Focal Segmental Glomerulosclerosis

Complex MONDO:0100313 Pathograph 33 Show in embeddings browser Glomerular Diseases Nephrotic Syndrome

Focal segmental glomerulosclerosis (FSGS) is a histopathologic pattern of podocyte-driven glomerular injury rather than a single molecularly uniform disease. The broad MONDO root term encompasses primary, monogenic, maladaptive/secondary, viral, drug-associated, and collapsing forms that converge on proteinuria, segmental glomerular scarring, and progressive kidney dysfunction. The gene section below therefore highlights representative monogenic FSGS subsets rather than implying that the entire heterogeneous root is explained by a single-gene mechanism. The gene-defined subtypes fall into four mechanistic groups rather than one. ACTN4, INF2 and ANLN act on the podocyte actin cytoskeleton and MYO1E is a podocyte class I myosin; NPHS2, CRB2 and CD2AP act at the slit diaphragm and podocyte apico-basal polarity; TRPC6 is a podocyte cation channel; and PAX2 is a developmental transcription factor, the only gene here whose lesion is transcriptional. APOL1 is a common recessive risk genotype rather than a Mendelian cause and reaches the podocyte through monovalent cation flux.

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2
Mappings
8
Pathophys.
3
Histopath.
8
Phenotypes
33
Pathograph
13
Genes
6
Medical Actions
12
Subtypes
3
Datasets
18
References
1
Deep Research
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Mappings

MONDO
MONDO:0011917 focal segmental glomerulosclerosis 3, susceptibility to Not Yet Curated
skos:relatedMatch MONDO
A member of MONDO's numbered focal segmental glomerulosclerosis series by label, but not a subclass of focal segmental glomerulosclerosis in MONDO: it is a child of inherited disease susceptibility (MONDO:0020573) with a `predisposes towards` relation to inherited focal segmental glomerulosclerosis. Recorded as a related match, not a narrow one, because it denotes a susceptibility rather than a narrower disease; the CD2AP relationship itself is curated in the `genetic` section as SUSCEPTIBILITY.
MONDO:0012931 focal segmental glomerulosclerosis 4, susceptibility to Not Yet Curated
skos:relatedMatch MONDO
As for focal segmental glomerulosclerosis 3, this is a susceptibility concept that `predisposes towards` inherited focal segmental glomerulosclerosis rather than a subclass of it. The APOL1 relationship is curated in the `genetic` section as RISK_FACTOR.
◆

Subtypes

12
Primary FSGS MONDO:0100324
Idiopathic or presumed immune-mediated FSGS with no clear adaptive, infectious, drug-related, or inherited driver. Circulating permeability factors and podocyte-directed autoantibodies are implicated, and post-transplant recurrence risk is highest in this subtype.
Secondary FSGS
FSGS arising as an acquired or maladaptive response to another stressor, such as obesity, reduced nephron mass, reflux nephropathy, drugs, or viral infection.
Genetic FSGS MONDO:0005363
Monogenic or syndromic FSGS caused by variants affecting podocyte structure, slit diaphragm integrity, or glomerular development. Recurrence after kidney transplantation is usually lower than in primary FSGS, but is not uniformly zero across all genetic etiologies. MONDO:0005363 is the term that actually parents the numbered "focal segmental glomerulosclerosis N" series, which is listed below as children of this row.
  • FSGS1
  • FSGS2
  • FSGS5
  • FSGS6
  • FSGS7
  • FSGS8
  • FSGS9
Collapsing FSGS
Severe morphologic variant with segmental or global collapse of the glomerular tuft and marked podocyte hypertrophy/hyperplasia. Often occurs in the setting of viral infection, interferon exposure, or other intense podocyte stressors.
Tip Lesion Variant FSGS
Morphologic variant characterized by adhesion of the tuft to Bowman's capsule at the tip of a glomerular lobe. Can occur in both primary and secondary FSGS, including in association with autoimmune systemic diseases such as relapsing polychondritis. May respond well to corticosteroid therapy.
Focal segmental glomerulosclerosis 1 (ACTN4) MONDO:0011303
ACTN4 hgnc:166 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ACTN4 (hgnc:166). hgnc:166 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant FSGS caused by missense variants in ACTN4, encoding the actin-filament crosslinking protein alpha-actinin-4. The mutant protein binds F-actin more tightly than wild type, so the lesion is at the podocyte actin cytoskeleton. MONDO also files this concept under familial idiopathic steroid-resistant nephrotic syndrome.
Show evidence (1 reference)
PMID:10700177 SUPPORT Human Clinical
"Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS."
Establishes ACTN4 as the cause of dominant familial FSGS, the concept MONDO curates as FSGS1.
Focal segmental glomerulosclerosis 2 (TRPC6) MONDO:0011390
TRPC6 hgnc:12338 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TRPC6 (hgnc:12338). hgnc:12338 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant FSGS caused by gain-of-function missense variants in TRPC6, a cation channel highly expressed in podocytes, which increase podocyte calcium influx.
Show evidence (1 reference)
PMID:15879175 SUPPORT Human Clinical
"Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6)."
Establishes TRPC6 as the cause of hereditary FSGS, the concept MONDO curates as FSGS2.
Focal segmental glomerulosclerosis 5 (INF2) MONDO:0013191
INF2 hgnc:23791 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in INF2 (hgnc:23791). hgnc:23791 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant FSGS caused by missense variants clustered in the diaphanous inhibitory domain of INF2, a formin-family actin regulator. The separate INF2 phenotype combining FSGS with Charcot-Marie-Tooth neuropathy is curated by MONDO as Charcot-Marie-Tooth disease dominant intermediate E (MONDO:0013758), which is the concept ClinGen's Charcot-Marie-Tooth panel classifies as Definitive for INF2; no claim about that phenotype is made on this row.
Show evidence (1 reference)
PMID:20023659 SUPPORT Human Clinical
"we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino..."
Establishes INF2 as the cause of dominant FSGS across 11 families, the concept MONDO curates as FSGS5.
Focal segmental glomerulosclerosis 6 (MYO1E) MONDO:0013589
MYO1E hgnc:7599 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYO1E (hgnc:7599). hgnc:7599 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Autosomal recessive, childhood-onset, glucocorticoid-resistant FSGS caused by biallelic variants in MYO1E, a non-muscle class I myosin of the podocyte. Unlike the dominant actin-regulator subtypes, affected individuals are homozygous, and electron microscopy showed thickening and disorganisation of the glomerular basement membrane.
Show evidence (2 references)
PMID:21756023 SUPPORT Human Clinical
"We identified two mutations (A159P and Y695X) in MYO1E, which encodes a nonmuscle class I myosin, myosin 1E (Myo1E)."
Identifies the two MYO1E alleles behind this subtype.
PMID:21756023 SUPPORT Human Clinical
"MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis."
States the childhood-onset, steroid-resistant phenotype of this subtype.
Focal segmental glomerulosclerosis 7 (PAX2) MONDO:0014451
PAX2 hgnc:8616 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PAX2 (hgnc:8616). hgnc:8616 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant, adult-onset FSGS caused by heterozygous variants in the PAX2 transcription factor, arising without the overt extrarenal features of papillorenal syndrome. This is the only subtype on this entry whose gene acts as a developmental transcription factor rather than on podocyte structure. The papillorenal (renal-coloboma) phenotype of PAX2 is curated in Renal_Coloboma_Syndrome; only the isolated adult-onset FSGS claim is made here.
Show evidence (2 references)
PMID:24676634 SUPPORT Human Clinical
"Here, exome sequencing in members of an index family with dominant FSGS revealed a nonconservative, disease-segregating variant in the PAX2 transcription factor gene."
Identifies the segregating PAX2 variant in the index dominant-FSGS family.
PMID:24676634 SUPPORT Human Clinical
"Thus, mutations in PAX2 may contribute to adult-onset FSGS in the absence of overt extrarenal manifestations."
States the isolated adult-onset renal presentation that distinguishes this subtype from papillorenal syndrome.
Focal segmental glomerulosclerosis 8 (ANLN) MONDO:0014462
ANLN hgnc:14082 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ANLN (hgnc:14082). hgnc:14082 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Autosomal dominant FSGS caused by missense variants in ANLN, which encodes the F-actin binding protein anillin, identified by linkage plus exome sequencing in one kindred with a second variant segregating in a second family.
Show evidence (2 references)
PMID:24676636 SUPPORT Human Clinical
"Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS."
Establishes ANLN as a cause of familial FSGS, the concept MONDO curates as FSGS8.
PMID:24676636 SUPPORT Human Clinical
"We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS."
Records the second segregating family, which is the replication behind this subtype.
Focal segmental glomerulosclerosis 9 (CRB2) MONDO:0014539
CRB2 hgnc:18688 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CRB2 (hgnc:18688). hgnc:18688 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Autosomal recessive podocytopathy caused by biallelic CRB2 variants. The defining report describes it as steroid-resistant nephrotic syndrome rather than as FSGS specifically, and the mechanism is loss of podocyte apico-basal polarity, which distinguishes it from the actin-cytoskeleton subtypes. ClinGen's Glomerulopathy Gene Curation Expert Panel classifies CRB2-FSGS9 as Definitive with autosomal recessive inheritance.
Show evidence (2 references)
PMID:25557779 SUPPORT Human Clinical
"By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS."
Establishes biallelic CRB2 variants in four families, the concept MONDO curates as FSGS9.
PMID:25557779 SUPPORT Human Clinical
"These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS."
States the apico-basal polarity mechanism that distinguishes this subtype.
⚙

