What causes chronic elevated Immunoglobulin A (IgA) levels and a high Complement 3 (C3) ratio?

Causes of Chronic Elevated IgA Levels and High C3 Ratio

Chronic elevated IgA levels with high C3 ratio are most commonly associated with IgA nephropathy, but can also indicate other immune complex-mediated glomerulonephritis, infections, autoimmune diseases, or monoclonal gammopathies. 1, 2, 3

Primary Causes

1. IgA Nephropathy

• Most common cause of elevated IgA/C3 ratio (>3.01) 1, 3
• Characterized by:
  • Mesangial dominant or co-dominant IgA deposits 4
  • Microscopic hematuria (>5 RBCs in urinary sediment)
  • Persistent proteinuria (>0.3 g/day)
  • Serum IgA levels >315 mg/dl 1, 2

2. Immune Complex-Mediated Glomerulonephritis

• Infection-related immune complex GN:
  • Bacterial infections: endocarditis, visceral abscesses 4
  • Viral infections: hepatitis B, hepatitis C 4
  • Staphylococcal infections (dominant IgA pattern) 4

3. Autoimmune Diseases

• Systemic lupus erythematosus (SLE) 4, 5
• Sjögren's syndrome 4
• Rheumatoid arthritis 4
• Autoimmune hepatitis (characterized by polyclonal hypergammaglobulinemia) 4

4. Monoclonal Gammopathies

• Monoclonal immunoglobulin-associated diseases 4
• Plasma cell or B-cell disorders 4
• Fibrillary glomerulonephritis 4
• Particularly important to consider in patients >50 years of age 4, 5

Diagnostic Approach

Laboratory Evaluation

1. Complement assessment:

   • Measure both CH50 (classical pathway) and AH50 (alternative pathway) 5
   • C3 and C4 levels
   • IgA/C3 ratio (>3.01 highly suggestive of IgA nephropathy) 1, 3

2. Immunoglobulin panel:

   • Serum IgA, IgG, IgM levels
   • IgA >315 mg/dl is suggestive of IgA nephropathy 2

3. Renal function tests:

   • Serum creatinine, eGFR
   • Urinalysis (looking for hematuria)
   • Urine protein/creatinine ratio 5

4. Autoimmune workup:

   • ANA, anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm 5
   • Rheumatoid factor

5. Infection screening:

   • Hepatitis B and C serology
   • Blood cultures if endocarditis suspected
   • Streptococcal antibodies

6. Monoclonal protein assessment:

   • Serum and urine immunoelectrophoresis
   • Immunofixation
   • Free light chain analysis 5

Histological Evaluation

• Renal biopsy is essential for definitive diagnosis 4
• Key findings in IgA nephropathy:
  • Mesangial dominant or co-dominant IgA deposits
  • C3 often present along with IgA 4

Prognostic Significance

• Higher IgA/C3 ratio correlates with worse prognosis in IgA nephropathy 3, 6
• In European populations, IgA/C3 ratio >2.9 is associated with poorer renal survival 6
• Independent predictors of worse outcome include:
  • Higher serum creatinine
  • Higher proteinuria
  • Increased IgA/C3 ratio 6

Clinical Pearls

• Trends in complement levels over time are more valuable than single measurements 5, 7
• Complement samples should be placed on ice after drawing to prevent ex vivo degradation 5
• The presence of microscopic hematuria, persistent proteinuria, high serum IgA levels, and elevated IgA/C3 ratio can help distinguish IgA nephropathy from other renal diseases even before biopsy 1
• Elevated C-reactive protein (CRP) levels may indicate disease progression in IgA nephropathy 7

By systematically evaluating these parameters, clinicians can identify the underlying cause of chronic elevated IgA levels and high C3 ratio, which is crucial for appropriate management and prognostication.