Focal segmental glomerulosclerosis pathophysiology: Difference between revisions

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**Overexpression of tumor growth factor-beta ([[TGF-beta]]), [[platelet-derived growth factor]] (PDGF), and [[vascular endothelial growth factor]] (VEGF)<ref name="pmid12704576">{{cite journal| author=Fogo AB| title=Animal models of FSGS: lessons for pathogenesis and treatment. | journal=Semin Nephrol | year= 2003 | volume= 23 | issue= 2 |pages= 161-71 | pmid=12704576 | doi=10.1053/snep.2003.50015 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12704576  }} </ref><ref name="pmid18039119">{{cite journal| author=Kwoh C, Shannon MB, Miner JH, Shaw A| title=Pathogenesis of nonimmune glomerulopathies. | journal=Annu Rev Pathol | year= 2006 | volume= 1 | issue=  | pages= 349-74 | pmid=18039119 | doi=10.1146/annurev.pathol.1.110304.100119 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18039119  }} </ref><ref name="pmid12704579">{{cite journal| author=Hostetter TH| title=Hyperfiltration and glomerulosclerosis. | journal=Semin Nephrol | year= 2003 | volume= 23 | issue= 2 | pages= 194-9 | pmid=12704579 | doi=10.1053/anep.2003.50017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12704579  }} </ref>
**Overexpression of tumor growth factor-beta ([[TGF-beta]]), [[platelet-derived growth factor]] (PDGF), and [[vascular endothelial growth factor]] (VEGF)<ref name="pmid12704576">{{cite journal| author=Fogo AB| title=Animal models of FSGS: lessons for pathogenesis and treatment. | journal=Semin Nephrol | year= 2003 | volume= 23 | issue= 2 |pages= 161-71 | pmid=12704576 | doi=10.1053/snep.2003.50015 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12704576  }} </ref><ref name="pmid18039119">{{cite journal| author=Kwoh C, Shannon MB, Miner JH, Shaw A| title=Pathogenesis of nonimmune glomerulopathies. | journal=Annu Rev Pathol | year= 2006 | volume= 1 | issue=  | pages= 349-74 | pmid=18039119 | doi=10.1146/annurev.pathol.1.110304.100119 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18039119  }} </ref><ref name="pmid12704579">{{cite journal| author=Hostetter TH| title=Hyperfiltration and glomerulosclerosis. | journal=Semin Nephrol | year= 2003 | volume= 23 | issue= 2 | pages= 194-9 | pmid=12704579 | doi=10.1053/anep.2003.50017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12704579  }} </ref>


===Genetics===
==Genetics==
The development of focal segmental glomerulosclerosis is the result of multiple genetic mutations such as:<ref name="pmid9660941">{{cite journal| author=Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H et al.| title=Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. | journal=Mol Cell | year= 1998 | volume= 1 | issue= 4 | pages= 575-82 | pmid=9660941 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9660941  }} </ref><ref name="pmid18039119" /><ref name="pmid16571882">{{cite journal| author=Tryggvason K, Patrakka J, Wartiovaara J| title=Hereditary proteinuria syndromes and mechanisms of proteinuria. | journal=N Engl J Med | year= 2006 | volume= 354 | issue= 13 | pages= 1387-401 | pmid=16571882 | doi=10.1056/NEJMra052131 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16571882  }} </ref><ref name="pmid12764198">{{cite journal| author=Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH et al.| title=CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. | journal=Science | year= 2003 | volume= 300 | issue= 5623 | pages= 1298-300 | pmid=12764198 | doi=10.1126/science.1081068 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12764198  }} </ref><ref name="pmid10514378">{{cite journal| author=Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O et al.| title=Congenital nephrotic syndrome in mice lacking CD2-associated protein. | journal=Science | year= 1999 | volume= 286 | issue= 5438 | pages= 312-5 | pmid=10514378 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10514378  }} </ref><ref name="pmid10700177">{{cite journal| author=Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ et al.| title=Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. | journal=Nat Genet | year= 2000 | volume= 24 | issue= 3 | pages= 251-6 | pmid=10700177 | doi=10.1038/73456 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10700177  }} </ref><ref name="pmid12953036">{{cite journal| author=Winn MP| title=Approach to the evaluation of heritable diseases and update on familial focal segmental glomerulosclerosis. | journal=Nephrol Dial Transplant | year= 2003 | volume= 18 Suppl 6 | issue=  | pages= vi14-20 | pmid=12953036 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12953036  }} </ref><ref name="pmid23871408">{{cite journal| author=Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH et al.| title=KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. | journal=Am J Kidney Dis | year= 2013 | volume= 62 | issue= 3 | pages= 403-41 | pmid=23871408 | doi=10.1053/j.ajkd.2013.06.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23871408  }} </ref>
The development of focal segmental glomerulosclerosis is the result of multiple genetic mutations such as:<ref name="pmid9660941">{{cite journal| author=Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H et al.| title=Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. | journal=Mol Cell | year= 1998 | volume= 1 | issue= 4 | pages= 575-82 | pmid=9660941 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9660941  }} </ref><ref name="pmid18039119" /><ref name="pmid16571882">{{cite journal| author=Tryggvason K, Patrakka J, Wartiovaara J| title=Hereditary proteinuria syndromes and mechanisms of proteinuria. | journal=N Engl J Med | year= 2006 | volume= 354 | issue= 13 | pages= 1387-401 | pmid=16571882 | doi=10.1056/NEJMra052131 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16571882  }} </ref><ref name="pmid12764198">{{cite journal| author=Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH et al.| title=CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. | journal=Science | year= 2003 | volume= 300 | issue= 5623 | pages= 1298-300 | pmid=12764198 | doi=10.1126/science.1081068 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12764198  }} </ref><ref name="pmid10514378">{{cite journal| author=Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O et al.| title=Congenital nephrotic syndrome in mice lacking CD2-associated protein. | journal=Science | year= 1999 | volume= 286 | issue= 5438 | pages= 312-5 | pmid=10514378 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10514378  }} </ref><ref name="pmid10700177">{{cite journal| author=Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ et al.| title=Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. | journal=Nat Genet | year= 2000 | volume= 24 | issue= 3 | pages= 251-6 | pmid=10700177 | doi=10.1038/73456 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10700177  }} </ref><ref name="pmid12953036">{{cite journal| author=Winn MP| title=Approach to the evaluation of heritable diseases and update on familial focal segmental glomerulosclerosis. | journal=Nephrol Dial Transplant | year= 2003 | volume= 18 Suppl 6 | issue=  | pages= vi14-20 | pmid=12953036 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12953036  }} </ref><ref name="pmid23871408">{{cite journal| author=Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH et al.| title=KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. | journal=Am J Kidney Dis | year= 2013 | volume= 62 | issue= 3 | pages= 403-41 | pmid=23871408 | doi=10.1053/j.ajkd.2013.06.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23871408  }} </ref>
*Nephrin gene in congenital Finnish-type nephrotic syndrome - ''NPHS1''
*Nephrin gene in congenital Finnish-type nephrotic syndrome - ''NPHS1''

Revision as of 19:11, 25 June 2018

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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:

  • Soluble Urokinase Plasminogen Activating Receptor (suPAR) and MicroRNAs.[1]
  • 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 :

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. ↑ 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).
  2. ↑ 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. ↑ 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. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. ↑ 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.
  11. ↑ Hostetter TH (2003). "Hyperfiltration and glomerulosclerosis". Semin Nephrol. 23 (2): 194–9. doi:10.1053/anep.2003.50017. PMID 12704579.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.


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