Pathophysiology

8
Podocyte Injury and Loss
Podocyte injury and depletion are the central convergent event in FSGS. Immune-mediated, genetic, maladaptive, and toxic insults all destabilize the actin cytoskeleton, promote foot process effacement and detachment, and reduce the number of podocytes covering the glomerular basement membrane. Because podocytes regenerate poorly, cumulative loss beyond a threshold drives permanent scar formation.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
ACTN4 hgnc:166 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ACTN4 (hgnc:166). hgnc:166 is a gene from the HUGO Gene Nomenclature Committee. TRPC6 hgnc:12338 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRPC6 (hgnc:12338). hgnc:12338 is a gene from the HUGO Gene Nomenclature Committee. INF2 hgnc:23791 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves INF2 (hgnc:23791). hgnc:23791 is a gene from the HUGO Gene Nomenclature Committee. ANLN hgnc:14082 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANLN (hgnc:14082). hgnc:14082 is a gene from the HUGO Gene Nomenclature Committee. MYO1E hgnc:7599 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYO1E (hgnc:7599). hgnc:7599 is a gene from the HUGO Gene Nomenclature Committee.
podocyte apoptosis GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased podocyte apoptosis, annotated with apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. actin cytoskeleton reorganization GO:0030036 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal actin cytoskeleton reorganization, annotated with actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology.
Downstream
Glomerular Filtration Barrier Dysfunction Podocyte depletion and foot process effacement disrupt slit diaphragm integrity and increase glomerular albumin permeability.
Mesangial Expansion and Glomerulosclerosis Areas of denuded glomerular basement membrane adhere to Bowman's capsule and recruit segmental matrix deposition, producing focal scars.
Show evidence (3 references)
PMID:41009330 SUPPORT Other
"The pathophysiology is multifactorial and includes direct podocyte injury (e.g., genetic defects, mechanical or toxic injury), immune-mediated processes (e.g., circulating permeability factors, inflammatory mediators), and metabolic disturbances."
This comprehensive review establishes that podocyte injury arises from multiple converging mechanisms, including genetic, immune, and metabolic factors.
PMID:24676636 SUPPORT Human Clinical
"We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1-associated nephropathy."
Places the ANLN product in the podocyte in human FSGS biopsies, supporting the ANLN binding on this node.
PMID:21756023 SUPPORT Human Clinical
"Normal expression of Myo1E was documented in control human kidney-biopsy specimens in vivo and in glomerular podocytes in vitro."
Places the MYO1E product in the glomerular podocyte, supporting the MYO1E binding on this node.
Circulating Permeability Factor-Mediated Podocyte Injury
Primary FSGS is associated with circulating permeability factors and, in some patients, podocyte-directed autoantibodies. Candidate drivers include suPAR, cardiotrophin-like cytokine 1, angiopoietin-like 4, and anti-nephrin antibodies, but none explains every case. This mechanism is therefore best treated as an upstream hypothesis for primary disease rather than a universal explanation for all FSGS.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology. T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
immune response GO:0006955 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal immune response (GO:0006955). GO:0006955 is a biological process from the Gene Ontology. cytokine-mediated signaling pathway GO:0019221 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cytokine-mediated signaling pathway (GO:0019221). GO:0019221 is a biological process from the Gene Ontology.
Downstream
Podocyte Injury and Loss Circulating permeability factors and autoantibodies directly amplify podocyte stress, detachment, and depletion in primary FSGS.
Show evidence (2 references)
PMID:41133676 SUPPORT Other
"Primary podocytopathies, including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), are caused by a circulating factor or factors injurious to the podocyte."
Establishes circulating factors as the primary pathogenic mechanism in primary FSGS, with immune-mediated mechanisms supported by treatment responsiveness to immunosuppressants.
PMID:41133676 SUPPORT Other
"Potential non-antibody-mediated circulating factors have been identified, including cardiotrophin-like cytokine 1, soluble urokinase plasminogen activator receptor, and angiopoietin-like 4, among others."
Identifies specific candidate circulating permeability factors implicated in primary FSGS pathogenesis beyond classical autoantibodies.
Glomerular Filtration Barrier Dysfunction
Loss of podocyte structural integrity, especially foot process effacement and slit diaphragm disruption, increases glomerular permeability to albumin and other plasma proteins. Slit diaphragm proteins such as nephrin and podocin are essential structural and signaling components of the filtration barrier, so disruption of this compartment is a common final pathway in proteinuric FSGS. CRB2 and CD2AP act in this compartment rather than on the podocyte actin cytoskeleton: CRB2 is required for slit diaphragm formation and nephrin trafficking, and CD2AP links nephrin and podocin at the slit diaphragm.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
NPHS2 hgnc:13394 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NPHS2 (hgnc:13394). hgnc:13394 is a gene from the HUGO Gene Nomenclature Committee. CRB2 hgnc:18688 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CRB2 (hgnc:18688). hgnc:18688 is a gene from the HUGO Gene Nomenclature Committee. CD2AP hgnc:14258 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CD2AP (hgnc:14258). hgnc:14258 is a gene from the HUGO Gene Nomenclature Committee.
cell-cell junction assembly GO:0007043 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell-cell junction assembly (GO:0007043). GO:0007043 is a biological process from the Gene Ontology.
Downstream
Proteinuria Increased albumin leak across the filtration barrier produces the dominant clinical manifestation of FSGS.
Hematuria Barrier disruption can also permit erythrocytes to enter the urine, usually as microscopic hematuria.
Tubular Protein Overload and Interstitial Inflammation Filtered proteins injure tubular epithelial cells and trigger downstream interstitial inflammation.
Show evidence (3 references)
PMID:41009330 SUPPORT Other
"This pattern of injury can lead to progressive renal dysfunction and, in some cases, end-stage kidney disease."
Documents the clinical consequence of glomerular filtration barrier disruption: progressive loss of kidney function leading to end-stage kidney disease.
PMID:25557779 SUPPORT Model Organism
"By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking."
Places the CRB2 lesion at foot process and slit diaphragm formation, which is this node's compartment.
PMID:14643126 SUPPORT REVIEW SYNTHESIS Other
"CD2AP localises to the slit diaphragm and links nephrin and podocin to phosphoinositide 3-OH kinase; this complex has cell-signalling properties."
Places the CD2AP product at the slit diaphragm alongside nephrin and podocin, supporting the CD2AP binding on this node.
Mesangial Expansion and Glomerulosclerosis
Persistent podocyte depletion promotes tuft adhesion, mesangial matrix accumulation, and segmental obliteration of glomerular capillary loops, producing the defining histologic lesion of FSGS. Once established, glomerulosclerosis is largely irreversible and contributes to progressive nephron loss.
glomerular mesangial cell CL:0000650 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glomerular mesangial cell, annotated with mesangial cell (CL:0000650). CL:0000650 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. mesangial cell proliferation GO:0072126 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mesangial cell proliferation, annotated with positive regulation of glomerular mesangial cell proliferation (GO:0072126). GO:0072126 is a biological process from the Gene Ontology.
Downstream
Tubular Protein Overload and Interstitial Inflammation Progressive segmental scarring reduces nephron reserve and increases downstream tubular stress, amplifying tubulointerstitial injury.
Tubular Protein Overload and Interstitial Inflammation
Sustained heavy proteinuria and nephron loss trigger proximal tubular epithelial stress, complement activation, and macrophage recruitment in the interstitium. This inflammatory phase links glomerular injury to the later fibrotic remodeling that drives chronic kidney function loss.
proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. leukocyte migration GO:0050900 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased leukocyte migration (GO:0050900). GO:0050900 is a biological process from the Gene Ontology.
Downstream
Tubulointerstitial Fibrosis Persistent tubular injury and interstitial inflammation activate myofibroblasts and drive progressive matrix deposition.
Tubulointerstitial Fibrosis
Activated myofibroblasts deposit extracellular matrix throughout the cortical interstitium, producing tubular atrophy and irreversible loss of renal parenchyma. The burden of tubulointerstitial fibrosis tracks long-term kidney function decline more closely than glomerular scarring alone.
myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology.
TGF-beta receptor signaling GO:0007179 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased TGF-beta receptor signaling, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. extracellular matrix organization GO:0030198 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
Downstream
Progressive Renal Insufficiency Interstitial fibrosis and tubular atrophy are major determinants of ongoing GFR decline and eventual kidney failure.
Hypertension Nephron loss and chronic kidney injury promote sodium retention and sustained activation of vasoconstrictive pathways.
APOL1 Risk-Variant Cation Flux and Podocyte Cytotoxicity
G1 and G2 are the two APOL1 coding variants that carry the excess risk of kidney disease. For G1, which is the allele the cited work tested, induction of the protein drives monovalent cation flux across the podocyte membrane, with potassium efflux, downstream calcium release, impaired mitochondrial ATP production and inhibited translation. This is the mechanism by which a common risk genotype, rather than a Mendelian lesion, reaches the podocyte-injury node. It is an upstream modifier of susceptibility, not a subtype of FSGS, and the reversal of the phenotype by a small-molecule APOL1 blocker is what identifies the cation flux as proximal rather than incidental.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
APOL1 hgnc:618 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves APOL1 (hgnc:618). hgnc:618 is a gene from the HUGO Gene Nomenclature Committee.
potassium ion export across plasma membrane GO:0097623 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased potassium ion export across plasma membrane (GO:0097623). GO:0097623 is a biological process from the Gene Ontology.
Downstream
Podocyte Injury and Loss Risk-allele-driven cation flux and translational arrest injure the podocyte and produce proteinuria in the transgenic model.
Show evidence (2 references)
PMID:38227370 SUPPORT Model Organism
"Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147."
Establishes potassium efflux and podocyte injury in podocytes carrying the risk allele, and the reversal that makes the cation flux the proximal step.
PMID:38227370 SUPPORT In Vitro
"Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease."
States the authors' conclusion that cation transport is the proximal mechanism this node names.
PAX2 Transcription Factor Dysfunction
FSGS-associated PAX2 variants impair DNA binding and transactivation, or strengthen the interaction of PAX2 with repressor proteins, so the lesion is transcriptional rather than structural. This is the only route into FSGS on this entry that does not begin at a podocyte structural or slit-diaphragm protein. The steps between altered PAX2 transcriptional output and podocyte injury are not established in the source that defines this subtype, and the edge below is recorded at that strength.
PAX2 hgnc:8616 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PAX2 (hgnc:8616). hgnc:8616 is a gene from the HUGO Gene Nomenclature Committee.
DNA-binding transcription factor activity GO:0003700 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology.
Downstream
Podocyte Injury and Loss Altered PAX2 transcriptional output is associated with adult-onset FSGS in the absence of extrarenal features; the intervening steps to podocyte injury are not established in the cited source.
Show evidence (1 reference)
PMID:24676634 SUPPORT In Vitro
"As predicted by in silico structural modeling analyses, in vitro functional studies documented that several of the FSGS-associated PAX2 mutations perturb protein function by affecting proper binding to DNA and transactivation activity or by altering the interaction of PAX2 with repressor..."
Establishes the transcriptional nature of the PAX2 lesion, including the bidirectional effect on transactivation versus repression.
✶

Histopathology

3
Segmental glomerulosclerosis lesion
Kidney biopsy defines FSGS as a pattern lesion characterized by segmental glomerular scarring arising from diverse primary and secondary causes.
Show evidence (1 reference)
PMID:41009330 SUPPORT Other
"Focal segmental glomerulosclerosis (FSGS) is a histopathological pattern of segmental glomerulosclerosis that arises from diverse primary and secondary causes."
Supports the root-level framing of FSGS as a biopsy-defined histopathologic pattern rather than a single uniform molecular disease.
Podocyte foot process effacement
Electron microscopy can show focal podocyte foot process effacement, consistent with structural podocyte injury in some genetic and secondary FSGS forms.
Show evidence (1 reference)
PMID:20023659 SUPPORT Human Clinical
"In these biopsies, electron microscopy showed focal areas of podocyte foot process effacement, typical of secondary and some genetic forms of FSGS, as well as areas where foot processes and slit-diaphragms were well preserved."
Human renal biopsy ultrastructure from monogenic FSGS supports foot process effacement as a disease-relevant microscopic correlate of podocyte injury.
Tip lesion variant
Morphologic variant with adhesion of the glomerular tuft to Bowman's capsule at the tip of a glomerular lobe. This lesion pattern can occur in primary, secondary, and autoimmune-associated FSGS, including cases linked to systemic autoimmune diseases.
Show evidence (1 reference)
PMID:42234924 SUPPORT Human Clinical
"Repeated renal biopsy confirmed tip lesion variant of FSGS, demonstrating excellent response to corticosteroid therapy with prednisolone 1 mg/kg/day; proteinuria declined from 7g/24h to 0.98g/24h and serum albumin increased from 0.9g/dL to 2.2g/dL within three months."
First documented case of tip lesion FSGS variant in relapsing polychondritis, establishing the morphologic variant and demonstrating responsiveness to corticosteroid therapy in this autoimmune-associated presentation.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Focal Segmental Glomerulosclerosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Cardiovascular 1
Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Genitourinary 4
Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hypoalbuminemia Nephrotic Syndrome
Show evidence (1 reference)
PMID:41222995 SUPPORT Human Clinical
"More advanced chronic kidney disease and higher levels of proteinuria were both associated with greater health care resource utilization and costs."
Large US real-world study (9,899 FSGS patients) demonstrating that proteinuria is the central clinical driver of disease burden in FSGS.
Nephrotic Syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41906863 SUPPORT Other
"Focal segmental glomerulosclerosis (FSGS) is one of the major causes of nephrotic syndrome, which can progress to end-stage renal disease, leading to kidney transplantation."
Establishes FSGS as a major cause of nephrotic syndrome and documents the natural history of progression to end-stage renal disease.
Progressive Renal Insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083). HP:0000083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41009330 SUPPORT Other
"This pattern of injury can lead to progressive renal dysfunction and, in some cases, end-stage kidney disease."
Review confirms that glomerular injury in FSGS leads to progressive renal insufficiency, with a subset reaching end-stage kidney disease.
Hematuria HP:0000790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematuria (HP:0000790). HP:0000790 is a phenotype from the Human Phenotype Ontology.
Metabolism 3
Peripheral Edema HP:0012398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral edema (HP:0012398). HP:0012398 is a phenotype from the Human Phenotype Ontology.
Hypoalbuminemia HP:0003073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoalbuminemia (HP:0003073). HP:0003073 is a phenotype from the Human Phenotype Ontology.
Sequelae: Peripheral Edema Hyperlipidemia
Hyperlipidemia HP:0003077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperlipidemia (HP:0003077). HP:0003077 is a phenotype from the Human Phenotype Ontology.
🧬

