What is the difference in serum complement C3 levels between glomerular and non‑glomerular renal diseases?

Serum C3 Levels in Glomerular vs Non-Glomerular Renal Diseases

In glomerular diseases, serum C3 is typically low or normal depending on the specific pathology, whereas in non-glomerular renal diseases (such as nephrotic syndrome from podocytopathies), C3 is usually normal or elevated. 1

Key Diagnostic Patterns by Disease Category

Glomerular Diseases with Low C3

Complement-mediated glomerular diseases characteristically present with depressed serum C3 levels:

• C3 glomerulopathy shows isolated low C3 with normal C4, reflecting alternative pathway activation, and is defined by dominant C3 deposits (≥2 orders of magnitude greater than immunoglobulins) on immunofluorescence with minimal or absent immunoglobulin deposition 2, 3, 4

• Post-infectious glomerulonephritis demonstrates isolated low C3 with normal C4, though C3 typically normalizes within 8-12 weeks after infection resolution 1, 5

• Lupus nephritis and cryoglobulinemic glomerulonephritis show combined depression of both C3 and C4, indicating classical pathway activation 1

• Immune complex-mediated glomerulonephritis may show low C3 when C3 is deposited along with immunoglobulins (IgG, IgA, IgM) in glomerular capillary walls and mesangium 2

Glomerular Diseases with Normal or Elevated C3

Several glomerular diseases do not consume complement:

• Pauci-immune ANCA-associated glomerulonephritis shows negative or minimal immunoglobulin and complement deposits (typically ≤1+ staining intensity), with normal serum C3 levels 2

• Anti-GBM disease demonstrates linear IgG deposits along the glomerular basement membrane with frequent but not universal C3 deposition; serum C3 is typically normal 2

• IgA nephropathy shows dominant mesangial IgA deposits with variable C3 co-deposition, but serum C3 levels remain normal 2

Non-Glomerular Renal Diseases

Non-glomerular kidney diseases typically maintain normal or elevated C3:

• Nephrotic syndrome from podocytopathies (minimal change disease, focal segmental glomerulosclerosis) presents with normal or elevated C3; a low C3 in this setting should immediately trigger investigation for complement-mediated glomerular pathology 1, 6

• Acute tubular necrosis, interstitial nephritis, and obstructive uropathy do not activate complement pathways and maintain normal C3 levels 1

• Diabetic nephropathy shows normal C3 levels despite progressive proteinuria and renal dysfunction 2

Critical Diagnostic Algorithm

When evaluating low C3 in suspected glomerular disease, follow this sequence:

1. Measure C4 simultaneously to determine pathway activation: isolated low C3 (normal C4) suggests alternative pathway activation; combined low C3 and C4 indicates classical pathway activation 1

2. Obtain kidney biopsy with immunofluorescence to distinguish C3-dominant patterns (C3 glomerulopathy) from immunoglobulin-dominant patterns (immune complex disease) 2

3. Screen for infections (hepatitis B, hepatitis C, endocarditis) before diagnosing primary C3 glomerulopathy, as infection-related glomerulonephritis can mimic C3 glomerulopathy 2, 1, 3

4. Perform pronase digestion immunofluorescence on paraffin-embedded tissue when monoclonal gammopathy is suspected, as masked monoclonal deposits can falsely appear as C3-dominant disease 2, 1

5. Evaluate for monoclonal gammopathy in all adults ≥50 years with apparent C3 glomerulopathy using serum/urine protein electrophoresis, immunofixation, and free light chains 2, 1

Common Pitfalls to Avoid

Do not diagnose C3 glomerulopathy based solely on low serum C3—the diagnosis requires kidney biopsy demonstrating C3-dominant immunofluorescence (≥2 orders of magnitude greater than immunoglobulins) 2, 5

Do not assume all C3-dominant immunofluorescence represents primary C3 glomerulopathy—post-infectious glomerulonephritis and masked monoclonal deposits can present identically and require different management 2, 3, 5

Do not overlook the possibility of dual pathology—approximately 25% of anti-GBM disease patients also have circulating ANCA, and ANCA glomerulonephritis can coexist with IgA nephropathy 2

In nephrotic syndrome, a newly low C3 mandates immediate workup for complement-mediated glomerular disease, as this finding is distinctly abnormal and suggests lupus nephritis, C3 glomerulopathy, or infection-related glomerulonephritis rather than podocytopathy 1, 6