Focal segmental glomerulosclerosis pathophysiology: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
Rim Halaby (talk | contribs) |
||
| Line 6: | Line 6: | ||
==Pathophysiology== | ==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.<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> | |||
According to Asanuma and colleagues<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>, 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<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>: | |||
#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".<ref name="pmid4140273">{{cite journal| author=Shalhoub RJ| title=Pathogenesis of lipoid nephrosis: a disorder of T-cell function. | journal=Lancet | year= 1974 | volume= 2 | issue= 7880 | pages= 556-60 | pmid=4140273 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4140273 }} </ref> In fact, several elements favor the pathological role of "circulating permeability factor" in FSGS: | |||
*Recurrence of proteinuria following renal transplantation<ref name="pmid1994534">{{cite journal| author=Ingulli E, Tejani A| title=Incidence, treatment, and outcome of recurrent focal segmental glomerulosclerosis posttransplantation in 42 allografts in children--a single-center experience. | journal=Transplantation | year= 1991 | volume= 51 | issue= 2 | pages= 401-5 | pmid=1994534 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1994534 }} </ref> | |||
*Absence of proteinuria in patients following transplantation in recipients of kidneys from donors with FSGS<ref name="pmid11158426">{{cite journal| author=Rea R, Smith C, Sandhu K, Kwan J, Tomson C| title=Successful transplant of a kidney with focal segmental glomerulosclerosis. | journal=Nephrol Dial Transplant | year= 2001 | volume= 16 | issue= 2 | pages= 416-7 | pmid=11158426 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11158426 }} </ref> | |||
*Effectiveness of extracorporeal plasmapheresis in decreasing the degree of proteinuria<ref name="pmid11328888">{{cite journal| author=Ghiggeri GM, Artero M, Carraro M, Perfumo F| title=Permeability plasma factors in nephrotic syndrome: more than one factor, more than one inhibitor. | journal=Nephrol Dial Transplant | year= 2001 | volume= 16 | issue= 5 | pages= 882-5 | pmid=11328888 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11328888 }} </ref> | |||
*''In vitro'' studies showing permeability alterations by FSGS serum on isolated glomeruli<ref name="pmid12704575">{{cite journal| author=Savin VJ, McCarthy ET, Sharma M| title=Permeability factors in focal segmental glomerulosclerosis. | journal=Semin Nephrol | year= 2003 | volume= 23 | issue= 2 | pages= 147-60 | pmid=12704575 | doi=10.1053/snep.2003.50024 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12704575 }} </ref> | |||
*Transmissibility of glomerular permeability factor from the mother to her infant during gestation<ref name="pmid11195803">{{cite journal| author=Kemper MJ, Wolf G, Müller-Wiefel DE| title=Transmission of glomerular permeability factor from a mother to her child. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 5 | pages= 386-7 | pmid=11195803 | doi=10.1056/NEJM200102013440517 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11195803 }} </ref> | |||
===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).<ref name="pmid11158854">{{cite journal| author=Walls J| title=Relationship between proteinuria and progressive renal disease. | journal=Am J Kidney Dis | year= 2001 | volume= 37 | issue= 1 Suppl 2 | pages= S13-6 | pmid=11158854 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11158854 }} </ref> | |||
===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.<ref name="pmid11423572">{{cite journal| author=Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL et al.| title=Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. | journal=J Am Soc Nephrol | year= 2001 | volume= 12 | issue= 7 | pages= 1434-47 | pmid=11423572 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11423572 }} </ref><ref name="pmid16409155">{{cite journal| author=Harris RC, Neilson EG| title=Toward a unified theory of renal progression. | journal=Annu Rev Med | year= 2006 | volume= 57 | issue= | pages= 365-80 | pmid=16409155 | doi=10.1146/annurev.med.57.121304.131342 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16409155 }} </ref> Activated cytokines promote cellular infiltration and desposition of collagen along the mesangial matrix.<ref name="pmid16409155">{{cite journal| author=Harris RC, Neilson EG| title=Toward a unified theory of renal progression. | journal=Annu Rev Med | year= 2006 | volume= 57 | issue= | pages= 365-80 | pmid=16409155 | doi=10.1146/annurev.med.57.121304.131342 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16409155 }} </ref> | |||
===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.<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> 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).<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> | |||
===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.<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> | |||
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. | ||
Revision as of 20:29, 3 December 2013
|
Focal segmental glomerulosclerosis Microchapters |
|
Differentiating Focal segmental glomerulosclerosis from other Diseases |
|---|
|
Diagnosis |
|
Treatment |
|
Case Studies |
|
Focal segmental glomerulosclerosis pathophysiology On the Web |
|
American Roentgen Ray Society Images of Focal segmental glomerulosclerosis pathophysiology |
|
Focal segmental glomerulosclerosis pathophysiology in the news |
|
Directions to Hospitals Treating Focal segmental glomerulosclerosis |
|
Risk calculators and risk factors for Focal segmental glomerulosclerosis pathophysiology |
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.
Genetics
There are currently three known genetic causes of the hereditary forms of FSGS.
- The first gene involved with this disorder is ACTN4, which encodes alpha-actinin 4. This protein crosslinks bundles of actin filaments and is present in the podocyte. Mutations in this protein associated with FSGS result in increased affinity for actin binding, formation of intracellular aggregates, and decreased protein half-life. While it is unclear how these effects might lead to FSGS there are a number of theories. Firstly, protein aggregation may have a toxic affect on the podocyte. Secondly, decreased protein half-life or increased affinity for actin binding may alter actin polymerization and thereby affect the podocytes cytoskeletal architecture.[14]
- A second gene associated with FSGS is TRPC6, which encodes a member of the canonical family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocytes. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium influx. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia.[14]
- The final gene known to be involved in hereditary forms of FSGS is the p130(Cas) ligand. The mouse homologue of this protein, CD2, is located in podocytes where it interacts with fyn and synaptopodin. Mutations in this gene associated with FSGS occur at splice sites and lead to altered protein translation. This has been theorized to result in altered actin binding and, thus, alteration of the cytoskeletal podocyte architecture.[14]
References
- ↑ 1.0 1.1 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.
- ↑ 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.
- ↑ 14.0 14.1 14.2 Mukerji N, Damodaran TV, Winn MP (2007). "TRPC6 and FSGS: The latest TRP channelopathy". PMID 17459670.