Genetic Associations

13
NPHS2 (Causative in monogenic FSGS)
Gene: NPHS2 hgnc:13394 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NPHS2 (hgnc:13394). hgnc:13394 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (1 reference)
PMID:10742096 SUPPORT Human Clinical
"We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier."
Original discovery paper identifying NPHS2 mutations as the cause of autosomal recessive steroid-resistant nephrotic syndrome and FSGS, establishing podocin's essential role in glomerular filtration.
ACTN4 (Causative in monogenic FSGS)
Gene: ACTN4 hgnc:166 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACTN4 (hgnc:166). hgnc:166 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:10700177 SUPPORT Human Clinical
"Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS."
Original discovery paper establishing ACTN4 mutations as the cause of autosomal dominant familial FSGS, identifying podocyte cytoskeletal disruption as a pathogenic mechanism.
PMID:10700177 SUPPORT In Vitro
"In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4."
Mechanistic evidence showing that ACTN4 mutations cause aberrant actin binding, explaining how cytoskeletal disruption leads to podocyte dysfunction.
TRPC6 (Causative in monogenic FSGS)
Gene: TRPC6 hgnc:12338 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRPC6 (hgnc:12338). hgnc:12338 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (3 references)
PMID:15879175 SUPPORT Human Clinical
"Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6)."
Original discovery paper identifying TRPC6 missense mutations as the cause of familial FSGS, establishing a calcium channel mechanism distinct from previously known cytoskeletal FSGS genes.
PMID:38814201 SUPPORT Model Organism
"The 24 h uACR at 6 weeks was significantly higher in the pure-zygotes group than in the WT and heterozygotes groups, and this difference was found at 8 and 10 weeks.TRPC6 levels showed no significant difference between homozygote and WT mice. Compared to homozygote group, expression of podocin..."
Knock-in mouse data show proteinuria and slit-diaphragm injury, supporting an in vivo pathogenic effect of TRPC6 gain-of-function.
PMID:38814201 SUPPORT In Vitro
"The results of CCK-8 assay and apoptosis experiments showed that the TRPC6-N110S overexpression group had slower proliferative activity and increased apoptosis than the control group. FluO-3 assay revealed increased calcium influx in the TRPC6-N110S overexpression group."
Podocyte cell assays show enhanced calcium influx and apoptosis, providing in vitro support for the proposed TRPC6 mechanism.
INF2 (Causative in monogenic FSGS)
Gene: INF2 hgnc:23791 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is INF2 (hgnc:23791). hgnc:23791 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (3 references)
PMID:20023659 SUPPORT Human Clinical
"we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino..."
Original discovery paper identifying INF2 mutations as the cause of autosomal dominant FSGS, establishing actin polymerization regulation as critical to podocyte function.
PMID:39536114 SUPPORT Model Organism
"R218Q INF2 mice are susceptible to glomerular disease, in contrast to INF2 knockout mice."
PAN-injury mouse experiments show that the disease-associated INF2 allele confers in vivo glomerular susceptibility, supporting a gain-of-function rather than simple loss-of-function mechanism.
PMID:39536114 SUPPORT In Vitro
"Colocalization, coimmunoprecipitation analyses, and cellular actin measurements showed that INF2 R218Q confers a gain-of-function effect on the actin cytoskeleton."
Cell-based mechanistic assays show that mutant INF2 directly perturbs actin regulation, providing in vitro support for the gain-of-function mechanism in INF2-associated FSGS.
FAT1 (Pathogenic Variants)
Gene: FAT1 hgnc:3595 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FAT1 (hgnc:3595). hgnc:3595 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (1 reference)
CGGV:assertion_6dbbe3f1-4a7a-4c76-b047-1c1d95771b74-2023-11-13T070000.000Z SUPPORT Other
"FAT1 | HGNC:3595 | focal segmental glomerulosclerosis | MONDO:0100313 | AR | Strong"
ClinGen classifies the FAT1-focal segmental glomerulosclerosis gene-disease relationship as strong with autosomal recessive inheritance.
SYNPO (Pathogenic Variants)
Gene: SYNPO hgnc:30672 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SYNPO (hgnc:30672). hgnc:30672 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN
Show evidence (1 reference)
CGGV:assertion_12a82f02-cc6b-41a0-b2b7-7d8c18ff470b-2023-11-13T190000.000Z SUPPORT Other
"SYNPO | HGNC:30672 | focal segmental glomerulosclerosis | MONDO:0100313 | AD | Limited"
ClinGen classifies the SYNPO-focal segmental glomerulosclerosis gene-disease relationship as limited with autosomal dominant inheritance.
MYO1E (Causative in monogenic FSGS)
Gene: MYO1E hgnc:7599 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYO1E (hgnc:7599). hgnc:7599 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:21756023 SUPPORT Human Clinical
"The mutations in MYO1E segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and Family 2). Patients were homozygous for the mutations and did not have a response to glucocorticoid therapy."
Establishes recessive segregation in two independent pedigrees and the steroid-resistant course.
PMID:21756023 SUPPORT In Vitro
"Transfection studies revealed abnormal subcellular localization and function of the A159P-Myo1E mutant."
Functional support that the A159P allele is deleterious.
PAX2 (Causative in adult-onset dominant FSGS without extrarenal features)
Gene: PAX2 hgnc:8616 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PAX2 (hgnc:8616). hgnc:8616 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:24676634 SUPPORT Human Clinical
"Sequencing in probands of a familial FSGS cohort revealed seven rare and private heterozygous single nucleotide substitutions (4% of individuals)."
Quantifies the share of a familial FSGS cohort carrying rare heterozygous PAX2 variants.
ANLN (Causative in monogenic FSGS)
Gene: ANLN hgnc:14082 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANLN (hgnc:14082). hgnc:14082 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:24676636 SUPPORT Human Clinical
"Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS."
Establishes ANLN as a cause of familial FSGS and names the protein's actin-binding role.
CRB2 (Causative in recessive podocytopathy presenting as steroid-resistant nephrotic syndrome with FSGS)
Gene: CRB2 hgnc:18688 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CRB2 (hgnc:18688). hgnc:18688 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:25557779 SUPPORT Human Clinical
"By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS."
Establishes recessive CRB2 variants in four families as the cause of this subtype.
PMID:25557779 SUPPORT Model Organism
"By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking."
Zebrafish loss of function supplies the mechanism by which CRB2 loss damages the podocyte.
APOL1 (Recessive risk genotype, not a Mendelian FSGS subtype)
Gene: APOL1 hgnc:618 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is APOL1 (hgnc:618). hgnc:618 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR
Show evidence (1 reference)
PMID:21997394 SUPPORT Human Clinical
"In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN)."
Quantifies the recessive risk effect that makes this a risk genotype rather than a Mendelian cause.
CD2AP (Causative biallelic loss of CD2AP in childhood-onset FSGS with end-stage renal disease)
Gene: CD2AP hgnc:14258 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CD2AP (hgnc:14258). hgnc:14258 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:30612599 SUPPORT Human Clinical
"By whole-exome sequencing, we identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease."
The human recessive evidence behind this record - a homozygous null allele segregating with childhood-onset FSGS in three affected siblings.
PMID:30612599 SUPPORT Model Organism
"When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure."
The allele-matched mouse model that makes the human association causal rather than correlative.
CD2AP heterozygous variants (Single-allele-ablating CD2AP variants reported in idiopathic FSGS; effect uncertain)
Gene: CD2AP hgnc:14258 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CD2AP (hgnc:14258). hgnc:14258 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Autosomal dominant
Show evidence (3 references)
PMID:14643126 SUPPORT REVIEW SYNTHESIS Human Clinical
"These researchers found that 2 of 30 African-American patients with idiopathic focal segmental glomerulosclerosis had a CD2AP mutation that ablated expression of one allele."
The human genetic evidence for the heterozygous claim; this commentary restates the primary report rather than producing the finding.
PMID:14643126 SUPPORT REVIEW SYNTHESIS Human Clinical
"Further studies should address the normal distribution of the CD2AP heterozygous mutation in different ethnic populations, because the association with human idiopathic focal segmental glomerulosclerosis could be accidental."
The commentary's own caution about the heterozygous association, which is why this record is SUSCEPTIBILITY rather than CAUSATIVE.
PMID:17713465 REFUTE Human Clinical
"Heterozygous expression of the CD2AP mutation in both parents did not lead to any kidney pathology, as both have normal glomerular filtration rates and no proteinuria."
Argues against a dominant effect for at least this truncating allele - two obligate carriers were unaffected, which is the observation that separates this record from the recessive one.
💊

Medical Actions

6
Corticosteroids
Action: corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is corticosteroid therapy, annotated with Systemic Corticosteroid Therapy (NCIT:C122080). NCIT:C122080 is a clinical intervention from the NCI Thesaurus. Ontology label: Systemic Corticosteroid Therapy NCIT:C122080
Agent: prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest.
Prednisone remains standard initial immunosuppressive therapy for primary FSGS with nephrotic syndrome after secondary and monogenic causes have been excluded. Some patients achieve partial or complete remission, but steroid resistance is common.
Mechanism Target:
MODULATES Circulating Permeability Factor-Mediated Podocyte Injury — Dampens immune signaling implicated in primary FSGS and may reduce ongoing podocyte injury.
Show evidence (2 references)
PMID:39663153 SUPPORT Human Clinical
"Steroids remain the recommended initial treatment for pFSGS."
Network meta-analysis of 20 RCTs confirms corticosteroids as the recommended first-line treatment for primary FSGS.
PMID:42234924 SUPPORT Human Clinical
"Repeated renal biopsy confirmed tip lesion variant of FSGS, demonstrating excellent response to corticosteroid therapy with prednisolone 1 mg/kg/day; proteinuria declined from 7g/24h to 0.98g/24h and serum albumin increased from 0.9g/dL to 2.2g/dL within three months."
Case report documents excellent corticosteroid response in tip lesion FSGS variant associated with relapsing polychondritis, with marked proteinuria reduction and albumin recovery within three months of therapy.
Calcineurin Inhibitors
Action: calcineurin inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is calcineurin inhibitor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: cyclosporine CHEBI:4031 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclosporine, annotated with cyclosporin A (CHEBI:4031). CHEBI:4031 is a therapeutic agent from Chemical Entities of Biological Interest. tacrolimus CHEBI:61049 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tacrolimus, annotated with tacrolimus (anhydrous) (CHEBI:61049). CHEBI:61049 is a therapeutic agent from Chemical Entities of Biological Interest.
Cyclosporine or tacrolimus are established options for steroid-resistant primary FSGS. Their benefit likely reflects both immunomodulation and direct stabilization of podocyte structure.
Mechanism Target:
MODULATES Circulating Permeability Factor-Mediated Podocyte Injury — Suppresses immune pathways implicated in primary FSGS.
MODULATES Podocyte Injury and Loss — Stabilizes podocyte cytoskeletal dynamics and can reduce ongoing injury in proteinuric disease.
Show evidence (1 reference)
PMID:39663153 SUPPORT Human Clinical
"For those patients with SRNS, CSA + STE might be the best choice for improving the rate of TR. LEF + STE and MMF + STE also appear to offer a steroid-saving alternative to high-dose glucocorticoids for patients."
Network meta-analysis of 20 RCTs identifies cyclosporine plus steroids (CSA + STE) as the best option for steroid-resistant FSGS patients.
Sparsentan
Action: sparsentan therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is sparsentan therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: Sparsentan NCIT:C152412 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Sparsentan (NCIT:C152412). NCIT:C152412 is a therapeutic agent from the NCI Thesaurus.
Dual endothelin type A and angiotensin II type 1 receptor antagonist that lowers proteinuria in selected patients with FSGS. Its clearest current role is as an antiproteinuric therapy rather than reversal of established glomerular scarring.
Target Phenotypes: Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39333921 SUPPORT Human Clinical
"Sparsentan is effective and has a good safety profile for treating FSGS and patients with IgA nephropathy."
Meta-analysis of randomized trials supports sparsentan as an antiproteinuric option in selected patients with FSGS.
Renin-Angiotensin System Blockade
Action: renin-angiotensin system blockadeNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is renin-angiotensin system blockade, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: ACE inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus. angiotensin II receptor antagonist NCIT:C66930 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses angiotensin II receptor antagonist (NCIT:C66930). NCIT:C66930 is a therapeutic agent from the NCI Thesaurus.
ACE inhibitors or angiotensin receptor blockers are core supportive therapy to lower intraglomerular pressure, reduce proteinuria, and treat hypertension across primary and secondary FSGS.
Target Phenotypes: Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology. Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Mycophenolate Mofetil
Action: mycophenolate mofetil therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is mycophenolate mofetil therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: mycophenolate mofetil CHEBI:8764 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mycophenolate mofetil (CHEBI:8764). CHEBI:8764 is a therapeutic agent from Chemical Entities of Biological Interest.
Steroid-sparing immunosuppressive option sometimes used in selected primary FSGS regimens. Evidence is stronger for proteinuria reduction than for consistent disease remission.
Mechanism Target:
MODULATES Circulating Permeability Factor-Mediated Podocyte Injury — Provides additional immunosuppressive control in selected primary FSGS treatment plans.
Show evidence (1 reference)
PMID:39663153 SUPPORT Human Clinical
"Only mycophenolate mofetil-combined steroids (SMD -11, 95% CI -21 to -0.64) showed significant superiority in reducing 24-h UTP when compared with NIT."
Network meta-analysis shows MMF combined with steroids is the only regimen demonstrating statistically significant reduction in 24-hour urine protein vs non-immunosuppressive therapy.
Kidney Transplantation
Action: kidney transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is kidney transplantation, annotated with Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Platform: Surgery
Kidney transplantation is replacement therapy for FSGS-associated kidney failure rather than disease-modifying therapy for the native disease. Recurrence risk is highest in primary FSGS and is generally lower in many monogenic or maladaptive forms.
Target Phenotypes: Renal insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Renal insufficiency (HP:0000083). HP:0000083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41906863 SUPPORT Other
"Following renal transplantation, recurrence of FSGS (rFSGS) occurs in 30%-40% of patients with a high risk of graft loss."
Establishes the quantitative recurrence rate of primary FSGS after kidney transplantation, the key complication of this treatment.
🔬

Diagnosis

1
Kidney biopsy
Clinical and laboratory evaluation must be paired with renal histology to confirm the FSGS pattern and distinguish it from other causes of nephrotic syndrome.
Results: Histological examination with kidney biopsy remains the diagnostic gold standard.
Show evidence (1 reference)
PMID:41009330 SUPPORT Other
"Diagnosis relies on clinical assessment, laboratory testing, and histological examination, with kidney biopsy remaining the gold standard."
Supports biopsy-based confirmation of the FSGS lesion pattern within the broader diagnostic workup.
📊

Related Datasets

3
Tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis: a model for precision nephrology geo:GSE213030
Reporter genes for TNF activation have not been studied in nephrotic syndrome cases at the single nuclear RNA-seq level. Use of archived kidney biopsy material that was fragmented into individual nuclei and assayed for presence of genes involved in TNF activation in patients predicted to have high or low expression of these genes.
human SINGLE CELL RNA SEQ n=10
PMID:36442540
Identified by GEO DataSets index search for Focal Segmental Glomerulosclerosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis geo:GSE212610
Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx.
human BULK RNA SEQ n=9
PMID:36159820
Identified by GEO DataSets index search for Focal Segmental Glomerulosclerosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Pathogenesis of focal segmental glomerulosclerosis and minimal change disease massive:MSV000097297
Podocyte injury is the hallmark of both focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) and is ultimately reflected in foot process effacement proteinuria. Triggers and pathogenic pathways leading to podocyte cytoskeleton rearrangements are however incompletely explained. Here, we aimed to contribute to the understanding of these pathways using tissue bottom-up proteomic profiling of laser capture micro dissected glomeruli from MCD and FSGS.
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Focal Segmental Glomerulosclerosis"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Focal Segmental Glomerulosclerosis
creation_date: "2026-04-13T17:56:50Z"
category: Complex
description: >
  Focal segmental glomerulosclerosis (FSGS) is a histopathologic pattern of
  podocyte-driven glomerular injury rather than a single molecularly uniform
  disease. The broad MONDO root term encompasses primary, monogenic,
  maladaptive/secondary, viral, drug-associated, and collapsing forms that
  converge on proteinuria, segmental glomerular scarring, and progressive
  kidney dysfunction. The gene section below therefore highlights representative
  monogenic FSGS subsets rather than implying that the entire heterogeneous
  root is explained by a single-gene mechanism.

