Focal segmental glomerulosclerosis pathophysiology
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- Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Ali Poyan Mehr, M.D. [2]; Associate Editor-In-Chief:’’’ Cafer Zorkun, M.D., Ph.D. [3]; Olufunmilola Olubukola M.D.[4]
Overview
Pathophysiology
There are two types of FSGS, primary FSGS and secondary FSGS, pathophysiology is discussed below:
Pathogenesis of primary FSGS
The pathogenesis of primary or Idiopathic FSGS is not so clear. Many studies had theorized that FSGS occurs as a consequence of effects of circulating immune activating factors on the glomerular epithelium. Indeed, the damaging role of circulating factors like the soluble urokinase plasminogen activating receptor (suPAR) on the glomerular podocytes had been postulated. The underlying pathogenesis of FSGS is fusion or effacement of the foot processes (podocytes) of the glomeruli, with sclerosing of some part of the glomeruli (hence its name as focal segmental). As such, the involvement of the permselective filtration barrier and effacement of podocyte foot processes are inevitable. The four major causes that lead to the reaction of podocyte foot processes. These changes result in apoptosis, detachment from the glomerular basement membrane (GBM), and subsequent podocytopenia:[1][2][3][4]
- Interference with slit diaphragm and its corresponding lipid raft
- Interference with actin cytoskeleton
- Interference with the GBM or with the interaction of the GBM and the podocytes
- Interference with the negative charge of podocytes
There are various factors, which play important in the pathogenesis of FSGS:
Role of circulating permeability Factor
Circulating factors implicated in the pathogenesis of Primary FSGS include:
- suPAR is a heavily glycosylated protein that can be found in several places.[4][5][6][7]
- Cardiotrophin-like cytokine factor-1 (CLCF1)
Pathogenesis of secondary FSGS
The pathogenesis of secondary focal segmental glomerulosclerosis (FSGS) occurs due to the following factors :
- Glomerular hypertrophy and hyperfiltration, which is due to the following :[8][9]
- Scarring due to the previous injury
- Glomerular abnormality
- Direct toxic injury to podocytes.
- Various inflammatory mediators include
- Overexpression of tumor growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) contributes to the progression of disease and is associated with the extent of glomerulosclerosis. Activated cytokines promote cellular infiltration and desposition of collagen along the mesangial matrix.
Maladaptive Interactions
Following the loss of podocytes, maladaptive interactions occur between the GBM and the renal epithelial cells, leading to proliferation of epithelial, endothelial, and mesangial cells. The resultant collagen deposition then contributes to the scarring of the glomerular tufts that appear as focal and segmental regions of glomerulosclerosis as seen on pathology. The diseased regions then progress to involve larger areas of the kidneys and eventually become diffusely sclerotic, causing end-stage renal disease (ESRD).[3]
Role of Mechanical Stresses
Defects of the glomerular filtration barrier leads to an overwhelmingly increased single nephron glomerular filtration rate (SNGFR). This mechanical stress helps in the progression of FSGS by creating a state of hypertrophy that worsens the lack of balance between the GBM and the podocytopenia, and thus worsens the extent of injury.[10][11]
Genetics
The development of focal segmental glomerulosclerosis is the result of multiple genetic mutations such as:[12][10][13][14][15][16][17][18]
- Nephrin gene in congenital Finnish-type nephrotic syndrome - NPHS1
- Nephrin-like transmembrane gene - NEPH1
- Podocin gene - NPHS2
- CD2-associated protein (CD2AP)
- Alpha-actinin-4 gene
- Transient receptor potential cation channel - TRPC6
- Mutation in wilms tumor gene - WT1
- Mutation in SCARB2 (LIMP2) gene
- Mutation in formin gene - INF2
- Mitochondrial cytopathies
Associated Conditions
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ 1.0 1.1 Reiser J, Nast CC, Alachkar N (2014). "Permeability factors in focal and segmental glomerulosclerosis". Adv Chronic Kidney Dis. 21 (5): 417–21. doi:10.1053/j.ackd.2014.05.010. PMC 4149759. PMID 25168830 PMID 25168830 Check
|pmid=value (help). - ↑ Asanuma K, Mundel P (2003). "The role of podocytes in glomerular pathobiology". Clin Exp Nephrol. 7 (4): 255–9. doi:10.1007/s10157-003-0259-6. PMID 14712353.
