What are the causes of rapidly progressive glomerulonephritis?

Causes of Rapidly Progressive Glomerulonephritis

RPGN is classified into three major etiologic categories based on immunofluorescence patterns on kidney biopsy: pauci-immune (ANCA-associated vasculitis, 50-60% of cases), anti-GBM antibody disease (20% of cases), and immune complex-mediated disease (20-25% of cases). 1, 2

Pauci-Immune RPGN (Type III)

• ANCA-associated vasculitis is the most common cause of RPGN, accounting for 50-60% of all cases and representing the leading cause of rapidly progressive kidney failure. 1, 2
• Approximately 90% of pauci-immune RPGN patients have detectable ANCA antibodies (MPO-ANCA or PR3-ANCA), though ANCA negativity does not exclude the diagnosis. 2, 3
• The two main subtypes are:
  • Granulomatosis with polyangiitis (GPA) – typically PR3-ANCA positive 1, 2
  • Microscopic polyangiitis (MPA) – typically MPO-ANCA positive 1, 2
• Immunofluorescence shows no or only minimal immunoglobulin deposition in glomeruli. 4, 5

Anti-GBM Antibody Disease (Type I)

• Anti-GBM antibody disease (Goodpasture syndrome) accounts for approximately 20% of RPGN cases and represents the most severe form. 2, 6
• This disease often presents with pulmonary-renal syndrome, featuring simultaneous lung hemorrhage and kidney injury. 2, 3
• Immunofluorescence demonstrates linear deposition of IgG along the glomerular basement membrane. 4, 5
• Anti-GBM antibodies may be undetectable in approximately 10% of true anti-GBM disease cases, making kidney biopsy essential when clinical suspicion is high. 1

Immune Complex-Mediated RPGN (Type II)

• Immune complex-mediated disease accounts for 20-25% of RPGN cases, characterized by granular immunoglobulin deposition on immunofluorescence. 2, 4
• Major causes include:
  • IgA nephropathy with extensive crescent formation – the most common immune complex cause 2, 7
  • Lupus nephritis – particularly Class III or IV with crescentic changes 1, 3
  • Post-infectious glomerulonephritis – including hepatitis B and C-associated disease 1, 3
  • IgA vasculitis (Henoch-Schönlein purpura) 8, 5
  • Cryoglobulinemic vasculitis – often hepatitis C-related 3, 5
  • Membranoproliferative GN with crescents 8, 2

Overlap Syndromes

• Dual-positive disease can occur when ANCA-associated vasculitis overlaps with anti-GBM antibody disease, requiring plasma exchange in addition to standard immunosuppression. 1

Critical Diagnostic Distinction

• True RPGN requires BOTH histologic crescents (usually >50% of glomeruli) AND rapid deterioration of kidney function over days to weeks; the presence of crescents alone without rapid GFR decline does not constitute RPGN. 2, 4
• The clinical syndrome is characterized by nephritic features: glomerular hematuria with dysmorphic red blood cells, red cell casts, proteinuria (often sub-nephrotic), and pyuria without infection. 2, 3

Essential Serologic Testing

Before initiating immunosuppression, obtain the following autoimmune panel: 1, 3

• MPO-ANCA and PR3-ANCA – positive in ~90% of pauci-immune RPGN
• Anti-GBM antibodies – diagnostic for Goodpasture syndrome
• ANA and anti-dsDNA – when lupus nephritis is suspected
• Complement C3 and C4 – low levels support immune complex disease
• Hepatitis B and C serologies – mandatory before immunosuppression 1, 3

Common Pitfall to Avoid

Do not delay immunosuppressive therapy while awaiting kidney biopsy results if the clinical presentation is compatible with small-vessel vasculitis and MPO- or PR3-ANCA serology is positive, especially in rapidly deteriorating patients. 2 Treatment should be initiated immediately based on clinical criteria and positive serologies, as early intervention is the strongest predictor of renal recovery. 1, 3