  The gene-defined subtypes fall into four mechanistic groups rather than one.
  ACTN4, INF2 and ANLN act on the podocyte actin cytoskeleton and MYO1E is a
  podocyte class I myosin; NPHS2, CRB2 and CD2AP act at the slit diaphragm and
  podocyte apico-basal polarity; TRPC6 is a podocyte cation channel; and PAX2 is
  a developmental transcription factor, the only gene here whose lesion is
  transcriptional. APOL1 is a common recessive risk genotype rather than a
  Mendelian cause and reaches the podocyte through monovalent cation flux.
disease_term:
  preferred_term: Focal Segmental Glomerulosclerosis
  term:
    id: MONDO:0100313
    label: focal segmental glomerulosclerosis
parents:
- Glomerular Diseases
- Nephrotic Syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011917
      label: focal segmental glomerulosclerosis 3, susceptibility to
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      A member of MONDO's numbered focal segmental glomerulosclerosis series by
      label, but not a subclass of focal segmental glomerulosclerosis in MONDO:
      it is a child of inherited disease susceptibility (MONDO:0020573) with a
      `predisposes towards` relation to inherited focal segmental
      glomerulosclerosis. Recorded as a related match, not a narrow one, because
      it denotes a susceptibility rather than a narrower disease; the CD2AP
      relationship itself is curated in the `genetic` section as SUSCEPTIBILITY.
  - term:
      id: MONDO:0012931
      label: focal segmental glomerulosclerosis 4, susceptibility to
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      As for focal segmental glomerulosclerosis 3, this is a susceptibility
      concept that `predisposes towards` inherited focal segmental
      glomerulosclerosis rather than a subclass of it. The APOL1 relationship is
      curated in the `genetic` section as RISK_FACTOR.

has_subtypes:
- name: Primary FSGS
  subtype_term:
    preferred_term: primary focal segmental glomerulosclerosis
    term:
      id: MONDO:0100324
      label: primary focal segmental glomerulosclerosis
  description: >
    Idiopathic or presumed immune-mediated FSGS with no clear adaptive,
    infectious, drug-related, or inherited driver. Circulating permeability
    factors and podocyte-directed autoantibodies are implicated, and
    post-transplant recurrence risk is highest in this subtype.
- name: Secondary FSGS
  description: >
    FSGS arising as an acquired or maladaptive response to another stressor,
    such as obesity, reduced nephron mass, reflux nephropathy, drugs, or
    viral infection.
- name: Genetic FSGS
  subtype_term:
    preferred_term: inherited focal segmental glomerulosclerosis
    term:
      id: MONDO:0005363
      label: inherited focal segmental glomerulosclerosis
  description: >
    Monogenic or syndromic FSGS caused by variants affecting podocyte
    structure, slit diaphragm integrity, or glomerular development.
    Recurrence after kidney transplantation is usually lower than in primary
    FSGS, but is not uniformly zero across all genetic etiologies.
    MONDO:0005363 is the term that actually parents the numbered
    "focal segmental glomerulosclerosis N" series, which is listed below as
    children of this row.
  children:
  - FSGS1
  - FSGS2
  - FSGS5
  - FSGS6
  - FSGS7
  - FSGS8
  - FSGS9
- name: Collapsing FSGS
  description: >
    Severe morphologic variant with segmental or global collapse of the
    glomerular tuft and marked podocyte hypertrophy/hyperplasia. Often occurs
    in the setting of viral infection, interferon exposure, or other intense
    podocyte stressors.

- name: Tip Lesion Variant FSGS
  description: >
    Morphologic variant characterized by adhesion of the tuft to Bowman's capsule
    at the tip of a glomerular lobe. Can occur in both primary and secondary FSGS,
    including in association with autoimmune systemic diseases such as relapsing
    polychondritis. May respond well to corticosteroid therapy.

- name: FSGS1
  display_name: Focal segmental glomerulosclerosis 1 (ACTN4)
  subtype_term:
    preferred_term: focal segmental glomerulosclerosis 1
    term:
      id: MONDO:0011303
      label: focal segmental glomerulosclerosis 1
  description: >-
    Autosomal dominant FSGS caused by missense variants in ACTN4, encoding the
    actin-filament crosslinking protein alpha-actinin-4. The mutant protein binds
    F-actin more tightly than wild type, so the lesion is at the podocyte actin
    cytoskeleton. MONDO also files this concept under familial idiopathic
    steroid-resistant nephrotic syndrome.
  genes:
  - preferred_term: ACTN4
    term:
      id: hgnc:166
      label: ACTN4
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:10700177
    reference_title: "Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS."
    explanation: Establishes ACTN4 as the cause of dominant familial FSGS, the concept MONDO curates as FSGS1.
- name: FSGS2
  display_name: Focal segmental glomerulosclerosis 2 (TRPC6)
  subtype_term:
    preferred_term: focal segmental glomerulosclerosis 2
    term:
      id: MONDO:0011390
      label: focal segmental glomerulosclerosis 2
  description: >-
    Autosomal dominant FSGS caused by gain-of-function missense variants in
    TRPC6, a cation channel highly expressed in podocytes, which increase
    podocyte calcium influx.
  genes:
  - preferred_term: TRPC6
    term:
      id: hgnc:12338
      label: TRPC6
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15879175
    reference_title: "A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6)."
    explanation: Establishes TRPC6 as the cause of hereditary FSGS, the concept MONDO curates as FSGS2.
- name: FSGS5
  display_name: Focal segmental glomerulosclerosis 5 (INF2)
  subtype_term:
    preferred_term: focal segmental glomerulosclerosis 5
    term:
      id: MONDO:0013191
      label: focal segmental glomerulosclerosis 5
  description: >-
    Autosomal dominant FSGS caused by missense variants clustered in the
    diaphanous inhibitory domain of INF2, a formin-family actin regulator. The
    separate INF2 phenotype combining FSGS with Charcot-Marie-Tooth neuropathy is
    curated by MONDO as Charcot-Marie-Tooth disease dominant intermediate E
    (MONDO:0013758), which is the concept ClinGen's Charcot-Marie-Tooth panel
    classifies as Definitive for INF2; no claim about that phenotype is made on
    this row.
  genes:
  - preferred_term: INF2
    term:
      id: hgnc:23791
      label: INF2
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20023659
    reference_title: "Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues."
    explanation: Establishes INF2 as the cause of dominant FSGS across 11 families, the concept MONDO curates as
      FSGS5.
- name: FSGS6
  display_name: Focal segmental glomerulosclerosis 6 (MYO1E)
  subtype_term:
    preferred_term: focal segmental glomerulosclerosis 6
    term:
      id: MONDO:0013589
      label: focal segmental glomerulosclerosis 6
  description: >-
    Autosomal recessive, childhood-onset, glucocorticoid-resistant FSGS caused by
    biallelic variants in MYO1E, a non-muscle class I myosin of the podocyte.
    Unlike the dominant actin-regulator subtypes, affected individuals are
    homozygous, and electron microscopy showed thickening and disorganisation of
    the glomerular basement membrane.
  genes:
  - preferred_term: MYO1E
    term:
      id: hgnc:7599
      label: MYO1E
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:21756023
    reference_title: MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two mutations (A159P and Y695X) in MYO1E, which encodes a nonmuscle class I myosin, myosin 1E (Myo1E).
    explanation: Identifies the two MYO1E alleles behind this subtype.
  - reference: PMID:21756023
    reference_title: MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis.
    explanation: States the childhood-onset, steroid-resistant phenotype of this subtype.
- name: FSGS7
  display_name: Focal segmental glomerulosclerosis 7 (PAX2)
  subtype_term:
    preferred_term: focal segmental glomerulosclerosis 7
    term:
      id: MONDO:0014451
      label: focal segmental glomerulosclerosis 7
  description: >-
    Autosomal dominant, adult-onset FSGS caused by heterozygous variants in the
    PAX2 transcription factor, arising without the overt extrarenal features of
    papillorenal syndrome. This is the only subtype on this entry whose gene acts
    as a developmental transcription factor rather than on podocyte structure.
    The papillorenal (renal-coloboma) phenotype of PAX2 is curated in
    Renal_Coloboma_Syndrome; only the isolated adult-onset FSGS claim is made
    here.
  genes:
  - preferred_term: PAX2
    term:
      id: hgnc:8616
      label: PAX2
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:24676634
    reference_title: Mutations in PAX2 associate with adult-onset FSGS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, exome sequencing in members of an index family with dominant FSGS revealed a nonconservative, disease-segregating variant in the PAX2 transcription factor gene.
    explanation: Identifies the segregating PAX2 variant in the index dominant-FSGS family.
  - reference: PMID:24676634
    reference_title: Mutations in PAX2 associate with adult-onset FSGS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, mutations in PAX2 may contribute to adult-onset FSGS in the absence of overt extrarenal manifestations.
    explanation: States the isolated adult-onset renal presentation that distinguishes this subtype from
      papillorenal syndrome.
- name: FSGS8
  display_name: Focal segmental glomerulosclerosis 8 (ANLN)
  subtype_term:
    preferred_term: focal segmental glomerulosclerosis 8
    term:
      id: MONDO:0014462
      label: focal segmental glomerulosclerosis 8
  description: >-
    Autosomal dominant FSGS caused by missense variants in ANLN, which encodes
    the F-actin binding protein anillin, identified by linkage plus exome
    sequencing in one kindred with a second variant segregating in a second
    family.
  genes:
  - preferred_term: ANLN
    term:
      id: hgnc:14082
      label: ANLN
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:24676636
    reference_title: Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS.
    explanation: Establishes ANLN as a cause of familial FSGS, the concept MONDO curates as FSGS8.
  - reference: PMID:24676636
    reference_title: Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS.
    explanation: Records the second segregating family, which is the replication behind this subtype.
- name: FSGS9
  display_name: Focal segmental glomerulosclerosis 9 (CRB2)
  subtype_term:
    preferred_term: focal segmental glomerulosclerosis 9
    term:
      id: MONDO:0014539
      label: focal segmental glomerulosclerosis 9
  description: >-
    Autosomal recessive podocytopathy caused by biallelic CRB2 variants. The
    defining report describes it as steroid-resistant nephrotic syndrome rather
    than as FSGS specifically, and the mechanism is loss of podocyte apico-basal
    polarity, which distinguishes it from the actin-cytoskeleton subtypes.
    ClinGen's Glomerulopathy Gene Curation Expert Panel classifies
    CRB2-FSGS9 as Definitive with autosomal recessive inheritance.
  genes:
  - preferred_term: CRB2
    term:
      id: hgnc:18688
      label: CRB2
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25557779
    reference_title: Defects of CRB2 cause steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS.
    explanation: Establishes biallelic CRB2 variants in four families, the concept MONDO curates as FSGS9.
  - reference: PMID:25557779
    reference_title: Defects of CRB2 cause steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.
    explanation: States the apico-basal polarity mechanism that distinguishes this subtype.
pathophysiology:
- name: Podocyte Injury and Loss
  description: >
    Podocyte injury and depletion are the central convergent event in FSGS.
    Immune-mediated, genetic, maladaptive, and toxic insults all destabilize
    the actin cytoskeleton, promote foot process effacement and detachment,
    and reduce the number of podocytes covering the glomerular basement
    membrane. Because podocytes regenerate poorly, cumulative loss beyond a
    threshold drives permanent scar formation.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  genes:
  - preferred_term: ACTN4
    term:
      id: hgnc:166
      label: ACTN4
  - preferred_term: TRPC6
    term:
      id: hgnc:12338
      label: TRPC6
  - preferred_term: INF2
    term:
      id: hgnc:23791
      label: INF2
  - preferred_term: ANLN
    term:
      id: hgnc:14082
      label: ANLN
  - preferred_term: MYO1E
    term:
      id: hgnc:7599
      label: MYO1E
  biological_processes:
  - preferred_term: podocyte apoptosis
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  - preferred_term: actin cytoskeleton reorganization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:41009330
    reference_title: "Focal Segmental Glomerulosclerosis: Comprehensive Review and Exploration of the Dual Potential of Cyclodextrins in Therapeutic Optimization."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pathophysiology is multifactorial and includes direct podocyte injury (e.g., genetic defects, mechanical or toxic injury), immune-mediated processes (e.g., circulating permeability factors, inflammatory mediators), and metabolic disturbances."
    explanation: >
      This comprehensive review establishes that podocyte injury arises from multiple
      converging mechanisms, including genetic, immune, and metabolic factors.
  - reference: PMID:24676636
    reference_title: Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1-associated nephropathy.
    explanation: Places the ANLN product in the podocyte in human FSGS biopsies, supporting the ANLN binding on
      this node.
  - reference: PMID:21756023
    reference_title: MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Normal expression of Myo1E was documented in control human kidney-biopsy specimens in vivo and in glomerular podocytes in vitro.
    explanation: Places the MYO1E product in the glomerular podocyte, supporting the MYO1E binding on this node.
  downstream:
  - target: Glomerular Filtration Barrier Dysfunction
    description: >
      Podocyte depletion and foot process effacement disrupt slit diaphragm
      integrity and increase glomerular albumin permeability.
  - target: Mesangial Expansion and Glomerulosclerosis
    description: >
      Areas of denuded glomerular basement membrane adhere to Bowman's
      capsule and recruit segmental matrix deposition, producing focal scars.

