Rapidly progressive glomerulonephritis pathophysiology: Difference between revisions

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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]].
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.
=== .Pathogenesis ===
* Rapidly progressive glomerulonephritis is a disease of the kidney in which the [[renal function]] deteriorates in a few days.


Atleast 50% reduction in GFR occurs in RPGN in a few days to weeks.
* Atleast 50% reduction in [[Glomerular filtration rate|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.
* RPGN occurs from severe and fast damage to the [[GBM]] which results in [[Crescent Rising|crescent]] formation, the main pathological finding in RPGN.
 
* The injury to [[GBM]] can be caused by multiple factors.
=== Pathogenesis ===
* [[Crescent Rising|Crescent]] formation is the major pathological finding.
* 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.
* In some cases crescents might be absent.


====== Cresent formation ======
====== Cresent formation ======
* Crescents are defined as 2 or more layers of proliferating cells in the Bowman's space.
* Crescents are defined as 2 or more layers of proliferating cells in the [[Bowman's capsule|Bowman's space.]]
* The crescents are made up of epithelial cells and macrophages which undergo fibrosis.response t
* The crescents are made up of [[Epithelium|epithelial cells]] and macrophages which undergo [[fibrosis]].
* Crescents are formed after a severe injury to the glomerulus.in depos
* Crescents are formed after a severe injury to the [[glomerulus]].
* Injury to the glomerulus causes leakage of cells(epithelia, macrophages, coagulation proteins and fibroblasts) and cytokines(IL-12, TNF-alpha) into the Bowmans space.
* Injury to the glomerulus causes leakage of cells(epithelial[[Macrophages|, macrophages]], [[Coagulation|coagulation proteins]] and [[Fibroblast|fibroblasts]]) and [[Cytokine|cytokines]]([[Interleukin 12|IL-12]], [[Tumor necrosis factor-alpha|TNF-alpha]]) into the [[Bowman's capsule|Bowmans space]].
* The presence of cytokines and coagulation proteins initiates fibrosis around the epithelial cells.
* The presence of cytokines and coagulation proteins initiates [[fibrosis]] around the epithelial cells.
* The fibrosis blocks the glomerulus and filteration is hindered.
* The fibrosis blocks the [[glomerulus]] and [[Glomerular filtration|filteration]] is hindered.
* This results in renal failure.
* This results in [[Renal insufficiency|renal failure]].


====== Glomerular injury ======
====== Glomerular injury ======
* Injury to the glomerulus is the initiating factor for crescent formation.
* Injury to the glomerulus is the initiating factor for crescent formation.
* Injury can occur by the following
* Injury can occur by the following.
*# Anti GBM antibodies-Type I RPGN
# Anti [[GBM]] antibodies-Type I RPGN
*##** These are autoantibodies that cross react with type IV collagen of the GBM.
* These are [[Autoantibody|autoantibodie]]<nowiki/>s that cross react with [[Type-IV collagen|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 can be produced due to genetic causes such as in [[Goodpasture syndrome]] or they can be produced after viral [[Upper respiratory tract infection|URTI]] or cigarette smoking.
*##** These autoantibodies react with the GBM resulting in IgG deposition over the GBM.
* These autoantibodies react with the GBM resulting in [[Immunoglobulin G|IgG]] deposition over the GBM.
*##** The IgG activates helper T cells that attract the inflammatory mediators to the GBM damaging the glomeruli.
* The IgG activates [[T helper cell|helper T cells]] that attract the [[Inflammation|inflammatory]] mediators to the GBM damaging the glomeruli.
*##** This damage causes leakage of cells and inflammatory mediators  resulting in crescent formation.
* 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.
* The anti GBM antibodies can affect the lungs as well as in [[Goodpasture syndrome]] resulting in glomerular [[necrosis]] and pulmonary [[Bleeding|haemorrhages]].
2. Immune complex- Type II RPGN
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.
* Immune complexes are formed in certain infections, [[Connective tissue disease|connective tissue diseases]], side effects of some drugs and in some [[Myeloproliferative neoplasm|myeloproliferative]] disorders.
* These immune complexes are deposited over the GBM.
* These immune complexes are deposited over the GBM.
* The immune complexes activate the complement system which sets off the inflammatory process.
* The immune complexes activate the [[complement]] system which sets off the inflammatory process.
* The complement cascade is activated, attracting [[Inflammation|inflammatory]] cells and mediators to the GBM.
* The complement cascade is activated, attracting [[Inflammation|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.  
* The serum levels of [[C3-convertase|c3]] and [[C4A|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.       
* This damages the glomeruli and causes leakage of cells and inflammatory mediators resulting in crescent formation.       
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** [[Membranoproliferative glomerulonephritis]]       
** [[Membranoproliferative glomerulonephritis]]       
3. Pauci immune RPGN-Type III RPGN
3. Pauci immune RPGN-Type III RPGN
* No circulating immune complexes or antibodies.
* No circulating [[Immune complex|immune complexes]] or [[antibodies]].
* Glomerular damage is caused by circulating ANCAs(anti nuclear cytoplasmic antibodies) or it can be idiopathic(non ANCA).
* Glomerular damage is caused by circulating [[Antinuclear antibodies|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.
* ANCAs cause glomerular damage by releasing lytic enzymes from white blood cells such as [[Neutrophil|neutrophils]].
* These lytic enzymes damage the GBM and cause leakage of circulating cells and initiate crescent formationin the Bowmans space.
* 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.
* ANCAs are associated with systemic [[Vasculitis|vasculitis.]]
*  Examples include
*  Examples include
** [[Granulomatosis with polyangiitis]] (Wegener granulomatosis)
** [[Granulomatosis with polyangiitis]] (Wegener granulomatosis)
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** Renal-limited necrotizing crescentic glomerulonephritis (NCGN)
** Renal-limited necrotizing crescentic glomerulonephritis (NCGN)
** [[Langerhans cell histiocytosis|Eosinophilic granulomatosis]] with polyangiitis (EGPA; Churg-Strauss syndrome)
** [[Langerhans cell histiocytosis|Eosinophilic granulomatosis]] with polyangiitis (EGPA; Churg-Strauss syndrome)
** Drugs- hydralazine, allopurinol and rifampin.
** Drugs- [[hydralazine]], [[allopurinol]] and [[rifampin]].