- ↑ 3.0 3.1 Fogo AB (2003). "Animal models of FSGS: lessons for pathogenesis and treatment". Semin Nephrol. 23 (2): 161–71. doi:10.1053/snep.2003.50015. PMID 12704576.
- ↑ 4.0 4.1 Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ; et al. (2012). "Circulating suPAR in two cohorts of primary FSGS". J Am Soc Nephrol. 23 (12): 2051–9. doi:10.1681/ASN.2012030302. PMC 3507361. PMID 23138488.
- ↑ Rea R, Smith C, Sandhu K, Kwan J, Tomson C (2001). "Successful transplant of a kidney with focal segmental glomerulosclerosis". Nephrol Dial Transplant. 16 (2): 416–7. PMID 11158426.
- ↑ Ghiggeri GM, Artero M, Carraro M, Perfumo F (2001). "Permeability plasma factors in nephrotic syndrome: more than one factor, more than one inhibitor". Nephrol Dial Transplant. 16 (5): 882–5. PMID 11328888.
- ↑ Kemper MJ, Wolf G, Müller-Wiefel DE (2001). "Transmission of glomerular permeability factor from a mother to her child". N Engl J Med. 344 (5): 386–7. doi:10.1056/NEJM200102013440517. PMID 11195803.
- ↑ Harris RC, Neilson EG (2006). "Toward a unified theory of renal progression". Annu Rev Med. 57: 365–80. doi:10.1146/annurev.med.57.121304.131342. PMID 16409155.
- ↑ Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL; et al. (2001). "Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1". J Am Soc Nephrol. 12 (7): 1434–47. PMID 11423572.
- ↑ 10.0 10.1 Kwoh C, Shannon MB, Miner JH, Shaw A (2006). "Pathogenesis of nonimmune glomerulopathies". Annu Rev Pathol. 1: 349–74. doi:10.1146/annurev.pathol.1.110304.100119. PMID 18039119.
- ↑ Hostetter TH (2003). "Hyperfiltration and glomerulosclerosis". Semin Nephrol. 23 (2): 194–9. doi:10.1053/anep.2003.50017. PMID 12704579.
- ↑ Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H; et al. (1998). "Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome". Mol Cell. 1 (4): 575–82. PMID 9660941.
- ↑ Tryggvason K, Patrakka J, Wartiovaara J (2006). "Hereditary proteinuria syndromes and mechanisms of proteinuria". N Engl J Med. 354 (13): 1387–401. doi:10.1056/NEJMra052131. PMID 16571882.
- ↑ Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH; et al. (2003). "CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility". Science. 300 (5623): 1298–300. doi:10.1126/science.1081068. PMID 12764198.
- ↑ Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O; et al. (1999). "Congenital nephrotic syndrome in mice lacking CD2-associated protein". Science. 286 (5438): 312–5. PMID 10514378.
- ↑ Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ; et al. (2000). "Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis". Nat Genet. 24 (3): 251–6. doi:10.1038/73456. PMID 10700177.
- ↑ Winn MP (2003). "Approach to the evaluation of heritable diseases and update on familial focal segmental glomerulosclerosis". Nephrol Dial Transplant. 18 Suppl 6: vi14–20. PMID 12953036.
- ↑ Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH; et al. (2013). "KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis". Am J Kidney Dis. 62 (3): 403–41. doi:10.1053/j.ajkd.2013.06.002. PMID 23871408.