- name: Circulating Permeability Factor-Mediated Podocyte Injury
  description: >
    Primary FSGS is associated with circulating permeability factors and, in
    some patients, podocyte-directed autoantibodies. Candidate drivers include
    suPAR, cardiotrophin-like cytokine 1, angiopoietin-like 4, and
    anti-nephrin antibodies, but none explains every case. This mechanism is
    therefore best treated as an upstream hypothesis for primary disease
    rather than a universal explanation for all FSGS.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: immune response
    term:
      id: GO:0006955
      label: immune response
    modifier: ABNORMAL
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: ABNORMAL
  evidence:
  - reference: PMID:41133676
    reference_title: "Serum Factors in Primary Podocytopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Primary podocytopathies, including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), are caused by a circulating factor or factors injurious to the podocyte."
    explanation: >
      Establishes circulating factors as the primary pathogenic mechanism in
      primary FSGS, with immune-mediated mechanisms supported by treatment
      responsiveness to immunosuppressants.
  - reference: PMID:41133676
    reference_title: "Serum Factors in Primary Podocytopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Potential non-antibody-mediated circulating factors have been identified, including cardiotrophin-like cytokine 1, soluble urokinase plasminogen activator receptor, and angiopoietin-like 4, among others."
    explanation: >
      Identifies specific candidate circulating permeability factors implicated in
      primary FSGS pathogenesis beyond classical autoantibodies.
  downstream:
  - target: Podocyte Injury and Loss
    description: >
      Circulating permeability factors and autoantibodies directly amplify
      podocyte stress, detachment, and depletion in primary FSGS.

- name: Glomerular Filtration Barrier Dysfunction
  conforms_to: "nephrotic_podocyte_injury#Glomerular Filtration Barrier Breakdown"
  description: >
    Loss of podocyte structural integrity, especially foot process effacement
    and slit diaphragm disruption, increases glomerular permeability to
    albumin and other plasma proteins. Slit diaphragm proteins such as
    nephrin and podocin are essential structural and signaling components of
    the filtration barrier, so disruption of this compartment is a common
    final pathway in proteinuric FSGS. CRB2 and CD2AP act in this compartment
    rather than on the podocyte actin cytoskeleton: CRB2 is required for slit
    diaphragm formation and nephrin trafficking, and CD2AP links nephrin and
    podocin at the slit diaphragm.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  genes:
  - preferred_term: NPHS2
    term:
      id: hgnc:13394
      label: NPHS2
  - preferred_term: CRB2
    term:
      id: hgnc:18688
      label: CRB2
  - preferred_term: CD2AP
    term:
      id: hgnc:14258
      label: CD2AP
  biological_processes:
  - preferred_term: cell-cell junction assembly
    term:
      id: GO:0007043
      label: cell-cell junction assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:41009330
    reference_title: "Focal Segmental Glomerulosclerosis: Comprehensive Review and Exploration of the Dual Potential of Cyclodextrins in Therapeutic Optimization."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This pattern of injury can lead to progressive renal dysfunction and, in some cases, end-stage kidney disease."
    explanation: >
      Documents the clinical consequence of glomerular filtration barrier
      disruption: progressive loss of kidney function leading to end-stage
      kidney disease.
  - reference: PMID:25557779
    reference_title: Defects of CRB2 cause steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking.
    explanation: Places the CRB2 lesion at foot process and slit diaphragm formation, which is this node's compartment.
  - reference: PMID:14643126
    reference_title: CD2-associated protein and glomerular disease.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      CD2AP localises to the slit diaphragm and links nephrin and podocin to phosphoinositide 3-OH kinase; this complex has cell-signalling properties.
    explanation: Places the CD2AP product at the slit diaphragm alongside nephrin and podocin, supporting the CD2AP
      binding on this node.
  downstream:
  - target: Proteinuria
    description: >
      Increased albumin leak across the filtration barrier produces the
      dominant clinical manifestation of FSGS.
  - target: Hematuria
    description: >
      Barrier disruption can also permit erythrocytes to enter the urine,
      usually as microscopic hematuria.
  - target: Tubular Protein Overload and Interstitial Inflammation
    description: >
      Filtered proteins injure tubular epithelial cells and trigger
      downstream interstitial inflammation.

- name: Mesangial Expansion and Glomerulosclerosis
  description: >
    Persistent podocyte depletion promotes tuft adhesion, mesangial matrix
    accumulation, and segmental obliteration of glomerular capillary loops,
    producing the defining histologic lesion of FSGS. Once established,
    glomerulosclerosis is largely irreversible and contributes to progressive
    nephron loss.
  cell_types:
  - preferred_term: glomerular mesangial cell
    term:
      id: CL:0000650
      label: mesangial cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: mesangial cell proliferation
    term:
      id: GO:0072126
      label: positive regulation of glomerular mesangial cell proliferation
    modifier: INCREASED
  evidence: []
  downstream:
  - target: Tubular Protein Overload and Interstitial Inflammation
    description: >
      Progressive segmental scarring reduces nephron reserve and increases
      downstream tubular stress, amplifying tubulointerstitial injury.

- name: Tubular Protein Overload and Interstitial Inflammation
  description: >
    Sustained heavy proteinuria and nephron loss trigger proximal tubular
    epithelial stress, complement activation, and macrophage recruitment in
    the interstitium. This inflammatory phase links glomerular injury to the
    later fibrotic remodeling that drives chronic kidney function loss.
  cell_types:
  - preferred_term: proximal tubule epithelial cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  evidence: []
  downstream:
  - target: Tubulointerstitial Fibrosis
    description: >
      Persistent tubular injury and interstitial inflammation activate
      myofibroblasts and drive progressive matrix deposition.

- name: Tubulointerstitial Fibrosis
  description: >
    Activated myofibroblasts deposit extracellular matrix throughout the
    cortical interstitium, producing tubular atrophy and irreversible loss of
    renal parenchyma. The burden of tubulointerstitial fibrosis tracks
    long-term kidney function decline more closely than glomerular scarring
    alone.
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence: []
  downstream:
  - target: Progressive Renal Insufficiency
    description: >
      Interstitial fibrosis and tubular atrophy are major determinants of
      ongoing GFR decline and eventual kidney failure.
  - target: Hypertension
    description: >
      Nephron loss and chronic kidney injury promote sodium retention and
      sustained activation of vasoconstrictive pathways.

- name: APOL1 Risk-Variant Cation Flux and Podocyte Cytotoxicity
  description: >-
    G1 and G2 are the two APOL1 coding variants that carry the excess risk of
    kidney disease. For G1, which is the allele the cited work tested, induction of
    the protein drives monovalent cation flux across the podocyte membrane, with
    potassium efflux, downstream calcium release, impaired mitochondrial ATP
    production and inhibited translation. This is the mechanism by which a common
    risk genotype, rather than a Mendelian lesion, reaches the podocyte-injury
    node. It is an upstream modifier of susceptibility, not a subtype of FSGS,
    and the reversal of the phenotype by a small-molecule APOL1 blocker is what
    identifies the cation flux as proximal rather than incidental.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: APOL1
    term:
      id: hgnc:618
      label: APOL1
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: potassium ion export across plasma membrane
    term:
      id: GO:0097623
      label: potassium ion export across plasma membrane
    modifier: INCREASED
  evidence:
  - reference: PMID:38227370
    reference_title: APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147.
    explanation: Establishes potassium efflux and podocyte injury in podocytes carrying the risk allele, and the
      reversal that makes the cation flux the proximal step.
  - reference: PMID:38227370
    reference_title: APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.
    explanation: States the authors' conclusion that cation transport is the proximal mechanism this node names.
  downstream:
  - target: Podocyte Injury and Loss
    description: >-
      Risk-allele-driven cation flux and translational arrest injure the podocyte
      and produce proteinuria in the transgenic model.
    evidence:
    - reference: PMID:38227370
      reference_title: APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147.
      explanation: >-
        The same experiment that shows the cation flux also shows the podocyte injury and
        proteinuria downstream of it, and shows both reversing together.

- name: PAX2 Transcription Factor Dysfunction
  description: >-
    FSGS-associated PAX2 variants impair DNA binding and transactivation, or
    strengthen the interaction of PAX2 with repressor proteins, so the lesion is
    transcriptional rather than structural. This is the only route into FSGS on
    this entry that does not begin at a podocyte structural or slit-diaphragm
    protein. The steps between altered PAX2 transcriptional output and podocyte
    injury are not established in the source that defines this subtype, and the
    edge below is recorded at that strength.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PAX2
    term:
      id: hgnc:8616
      label: PAX2
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24676634
    reference_title: Mutations in PAX2 associate with adult-onset FSGS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      As predicted by in silico structural modeling analyses, in vitro functional studies documented that several of the FSGS-associated PAX2 mutations perturb protein function by affecting proper binding to DNA and transactivation activity or by altering the interaction of PAX2 with repressor proteins, resulting in enhanced repressor activity.
    explanation: Establishes the transcriptional nature of the PAX2 lesion, including the bidirectional effect on
      transactivation versus repression.
  downstream:
  - target: Podocyte Injury and Loss
    description: >-
      Altered PAX2 transcriptional output is associated with adult-onset FSGS in
      the absence of extrarenal features; the intervening steps to podocyte
      injury are not established in the cited source.
    evidence:
    - reference: PMID:24676634
      reference_title: Mutations in PAX2 associate with adult-onset FSGS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, mutations in PAX2 may contribute to adult-onset FSGS in the absence of overt extrarenal manifestations.
      explanation: The authors' own hedged statement of the clinical consequence, which is the strength at which
        this edge is asserted.

phenotypes:
- name: Proteinuria
  description: >
    Heavy urinary protein loss is the hallmark manifestation of FSGS and
    reflects failure of the glomerular filtration barrier. Proteinuria burden
    tracks both clinical severity and long-term renal outcomes.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  sequelae:
  - target: Hypoalbuminemia
    description: >
      Persistent albumin loss in the urine lowers serum albumin
      concentration.
  - target: Nephrotic Syndrome
    description: >
      Nephrotic-range proteinuria anchors the classic nephrotic
      presentation of primary FSGS.
  evidence:
  - reference: PMID:41222995
    reference_title: "Prevalence, resource utilization, and economic impact of kidney function and proteinuria in patients with focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More advanced chronic kidney disease and higher levels of proteinuria were both associated with greater health care resource utilization and costs."
    explanation: >
      Large US real-world study (9,899 FSGS patients) demonstrating that proteinuria
      is the central clinical driver of disease burden in FSGS.

- name: Nephrotic Syndrome
  description: >
    Full nephrotic syndrome (nephrotic-range proteinuria, hypoalbuminemia, edema,
    hyperlipidemia) is present in many primary FSGS cases at diagnosis, particularly
    in children and young adults. FSGS is one of the major causes of nephrotic
    syndrome globally.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:41906863
    reference_title: "Recurrence of focal segmental glomerulosclerosis: An updated review of pathophysiology, biomarkers, and therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Focal segmental glomerulosclerosis (FSGS) is one of the major causes of nephrotic syndrome, which can progress to end-stage renal disease, leading to kidney transplantation."
    explanation: >
      Establishes FSGS as a major cause of nephrotic syndrome and documents
      the natural history of progression to end-stage renal disease.

- name: Hypertension
  description: >
    Hypertension is common in FSGS, arising from sodium retention, RAAS activation,
    and reduced nephron mass. It accelerates GFR decline and contributes to
    cardiovascular risk.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence: []

- name: Progressive Renal Insufficiency
  description: >
    Progressive loss of kidney function reflects ongoing podocyte depletion,
    glomerular scarring, and tubulointerstitial fibrosis. A substantial subset
    of patients ultimately develops kidney failure.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:41009330
    reference_title: "Focal Segmental Glomerulosclerosis: Comprehensive Review and Exploration of the Dual Potential of Cyclodextrins in Therapeutic Optimization."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This pattern of injury can lead to progressive renal dysfunction and, in some cases, end-stage kidney disease."
    explanation: >
      Review confirms that glomerular injury in FSGS leads to progressive
      renal insufficiency, with a subset reaching end-stage kidney disease.

