Rapidly progressive glomerulonephritis pathophysiology: Difference between revisions

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Revision as of 21:27, 18 July 2018

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.
It is a response that occurs following severe damage to the glomerulus.
Crescents are formed when fibrin deposition occurs in Bowmans 'space.
Fibrin formation in Bowman's space is a complex process which involves multiple components.
Fibrin formation is precipitated by leakage of multiple cells and inflammation mediators through glomerular capliiary wall,GBM and Bowman's capsule.
This leakage occurs from damage caused by multiple factors:
- Anti GBM antiboides
- Immune complexes
- ANCA or vasculitis
The cells include coagulation proteins,macrophages,T cells and other inflammatory mediators.
This leads to fibrous tissue formation in the Bowman's space known as crescents.

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 alveolar 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.

3. Pauci immune RPGN-Type III RPGN

No circulating immune complexes or antibodies.
Glomerular damage is caused by circulating ANCAs(anti nuclear cytoplasmic antibodies) .
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 that result in fibrin formation in the Bowmans space.
ANCAs are associated with systemic vasculitis.

Microscopic pathology

References

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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]].
+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 ===
-* Although the pathogenesis of RPGN is poorly understood, it is thought that some circulating factors have a significant role in the progression of the glomerulonephritis.<ref name="pmid2161532">{{cite journal| author=Falk RJ, Terrell RS, Charles LA, Jennette JC| title=Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 11 | pages= 4115-9 | pmid=2161532 | doi= | pmc=PMC54058 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2161532 }} </ref>
+* RPGN is characterized by severe and fast damage to the GBM that results in atleast 50% reduction in GFR in a few days.
-* The pathophysiology of RPGN is considered as a combination of pathways that lead to the glomerular injury as an outcome. Genetic susceptibility has been shown to be associated with elevated levels of circulating antibodies, such as anti-GBM and ANCA, but little has been elaborated.<ref name="pmid7544065">{{cite journal| author=Short AK, Esnault VL, Lockwood CM| title=Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis. | journal=Am J Kidney Dis | year= 1995 | volume= 26 | issue= 3 | pages= 439-45 | pmid=7544065 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7544065 }} </ref>
+* The injury to GBM can be caused by multiple factors.
-* The pathogenesis according to the different types of RPGN as the following:
+* Crescent formation is the major pathological finding.
-** Type I anti-GBM glomerulonephritis:<ref name="pmid18590526">{{cite journal| author=Ramaswami A, Kandaswamy T, Rajendran T, Aung H, Jacob CK, Zinna HS et al.| title=Goodpasture's syndrome with positive C-ANCA and normal renal function: a case report. | journal=J Med Case Rep | year= 2008 | volume= 2 | issue= | pages= 223 | pmid=18590526 | doi=10.1186/1752-1947-2-223 | pmc=PMC2475522 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18590526 }} </ref><ref name="pmid4937848">{{cite journal| author=Lewis EJ, Cavallo T, Harrington JT, Cotran RS| title=An immunopathologic study of rapidly progressive glomerulonephritis in the adult. | journal=Hum Pathol | year= 1971 | volume= 2 | issue= 2 | pages= 185-208 | pmid=4937848 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4937848 }} </ref><ref name="pmid7360526">{{cite journal| author=Cunningham RJ, Gilfoil M, Cavallo T, Brouhard BH, Travis LB, Berger M et al.| title=Rapidly progressive glomerulonephritis in children: a report of thirteen cases and a review of the literature. | journal=Pediatr Res | year= 1980 | volume= 14 | issue= 2 | pages= 128-32 | pmid=7360526 | doi=10.1203/00006450-198002000-00012 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7360526 }} </ref>
+* In some cases crescents might be absent.
-*** Antibodies against non-collagenous domain of alpha 3 chain of type IV collagen of the glomerular basement membrane.
-*** Linear pattern on immunofluorescence which indicates deposition of IgG and C3.
+====== Cresent formation ======
-*** This type is predominent in Goodpasture syndrome.
+* Crescents are defined as 2 or more layers of proliferating cells in the Bowman's space.
-** Type II pauci-immune glomerulonephritis: <ref name="pmid2161532">{{cite journal| author=Falk RJ, Terrell RS, Charles LA, Jennette JC| title=Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 11 | pages= 4115-9 | pmid=2161532 | doi= | pmc=PMC54058 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2161532 }} </ref><ref name="pmid6297657">{{cite journal| author=Davies DJ, Moran JE, Niall JF, Ryan GB| title=Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? | journal=Br Med J (Clin Res Ed) | year= 1982 | volume= 285 | issue= 6342 | pages= 606 | pmid=6297657 | doi= | pmc=PMC1499415 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6297657 }} </ref><ref name="pmid3009619">{{cite journal| author=Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM et al.| title=Stimulation of neutrophils by tumor necrosis factor. | journal=J Immunol | year= 1986 | volume= 136 | issue= 11 | pages= 4220-5 | pmid=3009619 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3009619 }} </ref><ref name="pmid7044447">{{cite journal| author=Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Cehrs K, Mounessa N| title=Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response. | journal=Blood | year= 1982 | volume= 59 | issue= 6 | pages= 1317-29 | pmid=7044447 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7044447 }} </ref>
