What are the classifications of glomerulonephritis?

Classification of Glomerulonephritis

Glomerulonephritis should be classified by etiology and pathogenesis into five major categories: immune-complex GN, pauci-immune GN, anti-glomerular basement membrane GN, monoclonal immunoglobulin GN, and C3 glomerulopathy. 1

Modern Pathogenesis-Based Classification System

The Mayo Clinic/Renal Pathology Society consensus explicitly states that pattern-based diagnosis alone is inadequate and that all GN must be classified by underlying pathogenic mechanism rather than histologic pattern. 1

Type 1: Immune-Complex Glomerulonephritis

This category is characterized by granular immunoglobulin deposits on immunofluorescence, indicating activation of the classical complement pathway. 1, 2

Primary immune-complex diseases include:

• IgA nephropathy - mesangial IgA deposits with variable hematuria and proteinuria 3
• Membranous nephropathy - autoimmune disease with antibodies targeting podocyte antigens, typically presenting with nephrotic syndrome 3
• Lupus nephritis - classified by ISN/RPS criteria (Classes I-VI), with Classes III and IV requiring aggressive immunosuppression 1, 3
• Post-infectious glomerulonephritis - follows bacterial, viral, or parasitic infections 3, 4
• IgA vasculitis - systemic disease with mesangial IgA deposits 3

Secondary causes of immune-complex MPGN pattern include: 1

• Infectious: Hepatitis B and C, chronic bacterial/fungal/parasitic infections
• Autoimmune: SLE, Sjögren syndrome, rheumatoid arthritis, mixed cryoglobulinemia
• Neoplastic: Chronic lymphocytic leukemia, lymphoma, carcinoma, MGUS
• Miscellaneous: Castleman disease, cystic fibrosis, celiac disease, sarcoidosis

Type 2: Pauci-Immune Glomerulonephritis

This category shows negative or minimal immunoglobulin deposits on immunofluorescence, with 80-90% of patients having serologic ANCA positivity (MPO-ANCA or PR3-ANCA). 1, 2, 4

The diagnosis must specify both:

• Clinicopathologic phenotype: microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis 1
• ANCA specificity: MPO-ANCA or PR3-ANCA 1

The remaining 10-20% are ANCA-negative pauci-immune GN. 1

Type 3: Anti-Glomerular Basement Membrane GN

This is characterized by linear deposits of IgG (not granular) and frequently C3 along the GBM on immunofluorescence, confirmed by circulating anti-GBM antibodies. 1, 2

Critical features: 1, 2

• Most cases present with severe necrotizing and crescentic pattern
• Approximately 25% have concurrent ANCA positivity (double-positive disease)
• May include pulmonary involvement (Goodpasture syndrome) 3

Type 4: Monoclonal Immunoglobulin GN

This encompasses glomerular diseases caused by monoclonal immunoglobulin deposition, including: 1

Organized deposits:

• Immunotactoid glomerulonephritis - microtubular deposits (17-52 nm diameter) with hollow centers 1
• Fibrillary glomerulonephritis - fibrils 10-30 nm, DNAJB9-positive, usually polyclonal but 7-17% monoclonal 1
• Cryoglobulinemic GN - Type I and II cryoglobulinemia with microtubular deposits 1

Non-organized deposits:

• Light chain deposition disease (LCDD) - punctate deposits along GBM and tubular basement membranes 1
• Proliferative GN with monoclonal immunoglobulin deposits (PGNMID) - restricted to glomeruli 1

Type 5: C3 Glomerulopathy

This category shows dominant C3 deposits with minimal or no immunoglobulin on immunofluorescence, indicating alternative complement pathway dysregulation. 1, 3

Two subtypes exist: 1

• Dense deposit disease (DDD) - formerly MPGN Type II
• C3 glomerulonephritis - C3 deposits without dense deposits

Workup should include: 1

• Genetic screening: mutations in C3, complement factors H/I/B, CD46, CFHR 1-5
• Acquired factors: C3 nephritic factor (C3Nef), anti-factor H antibodies

Critical Diagnostic Approach

Immunofluorescence Pattern Determines Category

The pattern on immunofluorescence microscopy is the primary determinant of pathogenic type: 1, 2

• Granular deposits → immune-complex GN
• Linear deposits → anti-GBM GN
• Negative/minimal Ig deposits → pauci-immune GN
• Dominant C3 only → C3 glomerulopathy
• Monoclonal Ig restriction → monoclonal Ig GN

Common Pitfall to Avoid

Segmental IgM and C3 staining in areas of segmental sclerosis represents nonspecific trapping and should NOT be used to classify the disease using immunofluorescence pattern descriptors. 2

Crescentic Glomerulonephritis Subclassification

When crescents involve ≥50% of glomeruli (though this threshold may not apply to ANCA-GN and anti-GBM GN), crescentic GN is further classified by the same pathogenic types: 2

• Type I (anti-GBM) - linear immunoglobulin deposits 2
• Type II (immune-complex) - granular deposits, includes lupus, IgA nephropathy, post-infectious GN 2
• Type III (pauci-immune) - minimal/absent deposits, 80-90% ANCA-positive 2

Crescent staging by reversibility: 2

• Cellular crescents (>50% cells) - potentially reversible
• Fibrocellular crescents (mixed) - partially reversible
• Fibrous crescents (>90% matrix) - irreversible scarring

Clinical Presentation Patterns

While pathogenesis-based classification is primary, understanding clinical syndromes aids recognition: 4, 5

Nephrotic syndrome (proteinuria >3 g/24h, hypoalbuminemia <3 g/dL, edema):

• Most common in minimal change disease (children), membranous nephropathy, FSGS 5

Nephritic syndrome (hematuria, proteinuria, hypertension, reduced kidney function):

• Post-infectious GN, IgA nephropathy, lupus nephritis 5

Rapidly progressive GN (acute presentation with rapid decline):

• ANCA-associated vasculitis, anti-GBM disease, post-infectious GN 4