- name: Peripheral Edema
  description: >
    Peripheral and periorbital edema result from hypoalbuminemia-driven reduction
    in plasma oncotic pressure combined with renal sodium retention.
  phenotype_term:
    preferred_term: Peripheral edema
    term:
      id: HP:0012398
      label: Peripheral edema
  evidence: []

- name: Hypoalbuminemia
  description: >
    Serum albumin is markedly reduced due to massive urinary protein losses
    exceeding hepatic albumin synthesis capacity.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  sequelae:
  - target: Peripheral Edema
    description: >
      Reduced plasma oncotic pressure favors dependent and periorbital
      fluid accumulation.
  - target: Hyperlipidemia
    description: >
      Low oncotic pressure stimulates hepatic lipoprotein production and
      produces the dyslipidemic component of nephrotic syndrome.
  evidence: []

- name: Hyperlipidemia
  description: >
    Compensatory hepatic lipoprotein overproduction in response to low oncotic
    pressure drives dyslipidemia. Elevated LDL and total cholesterol increase
    cardiovascular risk in FSGS patients.
  phenotype_term:
    preferred_term: Hyperlipidemia
    term:
      id: HP:0003077
      label: Hyperlipidemia
  evidence: []

- name: Hematuria
  description: >
    Microscopic hematuria may occur in FSGS, reflecting glomerular inflammation
    and disruption of the filtration barrier. Macroscopic hematuria is uncommon.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence: []

histopathology:
- name: Segmental glomerulosclerosis lesion
  description: >
    Kidney biopsy defines FSGS as a pattern lesion characterized by segmental
    glomerular scarring arising from diverse primary and secondary causes.
  diagnostic: true
  evidence:
  - reference: PMID:41009330
    reference_title: "Focal Segmental Glomerulosclerosis: Comprehensive Review and Exploration of the Dual Potential of Cyclodextrins in Therapeutic Optimization."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Focal segmental glomerulosclerosis (FSGS) is a histopathological pattern of segmental glomerulosclerosis that arises from diverse primary and secondary causes."
    explanation: >
      Supports the root-level framing of FSGS as a biopsy-defined
      histopathologic pattern rather than a single uniform molecular
      disease.
- name: Podocyte foot process effacement
  description: >
    Electron microscopy can show focal podocyte foot process effacement,
    consistent with structural podocyte injury in some genetic and secondary
    FSGS forms.
  context: Genetic FSGS / some secondary forms
  evidence:
  - reference: PMID:20023659
    reference_title: "Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these biopsies, electron microscopy showed focal areas of podocyte foot process effacement, typical of secondary and some genetic forms of FSGS, as well as areas where foot processes and slit-diaphragms were well preserved."
    explanation: >
      Human renal biopsy ultrastructure from monogenic FSGS supports foot
      process effacement as a disease-relevant microscopic correlate of
      podocyte injury.

- name: Tip lesion variant
  description: >
    Morphologic variant with adhesion of the glomerular tuft to Bowman's capsule
    at the tip of a glomerular lobe. This lesion pattern can occur in primary,
    secondary, and autoimmune-associated FSGS, including cases linked to systemic
    autoimmune diseases.
  context: Tip Lesion Variant FSGS
  evidence:
  - reference: PMID:42234924
    reference_title: "Tip Lesion Variant of Focal Segmental Glomerulosclerosis in Familial Relapsing Polychondritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated renal biopsy confirmed tip lesion variant of FSGS, demonstrating excellent response to corticosteroid therapy with prednisolone 1 mg/kg/day; proteinuria declined from 7g/24h to 0.98g/24h and serum albumin increased from 0.9g/dL to 2.2g/dL within three months."
    explanation: >
      First documented case of tip lesion FSGS variant in relapsing polychondritis,
      establishing the morphologic variant and demonstrating responsiveness to
      corticosteroid therapy in this autoimmune-associated presentation.

diagnosis:
- name: Kidney biopsy
  description: >
    Clinical and laboratory evaluation must be paired with renal histology to
    confirm the FSGS pattern and distinguish it from other causes of
    nephrotic syndrome.
  results: Histological examination with kidney biopsy remains the diagnostic gold standard.
  evidence:
  - reference: PMID:41009330
    reference_title: "Focal Segmental Glomerulosclerosis: Comprehensive Review and Exploration of the Dual Potential of Cyclodextrins in Therapeutic Optimization."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis relies on clinical assessment, laboratory testing, and histological examination, with kidney biopsy remaining the gold standard."
    explanation: >
      Supports biopsy-based confirmation of the FSGS lesion pattern within
      the broader diagnostic workup.

treatments:
- name: Corticosteroids
  description: >
    Prednisone remains standard initial immunosuppressive therapy for primary
    FSGS with nephrotic syndrome after secondary and monogenic causes have
    been excluded. Some patients achieve partial or complete remission, but
    steroid resistance is common.
  treatment_term:
    preferred_term: corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  target_mechanisms:
  - target: Circulating Permeability Factor-Mediated Podocyte Injury
    treatment_effect: MODULATES
    description: >
      Dampens immune signaling implicated in primary FSGS and may reduce
      ongoing podocyte injury.
  evidence:
  - reference: PMID:39663153
    reference_title: "Efficacy and safety of nine immunosuppressive agents for primary focal segmental glomerulosclerosis in adults: a pairwise and network meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Steroids remain the recommended initial treatment for pFSGS."
    explanation: >
      Network meta-analysis of 20 RCTs confirms corticosteroids as the
      recommended first-line treatment for primary FSGS.
  - reference: PMID:42234924
    reference_title: "Tip Lesion Variant of Focal Segmental Glomerulosclerosis in Familial Relapsing Polychondritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated renal biopsy confirmed tip lesion variant of FSGS, demonstrating excellent response to corticosteroid therapy with prednisolone 1 mg/kg/day; proteinuria declined from 7g/24h to 0.98g/24h and serum albumin increased from 0.9g/dL to 2.2g/dL within three months."
    explanation: >
      Case report documents excellent corticosteroid response in tip lesion FSGS
      variant associated with relapsing polychondritis, with marked proteinuria
      reduction and albumin recovery within three months of therapy.

- name: Calcineurin Inhibitors
  description: >
    Cyclosporine or tacrolimus are established options for steroid-resistant
    primary FSGS. Their benefit likely reflects both immunomodulation and
    direct stabilization of podocyte structure.
  treatment_term:
    preferred_term: calcineurin inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclosporine
      term:
        id: CHEBI:4031
        label: cyclosporin A
    - preferred_term: tacrolimus
      term:
        id: CHEBI:61049
        label: tacrolimus (anhydrous)
  target_mechanisms:
  - target: Circulating Permeability Factor-Mediated Podocyte Injury
    treatment_effect: MODULATES
    description: >
      Suppresses immune pathways implicated in primary FSGS.
  - target: Podocyte Injury and Loss
    treatment_effect: MODULATES
    description: >
      Stabilizes podocyte cytoskeletal dynamics and can reduce ongoing
      injury in proteinuric disease.
  evidence:
  - reference: PMID:39663153
    reference_title: "Efficacy and safety of nine immunosuppressive agents for primary focal segmental glomerulosclerosis in adults: a pairwise and network meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For those patients with SRNS, CSA + STE might be the best choice for improving the rate of TR. LEF + STE and MMF + STE also appear to offer a steroid-saving alternative to high-dose glucocorticoids for patients."
    explanation: >
      Network meta-analysis of 20 RCTs identifies cyclosporine plus steroids
      (CSA + STE) as the best option for steroid-resistant FSGS patients.

- name: Sparsentan
  description: >
    Dual endothelin type A and angiotensin II type 1 receptor antagonist that
    lowers proteinuria in selected patients with FSGS. Its clearest current
    role is as an antiproteinuric therapy rather than reversal of established
    glomerular scarring.
  treatment_term:
    preferred_term: sparsentan therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Sparsentan
      term:
        id: NCIT:C152412
        label: Sparsentan
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:39333921
    reference_title: "Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sparsentan is effective and has a good safety profile for treating FSGS and patients with IgA nephropathy."
    explanation: >
      Meta-analysis of randomized trials supports sparsentan as an
      antiproteinuric option in selected patients with FSGS.

- name: Renin-Angiotensin System Blockade
  description: >
    ACE inhibitors or angiotensin receptor blockers are core supportive
    therapy to lower intraglomerular pressure, reduce proteinuria, and treat
    hypertension across primary and secondary FSGS.
  treatment_term:
    preferred_term: renin-angiotensin system blockade
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: angiotensin II receptor antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence: []

- name: Mycophenolate Mofetil
  description: >
    Steroid-sparing immunosuppressive option sometimes used in selected
    primary FSGS regimens. Evidence is stronger for proteinuria reduction than
    for consistent disease remission.
  treatment_term:
    preferred_term: mycophenolate mofetil therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  target_mechanisms:
  - target: Circulating Permeability Factor-Mediated Podocyte Injury
    treatment_effect: MODULATES
    description: >
      Provides additional immunosuppressive control in selected primary
      FSGS treatment plans.
  evidence:
  - reference: PMID:39663153
    reference_title: "Efficacy and safety of nine immunosuppressive agents for primary focal segmental glomerulosclerosis in adults: a pairwise and network meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only mycophenolate mofetil-combined steroids (SMD -11, 95% CI -21 to -0.64) showed significant superiority in reducing 24-h UTP when compared with NIT."
    explanation: >
      Network meta-analysis shows MMF combined with steroids is the only regimen
      demonstrating statistically significant reduction in 24-hour urine protein
      vs non-immunosuppressive therapy.

- name: Kidney Transplantation
  description: >
    Kidney transplantation is replacement therapy for FSGS-associated kidney
    failure rather than disease-modifying therapy for the native disease.
    Recurrence risk is highest in primary FSGS and is generally lower in many
    monogenic or maladaptive forms.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_phenotypes:
  - preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:41906863
    reference_title: "Recurrence of focal segmental glomerulosclerosis: An updated review of pathophysiology, biomarkers, and therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following renal transplantation, recurrence of FSGS (rFSGS) occurs in 30%-40% of patients with a high risk of graft loss."
    explanation: >
      Establishes the quantitative recurrence rate of primary FSGS after
      kidney transplantation, the key complication of this treatment.

genetic:
- name: NPHS2
  association: Causative in monogenic FSGS
  relationship_type: CAUSATIVE
  subtype: Genetic FSGS
  gene_term:
    preferred_term: NPHS2
    term:
      id: hgnc:13394
      label: NPHS2
  inheritance:
  - name: Autosomal recessive
  notes: >
    Autosomal recessive NPHS2 variants cause a classic monogenic podocytopathy
    that often presents as childhood-onset steroid-resistant nephrotic
    syndrome with FSGS histology. Podocin is an essential slit diaphragm
    membrane protein.
  evidence:
  - reference: PMID:10742096
    reference_title: "NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier."
    explanation: >
      Original discovery paper identifying NPHS2 mutations as the cause of
      autosomal recessive steroid-resistant nephrotic syndrome and FSGS,
      establishing podocin's essential role in glomerular filtration.

- name: ACTN4
  association: Causative in monogenic FSGS
  relationship_type: CAUSATIVE
  subtype: FSGS1
  gene_term:
    preferred_term: ACTN4
    term:
      id: hgnc:166
      label: ACTN4
  inheritance:
  - name: Autosomal dominant
  notes: >
    Autosomal dominant mutations in ACTN4 (alpha-actinin-4), an actin-filament
    crosslinking protein expressed in podocytes, disrupt cytoskeletal architecture
    and cause familial FSGS. Mutant alpha-actinin-4 binds F-actin more strongly
    than wild-type, altering podocyte actin cytoskeleton dynamics.
  evidence:
  - reference: PMID:10700177
    reference_title: "Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS."
    explanation: >
      Original discovery paper establishing ACTN4 mutations as the cause of
      autosomal dominant familial FSGS, identifying podocyte cytoskeletal
      disruption as a pathogenic mechanism.
  - reference: PMID:10700177
    reference_title: "Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4."
    explanation: >
      Mechanistic evidence showing that ACTN4 mutations cause aberrant
      actin binding, explaining how cytoskeletal disruption leads to
      podocyte dysfunction.

- name: TRPC6
  association: Causative in monogenic FSGS
  relationship_type: CAUSATIVE
  subtype: FSGS2
  gene_term:
    preferred_term: TRPC6
    term:
      id: hgnc:12338
      label: TRPC6
  inheritance:
  - name: Autosomal dominant
  notes: >
    Gain-of-function mutations in TRPC6 (transient receptor potential cation
    channel, subfamily C, member 6) cause autosomal dominant FSGS by enhancing
    calcium influx in podocytes, leading to podocyte injury and apoptosis.
    TRPC6 is highly expressed in podocytes.
  evidence:
  - reference: PMID:15879175
    reference_title: "A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6)."
    explanation: >
      Original discovery paper identifying TRPC6 missense mutations as the cause
      of familial FSGS, establishing a calcium channel mechanism distinct from
      previously known cytoskeletal FSGS genes.
  - reference: PMID:38814201
    reference_title: "A novel gain-of-function mutation in transient receptor potential C6 that causes podocytes injury."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The 24 h uACR at 6 weeks was significantly higher in the pure-zygotes group than in the WT and heterozygotes groups, and this difference was found at 8 and 10 weeks.TRPC6 levels showed no significant difference between homozygote and WT mice. Compared to homozygote group, expression of podocin and nephrin were increased in WT, but levels of desmin was decreased in WT."
    explanation: >
      Knock-in mouse data show proteinuria and slit-diaphragm injury,
      supporting an in vivo pathogenic effect of TRPC6 gain-of-function.
  - reference: PMID:38814201
    reference_title: "A novel gain-of-function mutation in transient receptor potential C6 that causes podocytes injury."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results of CCK-8 assay and apoptosis experiments showed that the TRPC6-N110S overexpression group had slower proliferative activity and increased apoptosis than the control group. FluO-3 assay revealed increased calcium influx in the TRPC6-N110S overexpression group."
    explanation: >
      Podocyte cell assays show enhanced calcium influx and apoptosis,
      providing in vitro support for the proposed TRPC6 mechanism.

