What is rapid progressive glomerulonephritis, including its definition and pathophysiology?

Rapidly Progressive Glomerulonephritis: Definition and Pathophysiology

Clinical Definition

Rapidly progressive glomerulonephritis (RPGN) is defined by a rapid decline in kidney function occurring over days to weeks, typically accompanied by extensive crescent formation (usually >50% of glomeruli) on kidney biopsy. 1 The critical distinction is that true RPGN requires both histologic crescents and rapid deterioration of kidney function—the presence of crescents alone without concomitant rapid decline in GFR does not constitute RPGN. 1

The syndrome manifests as:

• Swift decline in kidney function over days to weeks (rarely months), with progressive rise in serum creatinine 2, 3
• Nephritic syndrome features including glomerular hematuria, proteinuria, and often decreased urine output 2
• Necrotizing extracapillary proliferative crescentic glomerulonephritis on histology 3

Pathophysiologic Classification

RPGN is classified into three major pathophysiologic types based on immunofluorescence patterns and immune deposit distribution:

Type I: Anti-GBM Antibody Disease (Linear Pattern)

• Accounts for approximately 20% of RPGN cases 1
• Characterized by linear IgG deposition along the glomerular basement membrane on immunofluorescence, which is pathognomonic 4, 3
• Circulating anti-GBM antibodies are present in approximately 90% of cases (10% may be falsely negative) 4
• Often presents as pulmonary-renal syndrome (Goodpasture's syndrome) with simultaneous lung and kidney injury 1
• Tends to have acute onset with more cellular crescent formation and the poorest kidney prognosis among all RPGN subtypes 5

Type II: Immune Complex-Mediated (Granular Pattern)

• Accounts for approximately 20-25% of RPGN cases 1
• Characterized by granular pattern of immunoglobulin deposition on immunofluorescence 3
• Common causes include IgA nephropathy with extensive crescent formation, lupus nephritis, Henoch-Schönlein purpura, and cryoglobulinemia 1, 3
• Can occur in nephrotic syndrome, particularly in idiopathic membranoproliferative glomerulonephritis with progressive decline in kidney function 1

Type III: Pauci-Immune (ANCA-Associated)

• Most common cause of RPGN, accounting for approximately 50-60% of cases 1
• Characterized by absent or minimal immunoglobulin deposition (pauci-immune) on immunofluorescence 3
• Approximately 90% of patients have detectable ANCA antibodies (MPO or PR3), though ANCA negativity does not exclude the diagnosis 1
• Common causes include granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 1
• Patients with type III CrGN have superior kidney survival compared to other types 5

Pathophysiologic Mechanisms

Crescent Formation and Glomerular Injury

The hallmark pathologic feature of RPGN is crescent formation, which results from:

• Podocyte activation and parietal epithelial cell proliferation within Bowman's space 6
• Glomerular necrosis with disruption of the glomerular capillary wall 3, 7
• Involvement of T cells, dendritic cells, and toll-like receptors in the inflammatory cascade 6
• Role of growth factors and Goodpasture autoantigen in disease onset 6

ANCA-Associated Mechanisms

In pauci-immune RPGN:

• Lysosome-associated membrane protein (LAMP)-2 and neutrophil extracellular traps play important roles, though the exact pathogenic contribution of LAMP-2 remains uncertain 6
• ANCA antibodies (MPO or PR3) trigger neutrophil activation and endothelial injury 7

Clinical Heterogeneity

There is substantial heterogeneity between different subtypes of RPGN in terms of presentation, severity, and prognosis 5. Type I CrGN patients tend to have higher proportions of acute kidney injury with more cellular crescent formation, higher serum creatinine, and elevated retinol binding protein levels 5.

Critical Clinical Pitfall

Multiple-system involvement is common (57.14% of patients may have kidney enlargement), and RPGN can present with seemingly nonspecific manifestations such as "flu-like syndrome" associated with glomerular hematuria before the rapid decline in renal function becomes evident 5, 7. Early recognition of these subtle signs is essential, as the best prognostic marker is the creatinine level at treatment initiation—early diagnosis and treatment dramatically improve outcomes in this otherwise life-threatening disease with 90% mortality in untreated cases 3, 7.