Rapidly Progressive Glomerulonephritis (RPGN)

Rapidly Progressive Glomerulonephritis (RPGN), also called crescentic glomerulonephritis, is a clinical syndrome characterized by acute nephritis with rapid deterioration of kidney function — loss of >50% of GFR over weeks to months — and the histological finding of crescents in more than 50% of glomeruli on kidney biopsy. It represents a true nephrology emergency, as delay in diagnosis and treatment leads to irreversible renal failure requiring dialysis.

Table of Contents

  1. Overview
  2. Epidemiology
  3. Classification: Three Types of RPGN
  4. Pathophysiology
  5. Clinical Presentation
  6. Diagnosis
  7. Serological Workup
  8. Treatment
  9. Type-Specific Treatment
  10. Prognosis
  11. Research Papers
  12. References
  13. Featured Videos

1. Overview

RPGN is defined by the clinical-pathological combination of:

Crescents represent proliferation of parietal epithelial cells (PECs) of Bowman's capsule in response to fibrin leakage through disrupted glomerular capillary walls (necrosis/breaks in GBM). Monocytes and macrophages migrate into the Bowman's space, amplifying proliferation. Initially cellular crescents can evolve to fibrocellular then fibrous crescents (irreversible scarring) within days to weeks, making early diagnosis and treatment critical.

RPGN is classified into three immunopathological types based on the pattern of immunofluorescence (IF) on kidney biopsy — the most important initial test:

Back to Table of Contents

2. Epidemiology

RPGN is uncommon, with an estimated annual incidence of 7–10 cases per million population. Type III (ANCA-associated) is the most common form in Western countries (~55–60%), followed by Type II (~25–30%) and Type I (~10–15%). Anti-GBM disease (Type I) has a bimodal age distribution: young males (20–30 years, pulmonary involvement prominent) and older females (50–65 years, renal-limited). ANCA-associated RPGN (Type III) peaks in the 6th–7th decade. Immune complex RPGN (Type II) occurs across all ages depending on the underlying condition (post-infectious GN in children; lupus GN in young women; IgA-related GN in young adults).

Back to Table of Contents

3. Classification: Three Types of RPGN

Type I — Anti-GBM Disease (Goodpasture Syndrome)

Pathogenesis: Autoantibodies directed against the non-collagenous domain 1 of the alpha-3 chain of type IV collagen [α3(IV)NC1] — expressed in GBM and alveolar basement membrane. HLA-DR2 (DR15) is a major predisposing allele, present in >80% of anti-GBM patients. Environmental triggers (hydrocarbons, cocaine, smoking, influenza) may expose cryptic epitopes in susceptible individuals.

Classic Goodpasture syndrome = pulmonary hemorrhage + crescentic GN. Renal-limited anti-GBM disease occurs in ~40%.

IF: Linear IgG along the GBM (the "railroad track" pattern).

Type II — Immune Complex GN

Granular "lumpy-bumpy" IgG/IgM/IgA deposits on IF (distinguish from linear Type I and paucity of deposits in Type III).

Causes include:

Type III — Pauci-Immune ANCA-Associated GN

Pauci-immune = few or no immune deposits on IF (despite severe glomerular injury). Associated with antineutrophil cytoplasmic antibodies (ANCA):

Double-positivity (anti-GBM + ANCA): 5–10% of RPGN patients; often MPO-ANCA + anti-GBM; particularly aggressive course; treat as anti-GBM disease primarily.

Back to Table of Contents

4. Pathophysiology

The final common pathway in all three types is disruption of the glomerular capillary wall:

  1. Necrosis/rupture of GBM: fibrin leakage into Bowman's space
  2. Parietal epithelial cell (PEC) proliferation: PECs line Bowman's capsule and are progenitor cells; injury induces rapid proliferation
  3. Monocyte/macrophage recruitment: driven by chemoattractants (MCP-1, IL-8, complement products); monocytes differentiate into macrophages within the crescent
  4. Extracellular matrix deposition: fibronectin, collagen IV, tenascin; early cellular crescents → fibrocellular → fibrous (permanent)
  5. Tubular atrophy: from reduced GFR, ischemia, and protein casts
  6. Interstitial inflammation: CD4+ T-cell infiltration; drives tubular injury

In Type III AAV, ANCA activates primed neutrophils → neutrophil extracellular traps (NETs) → endothelial injury → fibrinoid necrosis; MPO and PR3 released from degranulating neutrophils propagate inflammation and GBM injury.