- name: INF2
  association: Causative in monogenic FSGS
  relationship_type: CAUSATIVE
  subtype: FSGS5
  gene_term:
    preferred_term: INF2
    term:
      id: hgnc:23791
      label: INF2
  inheritance:
  - name: Autosomal dominant
  notes: >
    Autosomal dominant mutations in INF2 (inverted formin 2), a formin family
    actin-regulating protein expressed in podocytes, cause FSGS sometimes
    accompanied by Charcot-Marie-Tooth neuropathy. Mutations act through a
    gain-of-function mechanism affecting actin cytoskeleton dynamics in podocytes.
  evidence:
  - reference: PMID:20023659
    reference_title: "Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues."
    explanation: >
      Original discovery paper identifying INF2 mutations as the cause of
      autosomal dominant FSGS, establishing actin polymerization regulation
      as critical to podocyte function.
  - reference: PMID:39536114
    reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "R218Q INF2 mice are susceptible to glomerular disease, in contrast to INF2 knockout mice."
    explanation: >
      PAN-injury mouse experiments show that the disease-associated INF2
      allele confers in vivo glomerular susceptibility, supporting a
      gain-of-function rather than simple loss-of-function mechanism.
  - reference: PMID:39536114
    reference_title: "INF2 mutations cause kidney disease through a gain-of-function mechanism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Colocalization, coimmunoprecipitation analyses, and cellular actin measurements showed that INF2 R218Q confers a gain-of-function effect on the actin cytoskeleton."
    explanation: >-
      Cell-based mechanistic assays show that mutant INF2 directly perturbs
      actin regulation, providing in vitro support for the gain-of-function
      mechanism in INF2-associated FSGS.
- name: FAT1
  gene_term:
    preferred_term: FAT1
    term:
      id: hgnc:3595
      label: FAT1
  relationship_type: CAUSATIVE
  subtype: Genetic FSGS
  inheritance:
  - name: Autosomal recessive
  notes: >-
    MONDO records no numbered "focal segmental glomerulosclerosis N" concept for
    FAT1, so this gene sits on the Genetic FSGS grouping row rather than on a
    numbered subtype row. ClinGen classifies the relationship against the root
    term MONDO:0100313 itself.
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_6dbbe3f1-4a7a-4c76-b047-1c1d95771b74-2023-11-13T070000.000Z
    reference_title: "FAT1 / focal segmental glomerulosclerosis (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FAT1 | HGNC:3595 | focal segmental glomerulosclerosis | MONDO:0100313 | AR | Strong"
    explanation: ClinGen classifies the FAT1-focal segmental glomerulosclerosis gene-disease relationship as strong with autosomal recessive inheritance.
- name: SYNPO
  gene_term:
    preferred_term: SYNPO
    term:
      id: hgnc:30672
      label: SYNPO
  relationship_type: UNKNOWN
  subtype: Genetic FSGS
  notes: >-
    Recorded as UNKNOWN rather than CAUSATIVE because ClinGen classifies the
    SYNPO-FSGS relationship as Limited, meaning the evidence is currently
    insufficient to assert the gene-disease relationship. Limited is not the same
    as Disputed: no publication refutes the relationship. As with FAT1, MONDO
    records no numbered FSGS concept for SYNPO.
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_12a82f02-cc6b-41a0-b2b7-7d8c18ff470b-2023-11-13T190000.000Z
    reference_title: "SYNPO / focal segmental glomerulosclerosis (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SYNPO | HGNC:30672 | focal segmental glomerulosclerosis | MONDO:0100313 | AD | Limited"
    explanation: ClinGen classifies the SYNPO-focal segmental glomerulosclerosis gene-disease relationship as limited with autosomal dominant inheritance.
- name: MYO1E
  association: Causative in monogenic FSGS
  relationship_type: CAUSATIVE
  subtype: FSGS6
  gene_term:
    preferred_term: MYO1E
    term:
      id: hgnc:7599
      label: MYO1E
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Biallelic MYO1E variants cause childhood-onset, glucocorticoid-resistant
    FSGS. MYO1E is a non-muscle class I myosin normally expressed in glomerular
    podocytes; the A159P allele mislocalises in transfected cells and the Y695X
    allele removes the calmodulin-binding and tail domains. The ClinGen
    Gene-Disease Validity download of 2026-09-25 contains no MYO1E assertion.
  evidence:
  - reference: PMID:21756023
    reference_title: MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations in MYO1E segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and Family 2). Patients were homozygous for the mutations and did not have a response to glucocorticoid therapy.
    explanation: Establishes recessive segregation in two independent pedigrees and the steroid-resistant course.
  - reference: PMID:21756023
    reference_title: MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transfection studies revealed abnormal subcellular localization and function of the A159P-Myo1E mutant.
    explanation: Functional support that the A159P allele is deleterious.

- name: PAX2
  association: Causative in adult-onset dominant FSGS without extrarenal features
  relationship_type: CAUSATIVE
  subtype: FSGS7
  gene_term:
    preferred_term: PAX2
    term:
      id: hgnc:8616
      label: PAX2
  inheritance:
  - name: Autosomal dominant
  notes: >-
    PAX2 is a developmental transcription factor, so this is the one gene on this
    entry whose FSGS mechanism is transcriptional rather than structural. The
    reported FSGS-associated variants perturb DNA binding and transactivation or
    increase repressor activity. ClinGen's Glomerulopathy Gene Curation Expert
    Panel classifies PAX2-FSGS7 (MONDO:0014451) as Definitive with autosomal
    dominant inheritance, read from the Gene-Disease Validity download of
    2026-09-25. The papillorenal syndrome phenotype of PAX2 is curated in
    Renal_Coloboma_Syndrome and is not claimed here.
  evidence:
  - reference: PMID:24676634
    reference_title: Mutations in PAX2 associate with adult-onset FSGS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing in probands of a familial FSGS cohort revealed seven rare and private heterozygous single nucleotide substitutions (4% of individuals).
    explanation: Quantifies the share of a familial FSGS cohort carrying rare heterozygous PAX2 variants.

- name: ANLN
  association: Causative in monogenic FSGS
  relationship_type: CAUSATIVE
  subtype: FSGS8
  gene_term:
    preferred_term: ANLN
    term:
      id: hgnc:14082
      label: ANLN
  inheritance:
  - name: Autosomal dominant
  notes: >-
    ANLN encodes anillin, an F-actin binding protein, so this subtype belongs to
    the podocyte actin-cytoskeleton group alongside ACTN4 and INF2. Anillin is
    upregulated in podocytes in FSGS biopsies. The ClinGen Gene-Disease Validity
    download of 2026-09-25 contains no ANLN assertion.
  evidence:
  - reference: PMID:24676636
    reference_title: Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS.
    explanation: Establishes ANLN as a cause of familial FSGS and names the protein's actin-binding role.

- name: CRB2
  association: Causative in recessive podocytopathy presenting as steroid-resistant nephrotic syndrome with FSGS
  relationship_type: CAUSATIVE
  subtype: FSGS9
  gene_term:
    preferred_term: CRB2
    term:
      id: hgnc:18688
      label: CRB2
  inheritance:
  - name: Autosomal recessive
  notes: >-
    CRB2 is a conserved regulator of epithelial apico-basal polarity, and the
    mechanism is loss of podocyte polarity rather than a primary
    actin-cytoskeleton defect. The defining report frames the phenotype as
    steroid-resistant nephrotic syndrome; MONDO curates the concept as focal
    segmental glomerulosclerosis 9, and ClinGen's Glomerulopathy Gene Curation
    Expert Panel classifies CRB2-MONDO:0014539 as Definitive with autosomal
    recessive inheritance, read from the Gene-Disease Validity download of
    2026-09-25.
  evidence:
  - reference: PMID:25557779
    reference_title: Defects of CRB2 cause steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS.
    explanation: Establishes recessive CRB2 variants in four families as the cause of this subtype.
  - reference: PMID:25557779
    reference_title: Defects of CRB2 cause steroid-resistant nephrotic syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking.
    explanation: Zebrafish loss of function supplies the mechanism by which CRB2 loss damages the podocyte.

- name: APOL1
  association: Recessive risk genotype, not a Mendelian FSGS subtype
  relationship_type: RISK_FACTOR
  gene_term:
    preferred_term: APOL1
    term:
      id: hgnc:618
      label: APOL1
  notes: >-
    Two APOL1 renal-risk alleles raise FSGS risk substantially in people of
    recent African ancestry, but the genotype is common in that population and
    most carriers never develop kidney disease, so this is a susceptibility
    relationship rather than a Mendelian cause. MONDO models it the same way:
    "focal segmental glomerulosclerosis 4, susceptibility to" (MONDO:0012931) is
    a child of inherited disease susceptibility with a `predisposes towards`
    relation to inherited FSGS, not a subclass of focal segmental
    glomerulosclerosis, and is deliberately not given a `has_subtypes` row on
    this entry. ClinGen's Glomerulopathy Gene Curation Expert Panel classifies
    APOL1-MONDO:0012931 as Definitive with autosomal recessive inheritance, read
    from the Gene-Disease Validity download of 2026-09-25; that classification is
    about the susceptibility concept, not about a monogenic FSGS.
  evidence:
  - reference: PMID:21997394
    reference_title: APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN).
    explanation: Quantifies the recessive risk effect that makes this a risk genotype rather than a Mendelian cause.