== Gross pathology ==
== Gross pathology ==
* The kidneys appear to be having having haemorrhages and necrosed tissue.
* The kidneys appear to be having having [[Bleeding|haemorrhages]] and [[Necrosis|necrosed]] tissue.
* Pulmonary haemorrhages may also be present in Goodpasture syndrome and type III RPGN.
* Pulmonary haemorrhages may also be present in [[Goodpasture syndrome]] and type III RPGN.
* Type III RPGN may present with petechiae,rashes and purpuras.
* Type III RPGN may present with [[Petechia|petechiae]], [[Rash|rashes]] and purpuras.


== Microscopic pathology ==
== Microscopic pathology ==


=== Histopathology ===
=== Histopathology ===
* Glomerular inflammation with signs of necrosis are present.  
* [[Glomerular disease|Glomerular inflammation]] with signs of necrosis are present.  
* .Glomerular caplillary wall rupture and damage to GBM.
* .Glomerular caplillary wall rupture and damage to GBM.
* Crescents are present in the Bowmans space.
* Crescents are present in the [[Bowman's capsule|Bowmans space]].
* Crescents are formed by proliferating epithelial cells and monocytes
* Crescents are formed by proliferating epithelial cells and [[Monocyte|monocytes]]
* Fibroblasts migrate to the Bowman’s space and synthesize collagen.
* [[Fibroblast|Fibroblasts]] migrate to the Bowman’s space and synthesize [[collagen]].
* When cellular components are mixed with collagen the lesion is called fibroepithelial crescent.
* When cellular components are mixed with collagen the lesion is called [[Crescent Rising|fibroepithelial crescent]].
* Renal vessels can show transmural vasculitis, with necrosis and lymphocyte infiltrates.
* Renal vessels can show transmural [[vasculitis]], with necrosis and [[lymphocyte]] infiltrates.
* Tubular necrosis may also be present.
* [[Tubular]] necrosis may also be present.
* Interstitial granulomas in the glomeruli indicate Wegener’s granulomatosis.
* Interstitial [[Granuloma|granulomas]] in the glomeruli indicate [[Granulomatosis with polyangiitis|Wegener’s granulomatosis]].
[[Image:Post-rapidly progressive glomerulonephritis - very high mag (1).jpg|200px|centre|Source:By Nephron - Own work<ref/ https://commons.wikimedia.org/w/index.php?curid=17591464 ref>>]]
[[Image:Post-rapidly progressive glomerulonephritis - very high mag (1).jpg|200px|centre|Source:By Nephron - Own work<ref/ https://commons.wikimedia.org/w/index.php?curid=17591464 ref>>]]


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=== Immunoflourescence ===
=== Immunoflourescence ===
* In type I RPGN- diffuse and linear deposition of IgG along the GBM.
* In type I RPGN- diffuse and linear deposition of [[Immunoglobulin G|IgG]] along the [[GBM]].
* In ttype II RPGN- diffuse and irregular deposition of IgG and C3 in the mesangial matrix.
* In ttype II RPGN- diffuse and irregular deposition of IgG and C3 in the [[Mesangial cell|mesangial]] matrix.
* In type III RPGN- no finding.
* In type III RPGN- no finding.


=== Electron microscopy ===
=== Electron microscopy ===
* In type I and type III, no electron dense deposits are seen.  
* 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.  
* In type II RPGN, subepithelial electron dense deposits indiacting the presence of [[Immune complex|immune complexes]] are seen.  
* 


== Genetics ==
== Genetics ==
People with HLA DP1,DQ and DRB4 are more susceptible to develop RPGN.
People with [[Human leukocyte antigen|HLA]] DP1,DQ and DRB4 are more susceptible to develop RPGN.
* 
{{#ev:youtube|CqSyj4cVZPE}}
{{#ev:youtube|CqSyj4cVZPE}}


Revision as of 17:39, 23 July 2018

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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.

.Pathogenesis

  • Rapidly progressive glomerulonephritis is a disease of the kidney in which the renal function deteriorates in a few 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.
  • 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
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 syndrome 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

Gross pathology

Microscopic pathology

Histopathology

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. {{#ev:youtube|CqSyj4cVZPE}}

References

Template:WH Template:WS

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