Rapidly progressive glomerulonephritis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pathophysiology

Anatomy

Renal corpuscle. (Source: [Michal Komorniczak (Poland)[CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], from Wikimedia Commons])

Alveolar wall ([By Cruithne9 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons])

The key for the renal corpuscle figure is: A – Renal corpuscle, B – Proximal tubule, C – Distal convoluted tubule, D – Juxtaglomerular apparatus, 1. Basement membrane (Basal lamina), 2. Bowman's capsule – parietal layer, 3. Bowman's capsule – visceral layer, 3a. Pedicels (Foot processes from podocytes), 3b. Podocyte, 4. Bowman's space (urinary space), 5a. Mesangium – Intraglomerular cell, 5b. Mesangium – Extraglomerular cell, 6. Granular cells (Juxtaglomerular cells), 7. Macula densa, 8. Myocytes (smooth muscle), 9. Afferent arteriole, 10. Glomerulus Capillaries, 11. Efferent arteriole.

Rapidly progressive glomerulonephritis is a disease of the kidney in which the renal function deteriorates very quickly in a matter of days.

Atleast 50% reduction in GFR occurs in RPGN in a few days to weeks.

RPGN occurs from severe and fast damage to the GBM which results in crescent formation,the main pathological finding in RPGN.

Pathogenesis

• RPGN is characterized by severe and fast damage to the GBM that results in atleast 50% reduction in GFR in a few days.
• The injury to GBM can be caused by multiple factors.
• Crescent formation is the major pathological finding.
• In some cases crescents might be absent.

Cresent formation

• Crescents are defined as 2 or more layers of proliferating cells in the Bowman's space.
• The crescents are made up of epithelial cells and macrophages which undergo fibrosis.response t
• Crescents are formed after a severe injury to the glomerulus.in depos
• Injury to the glomerulus causes leakage of cells(epithelia, macrophages, coagulation proteins and fibroblasts) and cytokines(IL-12, TNF-alpha) into the Bowmans space.
• The presence of cytokines and coagulation proteins initiates fibrosis around the epithelial cells.
• The fibrosis blocks the glomerulus and filteration is hindered.
• This results in renal failure.

Glomerular injury

• Injury to the glomerulus is the initiating factor for crescent formation.
• Injury can occur by the following
  1. Anti GBM antibodies-Type I RPGN
     1. • • These are autoantibodies that cross react with type IV collagen of the GBM.
          • These can be produced due to genetic causes such as in Goodpasture diseases or they can be produced after viral URTI or cigarette smoking.
          • These autoantibodies react with the GBM resulting in IgG deposition over the GBM.
          • The IgG activates helper T cells that attract the inflammatory mediators to the GBM damaging the glomeruli.
          • This damage causes leakage of cells and inflammatory mediators resulting in crescent formation.
          • The anti GBM antibodies can affect the lungs as well as in Goodpasture syndrome resulting in glomerular necrosis and pulmonary haemorrhages.

2. Immune complex- Type II RPGN

• Immune complexes are formed in certain infections, connective tissue diseases, side effects of some drugs and in some myeloproliferative disorders.
• These immune complexes are deposited over the GBM.
• The immune complexes activate the complement system which sets off the inflammatory process.
• The complement cascade is activated, attracting inflammatory cells and mediators to the GBM.
• The serum levels of c3 and c4 fall down and is an indicator of immune complex mediated glomerular injury.

• This damages the glomeruli and causes leakage of cells and inflammatory mediators resulting in crescent formation.
  • Examples include:
  • Postinfectious (staphylococci/streptococci)
  • Connective tissue disorders
  • Lupus nephritis
  • Henoch-Schönlein purpural)
  • Immunoglobulin A nephropathy
  • Mixed cryoglobulinemia
  • Membranoproliferative glomerulonephritis

3. Pauci immune RPGN-Type III RPGN

• No circulating immune complexes or antibodies.
• Glomerular damage is caused by circulating ANCAs(anti nuclear cytoplasmic antibodies) or it can be idiopathic(non ANCA).
• ANCAs cause glomerular damage by releasing lytic enzymes from white blood cells such as neutrophils.
• These lytic enzymes damage the GBM and cause leakage of circulating cells and initiate crescent formationin the Bowmans space.
• ANCAs are associated with systemic vasculitis.
• Examples include
  • Granulomatosis with polyangiitis (Wegener granulomatosis)
  • Microscopic polyangiitis (MPA)
  • Renal-limited necrotizing crescentic glomerulonephritis (NCGN)
  • Eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome)
  • Drugs- hydralazine, allopurinol and rifampin.

Gross pathology

• The kidneys appear to be having having haemorrhages and necrosed tissue.
• Pulmonary haemorrhages may also be present in Goodpasture syndrome and type III RPGN.
• Type III RPGN may present with petechiae,rashes and purpuras.

Microscopic pathology

Histopathology

• Glomerular inflammation with signs of necrosis are present.
• .Glomerular caplillary wall rupture and damage to GBM.
• Crescents are present in the Bowmans space.
• Crescents are formed by proliferating epithelial cells and monocytes
• Fibroblasts migrate to the Bowman’s space and synthesize collagen.
• When cellular components are mixed with collagen the lesion is called fibroepithelial crescent.
• Renal vessels can show transmural vasculitis, with necrosis and lymphocyte infiltrates.
• Tubular necrosis may also be present.
• Interstitial granulomas in the glomeruli indicate Wegener’s granulomatosis.

Immunoflourescence

• In type I RPGN- diffuse and linear deposition of IgG along the GBM.
• In ttype II RPGN- diffuse and irregular deposition of IgG and C3 in the mesangial matrix.
• In type III RPGN- no finding.

Electron microscopy

• In type I and type III, electron

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