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Focal segmental glomerulosclerosis: molecular genetics and targeted therapies.

Chen YM, Liapis H - BMC Nephrol (2015)

Bottom Line: Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2.This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme.A stratified and targeted approach based on the underlying molecular defects is evolving.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA. ychen@dom.wustl.edu.

ABSTRACT
Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2. This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme. It also recounts recent recommendations for clinical management of FSGS based on translational studies and clinical trials. The advent of next-generation sequencing promises to provide nephrologists with rapid and novel approaches for the diagnosis and treatment of FSGS. A stratified and targeted approach based on the underlying molecular defects is evolving.

No MeSH data available.


Related in: MedlinePlus

Histopathological FSGS variants. a Adhesion of the capillary loops to Bowman’s capsule is thought of as a nidus for segmental sclerosis and an early stage of FSGS (Trichrome). b FSGS with amorphous (hyaline) deposits (Periodic acid–Schiff). c Segmental consolidation (<50 %) of the glomerulus is typical of FSGS NOS (Periodic acid–Schiff). d Collapsing FSGS is characterized by segmental (or global) proliferation of podocytes and segmental (or global) implosion of the capillary loops (Jones Methenamine Silver)
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Fig1: Histopathological FSGS variants. a Adhesion of the capillary loops to Bowman’s capsule is thought of as a nidus for segmental sclerosis and an early stage of FSGS (Trichrome). b FSGS with amorphous (hyaline) deposits (Periodic acid–Schiff). c Segmental consolidation (<50 %) of the glomerulus is typical of FSGS NOS (Periodic acid–Schiff). d Collapsing FSGS is characterized by segmental (or global) proliferation of podocytes and segmental (or global) implosion of the capillary loops (Jones Methenamine Silver)

Mentions: FSGS is defined as segmental solidification of the glomerular capillary tuft with accumulation of extracellular matrix initiated by an adhesion between the capillary tuft and the Bowman’s capsule (synechia) (Fig. 1a). Hyalinosis (Fig. 1b) and foam cells can also be present. The scarred segment can be perihilar or at the tip of the glomerulus (tip lesion). Segmental sclerosis or hyalinosis in any part of the glomerulus is classified as FSGS, NOS (Fig. 1c). A unique presentation of FSGS is collapsing FSGS characterized by proliferation of podocytes and implosion of the capillary tuft (Fig. 1d). While many studies have shown better prognosis for the tip lesion and worse for collapsing FSGS, the true value of classifying FSGS based on morphology has been debated, particularly when it comes to collapsing FSGS which shows no segmental solidification but implosion of the capillary loops and podocyte proliferation instead. In addition, the morphologic variants of FSGS fall short in distinguishing primary from secondary forms of FSGS. A recent study has proposed that adult FSGS patients presenting with NS, extensive FP effacement (≥80 %) on electron microscopy (EM) examination, and no risk factors associated with secondary FSGS are likely to have primary FSGS. Conversely, the absence of NS in a patient with segmental FP effacement on EM strongly suggests a secondary FSGS [60]. However, distinction between primary and secondary FSGS may not be clear-cut sometimes. For example, patients with two APOL1 renal risk alleles are prone to develop hypertension and chronic kidney disease complicated by FSGS [61]. In such patients, is FSGS primarily due to a specific genetic predisposition or secondary to hypertension-induced hyperfiltration?Fig. 1


Focal segmental glomerulosclerosis: molecular genetics and targeted therapies.

Chen YM, Liapis H - BMC Nephrol (2015)

Histopathological FSGS variants. a Adhesion of the capillary loops to Bowman’s capsule is thought of as a nidus for segmental sclerosis and an early stage of FSGS (Trichrome). b FSGS with amorphous (hyaline) deposits (Periodic acid–Schiff). c Segmental consolidation (<50 %) of the glomerulus is typical of FSGS NOS (Periodic acid–Schiff). d Collapsing FSGS is characterized by segmental (or global) proliferation of podocytes and segmental (or global) implosion of the capillary loops (Jones Methenamine Silver)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4496884&req=5

Fig1: Histopathological FSGS variants. a Adhesion of the capillary loops to Bowman’s capsule is thought of as a nidus for segmental sclerosis and an early stage of FSGS (Trichrome). b FSGS with amorphous (hyaline) deposits (Periodic acid–Schiff). c Segmental consolidation (<50 %) of the glomerulus is typical of FSGS NOS (Periodic acid–Schiff). d Collapsing FSGS is characterized by segmental (or global) proliferation of podocytes and segmental (or global) implosion of the capillary loops (Jones Methenamine Silver)
Mentions: FSGS is defined as segmental solidification of the glomerular capillary tuft with accumulation of extracellular matrix initiated by an adhesion between the capillary tuft and the Bowman’s capsule (synechia) (Fig. 1a). Hyalinosis (Fig. 1b) and foam cells can also be present. The scarred segment can be perihilar or at the tip of the glomerulus (tip lesion). Segmental sclerosis or hyalinosis in any part of the glomerulus is classified as FSGS, NOS (Fig. 1c). A unique presentation of FSGS is collapsing FSGS characterized by proliferation of podocytes and implosion of the capillary tuft (Fig. 1d). While many studies have shown better prognosis for the tip lesion and worse for collapsing FSGS, the true value of classifying FSGS based on morphology has been debated, particularly when it comes to collapsing FSGS which shows no segmental solidification but implosion of the capillary loops and podocyte proliferation instead. In addition, the morphologic variants of FSGS fall short in distinguishing primary from secondary forms of FSGS. A recent study has proposed that adult FSGS patients presenting with NS, extensive FP effacement (≥80 %) on electron microscopy (EM) examination, and no risk factors associated with secondary FSGS are likely to have primary FSGS. Conversely, the absence of NS in a patient with segmental FP effacement on EM strongly suggests a secondary FSGS [60]. However, distinction between primary and secondary FSGS may not be clear-cut sometimes. For example, patients with two APOL1 renal risk alleles are prone to develop hypertension and chronic kidney disease complicated by FSGS [61]. In such patients, is FSGS primarily due to a specific genetic predisposition or secondary to hypertension-induced hyperfiltration?Fig. 1

Bottom Line: Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2.This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme.A stratified and targeted approach based on the underlying molecular defects is evolving.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA. ychen@dom.wustl.edu.

ABSTRACT
Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2. This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme. It also recounts recent recommendations for clinical management of FSGS based on translational studies and clinical trials. The advent of next-generation sequencing promises to provide nephrologists with rapid and novel approaches for the diagnosis and treatment of FSGS. A stratified and targeted approach based on the underlying molecular defects is evolving.

No MeSH data available.


Related in: MedlinePlus