What is the current classification of Membranoproliferative Glomerulonephritis (MPGN)?

Current Classification of Membranoproliferative Glomerulonephritis (MPGN)

The current classification of MPGN has evolved from a histologic pattern-based approach to a pathogenesis-based classification that categorizes MPGN according to immunofluorescence findings, which better reflects underlying disease mechanisms and guides targeted evaluation and treatment.

Modern Classification System

The classification of MPGN is now based on three distinct patterns of immunofluorescence findings on kidney biopsy:

1. Immune Complex-Mediated MPGN (IC-MPGN)

• Immunofluorescence Pattern: Positive for immunoglobulins (with or without complement)
• Further Subclassification:
  • Monoclonal Restriction: Suggests plasma cell disorders or monoclonal gammopathy
  • Polyclonal Immune Complex Deposition: Associated with infections or autoimmune disorders

2. Complement-Dominant MPGN (C3 Glomerulopathy)

• Immunofluorescence Pattern: Negative for immunoglobulins but positive for complement (predominantly C3)
• Subtypes:
  • Dense Deposit Disease (DDD): Characterized by dense osmiophilic deposits within the GBM on electron microscopy
  • C3 Glomerulonephritis (C3GN): Less dense deposits than DDD

3. Immunofluorescence-Negative MPGN

• Immunofluorescence Pattern: Negative for both immunoglobulins and complement
• Common Causes: Thrombotic microangiopathies, sickle cell disease, malignant hypertension

Diagnostic Approach

After identifying the MPGN pattern on light microscopy, the diagnostic algorithm should follow these steps:

1. Determine the immunofluorescence pattern (as described above)

2. For IC-MPGN: Evaluate for:

   • Infections: Hepatitis B/C, endocarditis, chronic infections
   • Autoimmune diseases: SLE, Sjögren's syndrome, rheumatoid arthritis
   • Monoclonal gammopathies: Serum and urine electrophoresis, immunofixation

3. For C3 Glomerulopathy: Evaluate for complement dysregulation:

   • Measure C3, C4, and CH50 levels
   • Test for C3 nephritic factor (C3Nef)
   • Consider genetic testing for mutations in complement factors (H, I, B) and CD46

4. For Immunofluorescence-Negative MPGN: Evaluate for:

   • Thrombotic microangiopathies
   • Malignant hypertension
   • Sickle cell disease

Underlying Causes to Consider

IC-MPGN

• Infectious: Hepatitis B/C, endocarditis, shunt infections, chronic bacterial/parasitic infections
• Autoimmune: SLE, Sjögren's syndrome, rheumatoid arthritis, mixed connective tissue disease
• Neoplastic: Leukemia, lymphoma, carcinoma, monoclonal gammopathy

C3 Glomerulopathy

• Genetic: Mutations in complement factors H, I, B, CD46
• Acquired: C3 nephritic factor, anti-factor H antibodies

Clinical Implications

This pathogenesis-based classification has important clinical implications:

1. Targeted Evaluation: Directs the diagnostic workup based on immunofluorescence findings
2. Treatment Approach: Guides therapy toward the underlying cause rather than the histologic pattern
3. Prognosis Assessment: Helps predict outcomes based on the underlying pathophysiology

Pitfalls and Caveats

1. Overlap Between Categories: There can be overlap between IC-MPGN and C3G, with some patients showing features of both
2. "Idiopathic" Cases: True idiopathic MPGN is increasingly rare as more underlying causes are identified
3. Evolution Over Time: The classification continues to evolve as our understanding of complement dysregulation improves

The modern approach to MPGN classification emphasizes that it is not a single disease but rather a pattern of injury with multiple etiologies that require different treatment approaches 1, 2.