Focal segmental glomerulosclerosis pathophysiology: Difference between revisions

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=== Pathogenesis of primary FSGS ===
=== Pathogenesis of primary FSGS ===
*The pathogenesis of primary or Idiopathic FSGS is not so clear.<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  
*The [[pathogenesis]] of primary or [[Idiopathic]] FSGS is not so clear.<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  
*Many studies had theorized that FSGS occurs as a consequence of effects of circulating immune activating factors on the glomerular epithelium.<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  
*Many studies had theorized that FSGS occurs as a consequence of effects of circulating [[immune]] activating factors on the [[glomerular]] [[epithelium]].<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  
*Indeed, the damaging role of circulating factors like the soluble urokinase plasminogen activating receptor (suPAR) on the glomerular podocytes had been postulated.<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  
*Indeed, the damaging role of circulating factors like the [[soluble]] [[urokinase]] [[plasminogen]] activating [[receptor]] (suPAR) on the [[glomerular]] [[podocytes]] had been postulated.<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  
*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).   
*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.  
*As such, the involvement of the permselective [[filtration]] [[Barrier (pharmaceutical)|barrier]] and [[effacement]] of [[podocyte]] [[foot]] processes are inevitable.  
*The four major causes that lead to the reaction of podocyte foot processes.  
*The four major causes that lead to the reaction of [[podocyte]] [[foot]] processes.  
*These changes result in:<ref name="pmid14712353">{{cite journal| author=Asanuma K, Mundel P| title=The role of podocytes in glomerular pathobiology. | journal=Clin Exp Nephrol | year= 2003 | volume= 7 | issue= 4 | pages= 255-9 | pmid=14712353 | doi=10.1007/s10157-003-0259-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14712353  }} </ref><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="pmid23138488">{{cite journal| author=Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ et al.| title=Circulating suPAR in two cohorts of primary FSGS. | journal=J Am Soc Nephrol | year= 2012 | volume= 23 | issue= 12 | pages= 2051-9 | pmid=23138488 | doi=10.1681/ASN.2012030302 | pmc=3507361 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23138488  }} </ref>  
*These changes result in:<ref name="pmid14712353">{{cite journal| author=Asanuma K, Mundel P| title=The role of podocytes in glomerular pathobiology. | journal=Clin Exp Nephrol | year= 2003 | volume= 7 | issue= 4 | pages= 255-9 | pmid=14712353 | doi=10.1007/s10157-003-0259-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14712353  }} </ref><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="pmid23138488">{{cite journal| author=Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ et al.| title=Circulating suPAR in two cohorts of primary FSGS. | journal=J Am Soc Nephrol | year= 2012 | volume= 23 | issue= 12 | pages= 2051-9 | pmid=23138488 | doi=10.1681/ASN.2012030302 | pmc=3507361 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23138488  }} </ref>  
**[[Apoptosis]]
**[[Apoptosis]]
**Detachment from the glomerular basement membrane (GBM)
**Detachment from the [[glomerular]] [[basement membrane]] ([[GBM]])
**Subsequent podocytopenia
**Subsequent podocytopenia
**Interference  with slit diaphragm and its corresponding [[lipid raft]]
**[[Interference]] with [[Slit (protein)|slit]] [[diaphragm]] and its corresponding [[lipid raft]]
**Interference with [[actin]] cytoskeleton
**[[Interference]] with [[actin]] [[cytoskeleton]]
**Interference with the [[glomerular basement membrane|GBM]] or with the interaction of the [[glomerular basement membrane|GBM]] and the [[podocytes]]
**[[Interference]] with the [[glomerular basement membrane|GBM]] or with the [[interaction]] of the [[glomerular basement membrane|GBM]] and the [[podocytes]]
**Interference with the negative charge of [[podocytes]]
**[[Interference]] with the negative charge of [[podocytes]]
*Circulating factors implicated in the [[pathogenesis]] of Primary FSGS include:  
*Circulating factors implicated in the [[pathogenesis]] of Primary FSGS include:  
**Soluble urokinase Plasminogen Activating Receptor (suPAR) and [[MicroRNAs]].<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  
**Soluble urokinase Plasminogen Activating Receptor (suPAR) and [[MicroRNAs]].<ref name="pmidPMID 25168830">{{cite journal| author=Reiser J, Nast CC, Alachkar N| title=Permeability factors in focal and segmental glomerulosclerosis. | journal=Adv Chronic Kidney Dis | year= 2014 | volume= 21 | issue= 5 | pages= 417-21 | pmid=PMID 25168830 | doi=10.1053/j.ackd.2014.05.010 | pmc=4149759 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168830  }} </ref>  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Ali Poyan Mehr, M.D. [2]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [3], Manpreet Kaur, MD [4], Cafer Zorkun, M.D., Ph.D. [5], Olufunmilola Olubukola M.D.[6]

