Focal segmental glomerulosclerosis pathophysiology: Difference between revisions
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Recognition of these variants may have prognostic value in individuals with primary focal segmental glomerulosclerosis (i.e. where no underlying cause is identified). The collapsing variant is associated with higher rate of progression to end-stage renal disease, whereas glomerular tip lesion variant has low rate of progression to end-stage renal disease in most patients. Cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between these two variants. However, because collapsing and glomerular tip variant show overlapping pathologic features with cellular variant, this intermediate difference in clinical outcomes may reflect sampling bias in cases of cellular focal segmental glomerulosclerosis (i.e. unsampled collapsing variant or glomerular tip variant). The prognostic significance of perihilar and NOS variants has not yet been determined. The NOS variant is the most common subtype. | Recognition of these variants may have prognostic value in individuals with primary focal segmental glomerulosclerosis (i.e. where no underlying cause is identified). The collapsing variant is associated with higher rate of progression to end-stage renal disease, whereas glomerular tip lesion variant has low rate of progression to end-stage renal disease in most patients. Cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between these two variants. However, because collapsing and glomerular tip variant show overlapping pathologic features with cellular variant, this intermediate difference in clinical outcomes may reflect sampling bias in cases of cellular focal segmental glomerulosclerosis (i.e. unsampled collapsing variant or glomerular tip variant). The prognostic significance of perihilar and NOS variants has not yet been determined. The NOS variant is the most common subtype. | ||
===Genetics=== | ===Role of Genetics=== | ||
There are currently | There are currently several mutations in cytoskeletal and membrane proteins that lead to familial FSGS: | ||
*Nephrin gene in congenital Finnish-type nephrotic syndrome.<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">{{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> | |||
*Nephrin-like transmembrane gene (NEPH-1)<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> | |||
*Podocin gene<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> | |||
*CD2-associated protein (CD2AP)<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="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> | |||
*Alpha-actinin-4<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> | |||
* | *Transient receptor potential cation channel - TRPC6<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> | ||
==References== | ==References== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief:’’’ Cafer Zorkun, M.D., Ph.D. [2]
Overview
Pathophysiology
The clinical hallmark of focal segmental glomerulosclerosis (FSGS) is proteinuria and nephrotic syndrome. As such, the involvement of the permselective filtration barrier and effacement of podocyte foot processes are inevitable.[1] According to Asanuma and colleagues[1], 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[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
Role of "Circulating Permeability Factor"
The initial insult that causes effacement of foot processes is yet to be discovered. Nonetheless, Shalhoub and colleagues hypothesized in 1974 the involvement of "circulating permeability factor".[3] In fact, several elements favor the pathological role of "circulating permeability factor" in FSGS:
- Recurrence of proteinuria following renal transplantation[4]
- Absence of proteinuria in patients following transplantation in recipients of kidneys from donors with FSGS[5]
- Effectiveness of extracorporeal plasmapheresis in decreasing the degree of proteinuria[6]
- In vitro studies showing permeability alterations by FSGS serum on isolated glomeruli[7]
- Transmissibility of glomerular permeability factor from the mother to her infant during gestation[8]
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).[9]
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.[10][11] Activated cytokines promote cellular infiltration and desposition of collagen along the mesangial matrix.[11]
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.[12][13] Recognition of these variants may have prognostic value in individuals with primary focal segmental glomerulosclerosis (i.e. where no underlying cause is identified). The collapsing variant is associated with higher rate of progression to end-stage renal disease, whereas glomerular tip lesion variant has low rate of progression to end-stage renal disease in most patients. Cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between these two variants. However, because collapsing and glomerular tip variant show overlapping pathologic features with cellular variant, this intermediate difference in clinical outcomes may reflect sampling bias in cases of cellular focal segmental glomerulosclerosis (i.e. unsampled collapsing variant or glomerular tip variant). The prognostic significance of perihilar and NOS variants has not yet been determined. The NOS variant is the most common subtype.
Role of Genetics
There are currently several mutations in cytoskeletal and membrane proteins that lead to familial FSGS:
- Nephrin gene in congenital Finnish-type nephrotic syndrome.[14][12]
- Nephrin-like transmembrane gene (NEPH-1)[1]
- Podocin gene[15]
- CD2-associated protein (CD2AP)[16][17]
- Alpha-actinin-4[18]
- Transient receptor potential cation channel - TRPC6[19]
References
- ↑ 1.0 1.1 1.2 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.
- ↑ 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.
- ↑ 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.
- ↑ 11.0 11.1 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.
- ↑ 12.0 12.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.