resolving post-infectious disease and requires kidney biopsy with specialized complement workup 2, 1
Mechanistic Insights From C3 Patterns
The degree of C3 depression correlates with disease severity and complement activation site. Patients with profound C3 reduction show: 6
- 30-fold reduction in C3 synthesis
- Markedly elevated fractional catabolic rate (3.02–6.99%/hr vs. normal 1.56–2.12%/hr)
- Surface-bound convertase activation capable of cleaving both C3 and C5 6
C3 nephritic factor (C3NeF) autoantibody activity transiently appears in PSGN, stabilizing the alternative pathway convertase and driving hypocomplementemia; C3NeF disappears within 1–4 months as C3 normalizes. 7
Algorithmic Approach to Low C3 in Nephritis
Initial Laboratory Panel When C3 is Low
| Test | Purpose | Citation |
|---|---|---|
| C4 level | Distinguish alternative (C4 normal) from classical (C4 low) pathway activation | [1,4] |
| Anti-streptolysin O, anti-DNase B | Confirm recent streptococcal infection in suspected PSGN | [2] |
| ANA, anti-dsDNA | Screen for lupus nephritis when C3 and C4 both low | [5] |
| Hepatitis B, C, HIV serology | Exclude infection-related immune-complex disease | [2,1] |
| Cryoglobulins, rheumatoid factor | Evaluate for cryoglobulinemic vasculitis | [1] |
| Blood cultures | Rule out endocarditis in appropriate clinical context | [2] |
Decision Points for Kidney Biopsy
Biopsy is mandatory when: 2, 1
- C3 remains low beyond 12 weeks despite treated infection
- Clinical presentation is atypical for PSGN (age >40, no antecedent infection, nephrotic-range proteinuria)
- Rapid decline in kidney function or crescentic features on urinalysis
- Monoclonal gammopathy is detected (requires pronase-digestion immunofluorescence to unmask hidden deposits) 1
Biopsy immunofluorescence interpretation: 1
- C3-dominant pattern (C3 ≥100-fold greater than any immunoglobulin) = C3 glomerulopathy
- C3 with immunoglobulin co-deposition = immune-complex glomerulonephritis (PSGN, lupus, cryoglobulinemia)
- "Full-house" staining (IgG, IgM, IgA, C3, C1q) = lupus nephritis 5
C3 in Rheumatic Heart Disease Context
C3 has no diagnostic role in rheumatic heart disease (RHD) or acute rheumatic fever (ARF). These conditions result from molecular mimicry between streptococcal M protein and cardiac tissue, not complement-mediated glomerular injury. [@General Medicine Knowledge]
The confusion arises because both PSGN and ARF follow group A streptococcal infection, but:
- ARF develops 2–3 weeks after pharyngitis, causes carditis/arthritis/chorea, and maintains normal C3 levels
- PSGN develops 1–2 weeks after pharyngitis or 4–6 weeks after impetigo, causes nephritis, and shows profound C3 depression [@1@]
If a patient presents with both nephritis and carditis after streptococcal infection, order C3 to evaluate the nephritis component, not the cardiac involvement.
Common Pitfalls and How to Avoid Them
Pitfall 1: Assuming low C3 alone confirms C3 glomerulopathy – definitive diagnosis requires kidney biopsy showing C3-dominant immunofluorescence (≥100-fold greater than immunoglobulin). 1
Pitfall 2: Missing masked monoclonal deposits – approximately 5–10% of apparent C3 glomerulopathy cases in patients ≥50 years actually have membranoproliferative glomerulonephritis with hidden monoclonal immunoglobulin deposits that require pronase-digestion immunofluorescence to detect. 1
Pitfall 3: Delaying biopsy in "classic" PSGN – while most PSGN resolves spontaneously, biopsy is indicated when C3 remains low beyond 12 weeks, kidney function declines, or nephrotic syndrome develops. [@1@, 1]
Pitfall 4: Ordering C3 for rheumatic heart disease – C3 has no role in ARF/RHD diagnosis or management; reserve it for evaluating concurrent nephritis. [@General Medicine Knowledge]
Pitfall 5: Interpreting C4 depression as excluding alternative pathway disease – early PSGN can show transient C4 reduction during the initial phase, but C4 normalizes quickly while C3 remains depressed for weeks. 4, 8