Back to Table of Contents

5. Clinical Presentation

RPGN presents as a nephritic syndrome with rapid GFR decline:

Type-specific extra-renal features:

Back to Table of Contents

6. Diagnosis

Kidney biopsy is essential and urgent — cellular crescents evolve to irreversible fibrous crescents within days.

Back to Table of Contents

7. Serological Workup

Simultaneous serology and biopsy — do not delay biopsy for serological results:

Back to Table of Contents

8. Treatment: General Approach

RPGN is a nephrology emergency. Empirical treatment before biopsy results may be warranted in severe, rapidly deteriorating cases:

Back to Table of Contents

9. Type-Specific Treatment

Type I (Anti-GBM Disease)

Type II (Immune Complex GN)

Treat underlying cause:

Type III (ANCA-Associated Vasculitis)

Induction therapy — RAVE trial (2010), RITUXVAS trial (2010):

PEXIVAS trial (2020): Plasma exchange did NOT improve outcomes (ESRD or death) vs. no plasma exchange in AAV with severe renal involvement. Changed practice — plasmapheresis no longer recommended for ANCA-AAV (unlike anti-GBM where it remains standard).

Maintenance therapy:

Avacopan (C5a receptor antagonist): ADVOCATE trial (2021) — noninferior to high-dose prednisone with reduced glucocorticoid burden; FDA-approved for AAV; added to rituximab or cyclophosphamide induction.

Back to Table of Contents

10. Prognosis

Prognosis depends on type, serum creatinine at presentation, and degree of irreversible fibrosis (fibrous crescents):

Poor prognostic factors (all types): oliguria/anuria at presentation, creatinine >500–600 μmol/L, >50% fibrous crescents (irreversible), delayed diagnosis/treatment.

Back to Table of Contents

11. Research Papers

Back to Table of Contents

12. References

  1. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63(3):1164–1177. PMID: 12631105. https://doi.org/10.1046/j.1523-1755.2003.00843.x
  2. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis (RAVE). N Engl J Med. 2010;363(3):221–232. PMID: 20647199. https://doi.org/10.1056/NEJMoa0909905
  3. Jones RB, Tervaert JWC, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis (RITUXVAS). N Engl J Med. 2010;363(3):211–220. PMID: 20647198. https://doi.org/10.1056/NEJMoa0909169
  4. Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS). N Engl J Med. 2020;382(7):622–631. PMID: 32053299. https://doi.org/10.1056/NEJMoa1803537
  5. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis (MAINRITSAN). N Engl J Med. 2014;371(19):1771–1780. PMID: 25372085. https://doi.org/10.1056/NEJMoa1404231
  6. Jayne DRW, Merkel PA, Schall TJ, Bekker P, for the ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021;384(7):599–609. PMID: 33596356. https://doi.org/10.1056/NEJMoa2023386
  7. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001;134(11):1033–1042. PMID: 11388816. https://doi.org/10.7326/0003-4819-134-11-200106050-00009
  8. Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med. 2003;348(25):2543–2556. PMID: 12815141. https://doi.org/10.1056/NEJMra022296
  9. Pusey CD. Anti-glomerular basement membrane disease. Kidney Int. 2003;64(4):1535–1550. PMID: 12969174. https://doi.org/10.1046/j.1523-1755.2003.00247.x
  10. Bomback AS, Appel GB. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol. 2012;8(11):634–642. PMID: 22986481. https://doi.org/10.1038/nrneph.2012.213
  11. Sinico RA, Radice A. Antineutrophil cytoplasmic antibodies (ANCA) testing: detection methods and clinical application. Clin Exp Rheumatol. 2014;32(3 Suppl 82):S112–117. PMID: 24447286. https://pubmed.ncbi.nlm.nih.gov/24447286/
  12. McAdoo SP, Pusey CD. Anti-Glomerular Basement Membrane Disease. Clin J Am Soc Nephrol. 2017;12(7):1162–1172. PMID: 28515156. https://doi.org/10.2215/CJN.01380217

Back to Table of Contents

Connections

↑ Back to Table of Contents