Overview

Pathophysiology

There are two types of FSGS, primary FSGS and secondary FSGS, pathophysiology is discussed below:

Pathogenesis of primary FSGS

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

Conditions associated with focal segmental glomerulosclerosis (FSGS):[19][20][21][22][23][24][25]

  • Diabetes
  • Human immunodeficiency virus (HIV)
  • Sickle cell disease
  • Systemic lupus erythematosus (SLE)
  • Nephrotic syndrome
  • End stage renal disease (ESRD)
  • Minimal change disease

Microscopic Pathology

On microscopic histopathological analysis progressive changes seen are:[10][26]

  • Foot process effacement
  • Podocyte apoptosis
  • Exposed glomerular basement membrane
  • Capillary expansion
  • Formation of synechiae
  • Mesangial matrix proliferation

References

  1. ↑ 1.0 1.1 1.2 1.3 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 10.2 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.
  19. ↑ Hogan J, Radhakrishnan J (April 2013). "The treatment of minimal change disease in adults". J. Am. Soc. Nephrol. 24 (5): 702–11. doi:10.1681/ASN.2012070734. PMID 23431071.
  20. ↑ Collins AJ, Foley RN, Herzog C, Chavers B, Gilbertson D, Ishani A, Kasiske B, Liu J, Mau LW, McBean M, Murray A, St Peter W, Guo H, Gustafson S, Li Q, Li S, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Wang C, Weinhandl E, Zaun D, Arko C, Chen SC, Dalleska F, Daniels F, Dunning S, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L (January 2011). "US Renal Data System 2010 Annual Data Report". Am. J. Kidney Dis. 57 (1 Suppl 1): A8, e1–526. doi:10.1053/j.ajkd.2010.10.007. PMID 21184928.
  21. ↑ Cohen AH, Nast CC (March 1988). "HIV-associated nephropathy. A unique combined glomerular, tubular, and interstitial lesion". Mod. Pathol. 1 (2): 87–97. PMID 3070550.
  22. ↑ Ataga KI, Derebail VK, Archer DR (September 2014). "The glomerulopathy of sickle cell disease". Am. J. Hematol. 89 (9): 907–14. doi:10.1002/ajh.23762. PMC 4320776. PMID 24840607.
  23. ↑ Gopalakrishnan I, Iskandar SS, Daeihagh P, Divers J, Langefeld CD, Bowden DW, Hicks PJ, Rocco MV, Freedman BI (February 2011). "Coincident idiopathic focal segmental glomerulosclerosis collapsing variant and diabetic nephropathy in an African American homozygous for MYH9 risk variants". Hum. Pathol. 42 (2): 291–4. doi:10.1016/j.humpath.2010.07.016. PMC 3022108. PMID 21074826.
  24. ↑ Hanaoka H, Hashiguchi A, Konishi K, Kuwana M, Takeuchi T (May 2015). "An unusual association between focal segmental sclerosis and lupus nephritis: a distinct concept from lupus podocytopathy?". CEN Case Rep. 4 (1): 70–75. doi:10.1007/s13730-014-0142-1. PMC 5411626. PMID 28509272.
  25. ↑ Brown EJ, Pollak MR, Barua M (May 2014). "Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing". Kidney Int. 85 (5): 1030–8. doi:10.1038/ki.2014.48. PMC 4118212. PMID 24599252.
  26. ↑ Reidy K, Kaskel FJ (March 2007). "Pathophysiology of focal segmental glomerulosclerosis". Pediatr. Nephrol. 22 (3): 350–4. doi:10.1007/s00467-006-0357-2. PMC 1794138. PMID 17216262.


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