Rapidly progressive glomerulonephritis pathophysiology

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

Overview

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
          • 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.

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

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.
Source:By Nephron - Own work<ref/ https://commons.wikimedia.org/w/index.php?curid=17591464 ref>>
Source:By Nephron - Own work<ref/ https://commons.wikimedia.org/w/index.php?curid=17591464 ref>>


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, no electron dense deposits are seen.
  • In type II RPGN, subepithelial electron dense deposits indiacting the presence of immune complexes are seen.

Genetics

People with HLA DP1,DQ and DRB4 are more susceptible to develop RPGN.

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References

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