Rapidly progressive glomerulonephritis pathophysiology
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.Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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. Injury can occur by anti GBM antibodies-type I RPGN, Immune complex- type II RPGN or pauci immune RPGN(ANCAs)-type III RPGN. Crescents are present in the Bowmans space. Light, immunofluoresnce and electron microscopy are used to diagnose RPGN.
Pathophysiology
Anatomy
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[1][2].
- 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
- Crescents are defined as 2 or more layers of proliferating cells in the Bowman's space.[2][3][4]
- The crescents are made up of epithelial cells and macrophages which undergo fibrosis[5][6].
- Crescents are formed after a severe injury to the glomerulus.
- Injury to the glomerulus causes leakage of cells(epithelial, 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.
- 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[7].
- 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[8].
- 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[9]
- 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[10][11][12][13].
- 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.[14]
- 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[15][16].
- .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.
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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[17]. {{#ev:youtube|CqSyj4cVZPE}}
References
- ↑ Couser WG (1988). "Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy". Am J Kidney Dis. 11 (6): 449–64. PMID 3287904.
- ↑ 2.0 2.1 Couser WG (1998). "Pathogenesis of glomerular damage in glomerulonephritis". Nephrol Dial Transplant. 13 Suppl 1: 10–5. PMID 9507491.
- ↑ Roy S, Murphy WM, Arant BS (1981). "Poststreptococcal crescenteric glomerulonephritis in children: comparison of quintuple therapy versus supportive care". J Pediatr. 98 (3): 403–10. PMID 7205449.
- ↑ Atkins RC, Nikolic-Paterson DJ, Song Q, Lan HY (1996). "Modulators of crescentic glomerulonephritis". J Am Soc Nephrol. 7 (11): 2271–8. PMID 8959617.
- ↑ Bariéty J, Bruneval P, Meyrier A, Mandet C, Hill G, Jacquot C (2005). "Podocyte involvement in human immune crescentic glomerulonephritis". Kidney Int. 68 (3): 1109–19. doi:10.1111/j.1523-1755.2005.00503.x. PMID 16105041.
- ↑ Tipping PG, Timoshanko J (2005). "Contributions of intrinsic renal cells to crescentic glomerulonephritis". Nephron Exp Nephrol. 101 (4): e173–8. doi:10.1159/000088165. PMID 16155400.
- ↑ Huang XR, Tipping PG, Apostolopoulos J, Oettinger C, D'Souza M, Milton G; et al. (1997). "Mechanisms of T cell-induced glomerular injury in anti-glomerular basement membrane (GBM) glomerulonephritis in rats". Clin Exp Immunol. 109 (1): 134–42. PMC 1904710. PMID 9218836.
- ↑ Izzedine H, Camous L, Deray G (2007). "New insight on crescentic glomerulonephritis". Nephrol Dial Transplant. 22 (5): 1480–1. doi:10.1093/ndt/gfl742. PMID 17164315.
- ↑ "Chapter 10: Immunoglobulin A nephropathy". Kidney Int Suppl (2011). 2 (2): 209–217. 2012. doi:10.1038/kisup.2012.23. PMC 4089745. PMID 25018935.
- ↑ Heeringa P, Brouwer E, Klok PA, Huitema MG, van den Born J, Weening JJ; et al. (1996). "Autoantibodies to myeloperoxidase aggravate mild anti-glomerular-basement-membrane-mediated glomerular injury in the rat". Am J Pathol. 149 (5): 1695–706. PMC 1865281. PMID 8909258.
- ↑ Yang G, Tang Z, Chen Y, Zeng C, Chen H, Liu Z; et al. (2005). "Antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with anti-GBM crescentic glomerulonephritis". Clin Nephrol. 63 (6): 423–8. PMID 15960143.
- ↑ de Lind van Wijngaarden RA, Hauer HA, Wolterbeek R, Jayne DR, Gaskin G, Rasmussen N; et al. (2006). "Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: A prospective analysis of 100 patients with severe renal involvement". J Am Soc Nephrol. 17 (8): 2264–74. doi:10.1681/ASN.2005080870. PMID 16825335.
- ↑ Bomback AS, Appel GB, Radhakrishnan J, Shirazian S, Herlitz LC, Stokes B; et al. (2011). "ANCA-associated glomerulonephritis in the very elderly". Kidney Int. 79 (7): 757–64. doi:10.1038/ki.2010.489. PMID 21160463.
- ↑ Chen M, Yu F, Wang SX, Zou WZ, Zhao MH, Wang HY (2007). "Antineutrophil cytoplasmic autoantibody-negative Pauci-immune crescentic glomerulonephritis". J Am Soc Nephrol. 18 (2): 599–605. doi:10.1681/ASN.2006091021. PMID 17215440.
- ↑ Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K; et al. (2010). "Histopathologic classification of ANCA-associated glomerulonephritis". J Am Soc Nephrol. 21 (10): 1628–36. doi:10.1681/ASN.2010050477. PMID 20616173.
- ↑ Bonsib SM (1988). "Glomerular basement membrane necrosis and crescent organization". Kidney Int. 33 (5): 966–74. PMID 3392885.
- ↑ Jagiello P, Gross WL, Epplen JT (2005). "Complex genetics of Wegener granulomatosis". Autoimmun Rev. 4 (1): 42–7. doi:10.1016/j.autrev.2004.06.003. PMID 15652778.