+* It is a response that occurs following severe damage to the glomerulus.
-*** Findings of p-ANCA and c-ANCA in patients serum.
+* Crescents are formed when fibrin deposition occurs in Bowmans 'space.
-*** These findings indicate the interaction between ANCA and the myeloperoxidases on the surface of the neutrophils. This lead to oxidative burst and end up with production of oxygen radicals causing glomerular injury.
+* Fibrin formation in Bowman's space is a complex process which involves multiple components.
-*** Tumor Necrosis Factor (TNF) also plays a role in neutrophils degranulation and free radicals production.
+* Fibrin formation is precipitated by leakage of multiple cells and inflammation mediators through glomerular capliiary wall,GBM and Bowman's capsule.
-*** TNF production during infections and inflammatory diseases in vivo may prime neutrophils in ANCA-positive patients to facilitate neutrophilic activation and subsequent pro-inflammatory cascade of RPGN disease.
+* This leakage occurs from damage caused by multiple factors:
-*** Example of diseases: polyangiitis with granulomatosis and polyarteritis nodosa.
+** Anti GBM antiboides
+** Immune complexes
+** ANCA or vasculitis
+* The cells include coagulation proteins,macrophages,T cells and other inflammatory mediators.
+* This leads to fibrous tissue formation in the Bowman's space known as crescents.
+====== Glomerular injury ======
+* Injury to the glomerulus is the initiating factor for crescent formation.
+* Injury can occur by the following
+*# 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 alveolar haemorrhages.
+. 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.
+. Pauci immune RPGN-Type III RPGN
+* No circulating immune complexes or antibodies.
+* Glomerular damage is caused by circulating ANCAs(anti nuclear cytoplasmic antibodies) .
+* 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 that result in fibrin formation in the Bowmans space.
+* ANCAs are associated with systemic vasculitis.
-*The cause of [[renal injury]] is due to [[Anti-glomerular basement membrane antibody|anti-glomerular basement membrane antibodies]] ability to bind and activate [[complement system]] and [[proteases]], resulting in an interruption between the [[filtration]] barrier and the [[Bowman's capsule|Bowman’s capsule]].
-*The interruption of the [[Bowman's capsule]] and [[filtration]] barrier, induces [[Crescentic glomerulonephritis|crescent]] shaped antigen-antibody complex formation in the [[Renal corpuscles|renal corpuscles,]] invoking [[proteinuria]] and activating [[T cells]] ([[CD4+]] and [[CD8+ T cells|CD8+]]), [[macrophages]], and [[neutrophils]].<ref name="pmid12815141">{{cite journal |vauthors=Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG |title=Alport's syndrome, Goodpasture's syndrome, and type IV collagen |journal=N. Engl. J. Med. |volume=348 |issue=25 |pages=2543–56 |date=June 2003 |pmid=12815141 |doi=10.1056/NEJMra022296 |url=}}</ref><ref name="pmid21168945">{{cite journal |vauthors=Cui Z, Zhao J, Jia XY, Zhu SN, Zhao MH |title=Clinical features and outcomes of anti-glomerular basement membrane disease in older patients |journal=Am. J. Kidney Dis. |volume=57 |issue=4 |pages=575–82 |date=April 2011 |pmid=21168945 |doi=10.1053/j.ajkd.2010.09.022 |url=}}</ref>
-*While the majority of patients with pauci-immune RPGN indeed have elevated levels of ANCA, the remaining 20% of patients with the same disease do not. Interestingly, 30% of patients in remission continue to have elevated levels of ANCA. Both these problematic findings raise the question of the actual importance of ANCA in the pathogenesis of RPGN.<ref name="pmid11007827">{{cite journal| author=Hedger N, Stevens J, Drey N, Walker S, Roderick P| title=Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study. | journal=Nephrol Dial Transplant | year= 2000 | volume= 15 | issue= 10 | pages= 1593-9 | pmid=11007827 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11007827 }} </ref> A novel hypothesis currently suggests that RPGN is in fact a podocytopathy, defined as an intrinsic disease of the podocytes that normally maintains glomerular capillary membranes.<ref name="pmid14675045">{{cite journal| author=Yoshimoto K, Yokoyama H, Wada T, Furuichi K, Sakai N, Iwata Y et al.| title=Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy. | journal=Kidney Int | year= 2004 | volume= 65 | issue= 1 | pages= 148-53 | pmid=14675045 | doi=10.1111/j.1523-1755.2004.00403.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14675045 }} </ref> As such, it is thought that the CXCR4 and VHL-HIF pathway target gene expression in renal biopsies, based on experimental studies on mice.<ref name="pmid16906157">{{cite journal| author=Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM et al.| title=Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. | journal=Nat Med | year= 2006 | volume= 12 | issue= 9 | pages= 1081-7 | pmid=16906157 | doi=10.1038/nm1460 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16906157 }} </ref>
 == Microscopic pathology ==