Focal segmental glomerulosclerosis pathophysiology: Difference between revisions
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===Genetics=== | ===Genetics=== | ||
The development of focal segmental glomerulosclerosis is the result of multiple genetic mutations such as: | 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-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 ''SCARB2 (LIMP2)'' gene | ||
*Mutation in ''formin'' gene - ''INF2'' | *Mutation in ''formin'' gene - ''INF2'' | ||
*Mitochondrial cytopathies | *Mitochondrial cytopathies | ||
==References== | ==References== | ||
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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
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. According to Asanuma and colleagues, 4 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]
- 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
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. However, there are not enough clinical data to support this pathogenic theory probably because of the several other physiologic forms of suPAR that can be identified by ELISA.[3][4]
Role of circulating permeability Factor
The initial insult that causes effacement of foot processes is yet to be discovered. Circulating factors implicated in the pathogenesis of Primary FSGS include the Soluble Urokinase Plasminogen Activating Receptor (suPAR) and MicroRNAs. MicroRNAs are small endogenous (18 to 24 nucleotides long) noncoding single-stranded RNAs that regulate gene expression at the post-transcriptional level. Specifically, microRNAs bind to the messenger RNAs of various genes and lead to their breakdown. [3]Expression of a specific microRNA called miR-193a produced FSGS in mice but its implication in human podocytopathy has not been clearly defined.
suPAR is a heavily glycosylated protein that can be found in several places. It can be present as different fragments and also with various degrees of glycosylation. Both fragmentation and glycosylation of suPAR determine its function and the way it is measured (mainly by ELISA). The most pathogenic form of suPAR for podocytes is still not well defined but there are laboratory evidences of suPAR causing FSGS in lab mice[4] and several cohort studies linking high level of suPAR to FSGS.[5]
Nonetheless, Shalhoub and colleagues hypothesized in 1974 the involvement of "circulating permeability factor."[6] In fact, several elements favor the pathological role of "circulating permeability factor" in FSGS:
- Recurrence of proteinuria following renal transplantation[7]
- Absence of proteinuria in patients following transplantation in recipients of kidneys from donors with FSGS[8]
- Effectiveness of extracorporeal plasmapheresis in decreasing the degree of proteinuria[9]
- Transmissibility of glomerular permeability factor from the mother to her infant during gestation[11]
Role of Proteinuria
Proteinuria, an important predictor of prognosis, further exacerbates renal disease by inducing tubulointerstitial injury. Proteinuria induces the activation of immune cells, such as macrophages and T-cells, and cytokines, such as tumor growth factor-beta (TGF-beta), interleukin (IL) 1, and tumor necrosis factor-alpha (TNF-alpha).[12]
Role of Inflammatory Mediators
The progression of FSGS is highly dependent on the presence of pro-inflammatory cytokines and vasoactive factors that also play a major role in renal fibrosis. 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.[13][14] Activated cytokines promote cellular infiltration and desposition of collagen along the mesangial matrix.[14]
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.[2] 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).[2]
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.[15][16]
Genetics
The development of focal segmental glomerulosclerosis is the result of multiple genetic mutations such as:[17][15][18][19][20][21][22][23]
- 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
References
- ↑ 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.
- ↑ 2.0 2.1 2.2 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.
- ↑ 3.0 3.1 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). - ↑ 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.
- ↑ Huang J, Liu G, Zhang YM, Cui Z, Wang F, Liu XJ; et al. (2013). "Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis". Kidney Int. 84 (2): 366–72. doi:10.1038/ki.2013.55. PMID 23447064.
- ↑ Shalhoub RJ (1974). "Pathogenesis of lipoid nephrosis: a disorder of T-cell function". Lancet. 2 (7880): 556–60. PMID 4140273.
- ↑ Ingulli E, Tejani A (1991). "Incidence, treatment, and outcome of recurrent focal segmental glomerulosclerosis posttransplantation in 42 allografts in children--a single-center experience". Transplantation. 51 (2): 401–5. PMID 1994534.
- ↑ 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.
- ↑ Savin VJ, McCarthy ET, Sharma M (2003). "Permeability factors in focal segmental glomerulosclerosis". Semin Nephrol. 23 (2): 147–60. doi:10.1053/snep.2003.50024. PMID 12704575.
- ↑ 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.
- ↑ Walls J (2001). "Relationship between proteinuria and progressive renal disease". Am J Kidney Dis. 37 (1 Suppl 2): S13–6. PMID 11158854.
- ↑ 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.
- ↑ 14.0 14.1 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.
- ↑ 15.0 15.1 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.