- name: CD2AP
  association: Causative biallelic loss of CD2AP in childhood-onset FSGS with end-stage renal disease
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CD2AP
    term:
      id: hgnc:14258
      label: CD2AP
  inheritance:
  - name: Autosomal recessive
  notes: >-
    CD2AP links nephrin and podocin at the slit diaphragm. Biallelic loss is an
    established recessive cause of FSGS: ClinGen's Glomerulopathy Gene Curation
    Expert Panel classifies CD2AP-MONDO:0011917 as Definitive with autosomal
    recessive inheritance, read from the Gene-Disease Validity download of
    2026-09-25, and the defining report identifies a homozygous frameshift in
    three siblings and reproduces the disease with the same allele in mice. This
    record carries that recessive claim; the separate heterozygous claim is a
    weaker and distinct one and is recorded below. MONDO models the concept as
    "focal segmental glomerulosclerosis 3, susceptibility to" (MONDO:0011917), a
    child of inherited disease susceptibility that `predisposes towards`
    inherited FSGS rather than a subclass of FSGS, so neither record gets a
    `has_subtypes` row here; that is a disagreement with MONDO's modelling of a
    Definitive recessive gene-disease relationship as a susceptibility, not with
    ClinGen's grade.
  evidence:
  - reference: PMID:30612599
    reference_title: Recessive mutation in CD2AP causes focal segmental glomerulosclerosis in humans and mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By whole-exome sequencing, we identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease.
    explanation: >-
      The human recessive evidence behind this record - a homozygous null allele segregating
      with childhood-onset FSGS in three affected siblings.
  - reference: PMID:30612599
    reference_title: Recessive mutation in CD2AP causes focal segmental glomerulosclerosis in humans and mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure.
    explanation: The allele-matched mouse model that makes the human association causal rather than correlative.
- name: CD2AP heterozygous variants
  association: Single-allele-ablating CD2AP variants reported in idiopathic FSGS; effect uncertain
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CD2AP
    term:
      id: hgnc:14258
      label: CD2AP
  inheritance:
  - name: Autosomal dominant
  notes: >-
    Separate from the recessive record above, and much weaker. The heterozygous
    claim rests on single-allele-ablating variants found in 2 of 30
    African-American patients with idiopathic FSGS, and the accompanying Lancet
    commentary states plainly that the association could be accidental. ClinGen
    grades CD2AP against inherited FSGS (MONDO:0005363) as only Moderate with
    autosomal dominant inheritance, against Definitive for the recessive
    relationship, read from the same 2026-09-25 download. Against the
    heterozygous claim, both parents of the homozygous patient described in
    PMID:17713465 carried the truncating allele with normal glomerular filtration
    and no proteinuria. Cd2ap heterozygous mice do develop FSGS-like lesions, so
    the species disagree here and the human dominant effect is unresolved rather
    than excluded.
  evidence:
  - reference: PMID:14643126
    reference_title: CD2-associated protein and glomerular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      These researchers found that 2 of 30 African-American patients with idiopathic focal segmental glomerulosclerosis had a CD2AP mutation that ablated expression of one allele.
    explanation: The human genetic evidence for the heterozygous claim; this commentary restates the
      primary report rather than producing the finding.
  - reference: PMID:14643126
    reference_title: CD2-associated protein and glomerular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Further studies should address the normal distribution of the CD2AP heterozygous mutation in different ethnic populations, because the association with human idiopathic focal segmental glomerulosclerosis could be accidental.
    explanation: The commentary's own caution about the heterozygous association, which is why this record is
      SUSCEPTIBILITY rather than CAUSATIVE.
  - reference: PMID:17713465
    reference_title: Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous expression of the CD2AP mutation in both parents did not lead to any kidney pathology, as both have normal glomerular filtration rates and no proteinuria.
    explanation: >-
      Argues against a dominant effect for at least this truncating allele - two obligate
      carriers were unaffected, which is the observation that separates this record from the
      recessive one.
references:
- reference: DOI:10.1016/j.ekir.2022.10.004
  title: 'Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis'
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: 'Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis'
    supporting_text: 'Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis'
- reference: DOI:10.1016/j.ekir.2023.07.022
  title: 'Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial'
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: 'Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial'
    supporting_text: 'Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial'
- reference: DOI:10.1016/j.xkme.2023.100760
  title: 'Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden'
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: 'Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden'
    supporting_text: 'Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden'
- reference: DOI:10.1016/j.xkme.2024.100833
  title: 'Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety'
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: 'Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety'
    supporting_text: 'Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety'
- reference: DOI:10.1080/0886022x.2025.2465810
  title: The role of endothelin receptor antagonists in kidney disease
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: The role of endothelin receptor antagonists in kidney disease
    supporting_text: The role of endothelin receptor antagonists in kidney disease
- reference: DOI:10.1093/ndt/gfae025
  title: 'Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group'
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: 'Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group'
    supporting_text: The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies.
    evidence:
    - reference: DOI:10.1093/ndt/gfae025
      reference_title: 'Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies.
      explanation: Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
- reference: DOI:10.23876/j.krcp.23.227
  title: Precision medicine for focal segmental glomerulosclerosis
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: Focal segmental glomerulosclerosis (FSGS) is one of the common causes of nephrotic syndrome in adults and children worldwide.
    supporting_text: Focal segmental glomerulosclerosis (FSGS) is one of the common causes of nephrotic syndrome in adults and children worldwide.
    evidence:
    - reference: DOI:10.23876/j.krcp.23.227
      reference_title: Precision medicine for focal segmental glomerulosclerosis
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Focal segmental glomerulosclerosis (FSGS) is one of the common causes of nephrotic syndrome in adults and children worldwide.
      explanation: Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
- reference: DOI:10.3389/fimmu.2023.1247606
  title: Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated.
    supporting_text: The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated.
    evidence:
    - reference: DOI:10.3389/fimmu.2023.1247606
      reference_title: Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated.
      explanation: Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
- reference: DOI:10.3390/jcm13206056
  title: 'Endothelin Inhibitors in Chronic Kidney Disease: New Treatment Prospects'
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease.
    supporting_text: The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease.
    evidence:
    - reference: DOI:10.3390/jcm13206056
      reference_title: 'Endothelin Inhibitors in Chronic Kidney Disease: New Treatment Prospects'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease.
      explanation: Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
- reference: DOI:10.1186/s12882-024-03713-9
  title: 'Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials'
  found_in:
  - Focal_Segmental_Glomerulosclerosis-deep-research-falcon.md
  findings:
  - statement: 'Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials'
    supporting_text: 'Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials'
    evidence:
    - reference: DOI:10.1186/s12882-024-03713-9
      reference_title: 'Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials'
      explanation: Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
- reference: PMID:34436835
  title: Genetic Steroid-Resistant Nephrotic Syndrome Overview.
  tags:
  - GeneReviews
- reference: PMID:21756023
  title: MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
- reference: PMID:24676634
  title: Mutations in PAX2 associate with adult-onset FSGS.
- reference: PMID:24676636
  title: Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS.
- reference: PMID:25557779
  title: Defects of CRB2 cause steroid-resistant nephrotic syndrome.
- reference: PMID:21997394
  title: APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.
- reference: PMID:38227370
  title: APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.
- reference: PMID:14643126
  title: CD2-associated protein and glomerular disease.
datasets:
- accession: geo:GSE213030
  title: 'Tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis: a model for precision nephrology'
  description: Reporter genes for TNF activation have not been studied in nephrotic syndrome cases at the single nuclear RNA-seq level. Use of archived kidney biopsy material that was fragmented into individual nuclei and assayed for presence of genes involved in TNF activation in patients predicted to have high or low expression of these genes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 10
  publication: PMID:36442540
  notes: Identified by GEO DataSets index search for Focal Segmental Glomerulosclerosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE212610
  title: Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis
  description: Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 9
  publication: PMID:36159820
  notes: Identified by GEO DataSets index search for Focal Segmental Glomerulosclerosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: massive:MSV000097297
  title: Pathogenesis of focal segmental glomerulosclerosis and minimal change disease
  description: Podocyte injury is the hallmark of both focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) and is ultimately reflected in foot process effacement proteinuria. Triggers and pathogenic pathways leading to podocyte cytoskeleton rearrangements are however incompletely explained. Here, we aimed to contribute to the understanding of these pathways using tissue bottom-up proteomic profiling of laser capture micro dissected glomeruli from MCD and FSGS.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Focal Segmental Glomerulosclerosis"). Retrieved 2026-08-02.
notes: >-
  The `has_subtypes` list deliberately carries two axes, as the ADCA-I entry does.
  The first five rows are the clinicopathologic and etiologic classification
  (primary, secondary, genetic, collapsing, tip lesion) that clinical practice
  uses; the seven FSGS1-FSGS9 rows are the gene-defined members of MONDO's
  numbered series, and the Genetic FSGS row lists them as `children` so the
  relationship between the two axes is explicit rather than implied.

  MONDO's numbered series is not subtree-complete under this entry's term, and
  that is the main finding of the 2026-09-25 descendant enumeration. An OLS4 query
  for hierarchical descendants of MONDO:0100313 returns ten terms: the seven
  numbered FSGS concepts curated above, plus inherited focal segmental
  glomerulosclerosis (MONDO:0005363), primary focal segmental glomerulosclerosis
  (MONDO:0100324) and HIV-associated nephropathy (MONDO:0005798). The numbered
  terms all hang off MONDO:0005363 rather than off the root, which is why a
  root-keyed comparison can miss them. FSGS3 (CD2AP, MONDO:0011917) and FSGS4
  (APOL1, MONDO:0012931) are absent from that descendant set altogether: MONDO
  files both under inherited disease susceptibility (MONDO:0020573) with a
  `predisposes towards` relation to inherited FSGS. Both are recorded in
  `mappings.mondo_mappings` as related matches and their genes are curated in the
  `genetic` section with SUSCEPTIBILITY and RISK_FACTOR relationships, not as
  subtype rows. MONDO's placement and dismech's judgement agree here.

  HIV-associated nephropathy (MONDO:0005798) is a descendant of MONDO:0005363 in
  MONDO but is not given a subtype row: it is a viral nephropathy with its own
  aetiology, the acquired and collapsing patterns are already covered by the
  Secondary FSGS and Collapsing FSGS rows, and it has no causal gene edge of its
  own. MONDO classifying an infectious nephropathy as a form of *inherited*
  FSGS is a candidate upstream report.

  Claims left to the entries that own them: the papillorenal (renal-coloboma)
  phenotype of PAX2 is curated in Renal_Coloboma_Syndrome; the INF2 phenotype
  combining FSGS with Charcot-Marie-Tooth neuropathy is a separate MONDO concept
  (MONDO:0013758) and ClinGen curates INF2 as Definitive against that, not against
  FSGS; the NPHS1 and PLCE1 congenital and type-3 nephrotic syndromes, the COL4A3,
  COL4A4 and COL4A5 Alport phenotypes, the LMX1B nail-patella phenotype and the
  WT1 Denys-Drash phenotype all have their own entries or MONDO concepts and are
  not curated as FSGS subtypes here, even though several of them can show an FSGS
  lesion.

  ClinGen's Glomerulopathy Gene Curation Expert Panel has curated far fewer of
  these genes than the literature covers. Against the root term MONDO:0100313 it
  records only FAT1 (Strong) and SYNPO (Limited); against the numbered concepts it
  records PAX2-FSGS7, CRB2-FSGS9, CD2AP-FSGS3 and APOL1-FSGS4 as Definitive and
  CD2AP-inherited FSGS as Moderate. It has no assertion for ACTN4, TRPC6, MYO1E or
  ANLN against any FSGS concept, so the causal claims for those four rest on the
  cited primary literature. Read from the ClinGen Gene-Disease Validity download of
  2026-09-25.

  FAT1 and SYNPO are the two curated genes that reach no pathophysiology node.
  Their only evidence on this entry is the ClinGen validity row, which states the
  classification but not a mechanism, so wiring them would need literature this
  pass did not cover.
📚

References & Deep Research

References

18
DOI:10.1016/j.ekir.2022.10.004
Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis
1 finding
Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis
"Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis"
DOI:10.1016/j.ekir.2023.07.022
Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial
1 finding
Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial
"Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial"
DOI:10.1016/j.xkme.2023.100760
Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden
1 finding
Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden
"Kidney Failure Attributed to Focal Segmental Glomerulosclerosis: A USRDS Retrospective Cohort Study of Epidemiology, Treatment Modalities, and Economic Burden"
DOI:10.1016/j.xkme.2024.100833
Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety
1 finding
Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety
"Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety"
DOI:10.1080/0886022x.2025.2465810
The role of endothelin receptor antagonists in kidney disease
1 finding
The role of endothelin receptor antagonists in kidney disease
"The role of endothelin receptor antagonists in kidney disease"
DOI:10.1093/ndt/gfae025
Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group
1 finding
Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group
"The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies."
Show evidence (1 reference)
DOI:10.1093/ndt/gfae025 SUPPORT Other
"The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies."
Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
DOI:10.23876/j.krcp.23.227
Precision medicine for focal segmental glomerulosclerosis
1 finding
Focal segmental glomerulosclerosis (FSGS) is one of the common causes of nephrotic syndrome in adults and children worldwide.
"Focal segmental glomerulosclerosis (FSGS) is one of the common causes of nephrotic syndrome in adults and children worldwide."
Show evidence (1 reference)
DOI:10.23876/j.krcp.23.227 SUPPORT Human Clinical
"Focal segmental glomerulosclerosis (FSGS) is one of the common causes of nephrotic syndrome in adults and children worldwide."
Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
DOI:10.3389/fimmu.2023.1247606
Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis
1 finding
The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated.
"The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated."
Show evidence (1 reference)
DOI:10.3389/fimmu.2023.1247606 SUPPORT Human Clinical
"The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated."
Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
DOI:10.3390/jcm13206056
Endothelin Inhibitors in Chronic Kidney Disease: New Treatment Prospects
1 finding
The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease.
"The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease."
Show evidence (1 reference)
DOI:10.3390/jcm13206056 SUPPORT Human Clinical
"The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease."
Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
DOI:10.1186/s12882-024-03713-9
Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials
1 finding
Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials
"Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials"
Show evidence (1 reference)
DOI:10.1186/s12882-024-03713-9 SUPPORT Human Clinical
"Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and IgA nephropathy: a systematic review and meta-analysis of randomized controlled trials"
Deep research cited this publication as relevant literature for Focal Segmental Glomerulosclerosis.
PMID:34436835
Genetic Steroid-Resistant Nephrotic Syndrome Overview.
No top-level findings curated for this source.
PMID:21756023
MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
No top-level findings curated for this source.
PMID:24676634
Mutations in PAX2 associate with adult-onset FSGS.
No top-level findings curated for this source.
PMID:24676636
Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS.
No top-level findings curated for this source.
PMID:25557779
Defects of CRB2 cause steroid-resistant nephrotic syndrome.
No top-level findings curated for this source.
PMID:21997394
APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.
No top-level findings curated for this source.
PMID:38227370
APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.
No top-level findings curated for this source.
PMID:14643126
CD2-associated protein and glomerular disease.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸
1. Disease Information
Edison Scientific Literature 34 citations 2026-05-08T16:18:46.146625

1. Disease Information

1.1 Definition and overview

  • Definition (current understanding): FSGS is a histologic pattern of injury characterized by focal (some glomeruli) and segmental (part of the glomerular tuft) sclerosis, typically accompanied by variable podocyte foot process effacement on electron microscopy, reflecting injury and loss of podocytes (cos2023noveltreatmentparadigms pages 1-2, salfi2023currentunderstandingof pages 1-2).
  • Why classification matters: Because many different causal pathways produce the same lesion pattern, FSGS is clinically approached as a heterogeneous syndrome requiring etiology stratification (cos2023noveltreatmentparadigms pages 1-2, mirioglu2024managementofadult pages 2-3).

1.2 Disease identifiers and ontology mapping

  • MONDO (available from retrieved evidence):
  • “Inherited focal segmental glomerulosclerosis” MONDO_0005363 (OpenTargets Search: Focal segmental glomerulosclerosis)
  • Example inherited subtype entities returned by Open Targets include “FSGS 1” MONDO_0011303 (OpenTargets Search: Focal segmental glomerulosclerosis)
  • Open Targets disease ID: FSGS is indexed as EFO_0004236 in Open Targets output (OpenTargets Search: Focal segmental glomerulosclerosis).

Gap note (knowledge-base readiness): ICD-10/ICD-11, MeSH, Orphanet, and OMIM cross-references were not present in the retrieved texts and therefore cannot be asserted here without additional ontology lookups.

1.3 Synonyms / alternative names

  • “Focal segmental glomerulosclerosis” (FSGS) is often used interchangeably with its lesion description; in practice, it is frequently discussed under the umbrella of “podocytopathies” with minimal change disease (MCD) (mirioglu2024managementofadult pages 2-3, salfi2023currentunderstandingof pages 1-2).

1.4 Source type of information

  • The evidence synthesized here is primarily from aggregated disease-level resources (peer-reviewed reviews, registry-based cohorts, meta-analyses, and trial registries) rather than individual EHR case series (bensink2024kidneyfailureattributed pages 1-2, elnaga2024safetyandefficacy pages 1-2, mirioglu2024managementofadult pages 2-3).

2. Etiology

2.1 Primary causes (etiologic categories)

Recent reviews explicitly recommend an etiology-based framework: - Primary FSGS: typically conceptualized as immune-mediated and/or driven by circulating permeability factors, presenting with abrupt nephrotic syndrome and diffuse foot process effacement (cos2023noveltreatmentparadigms pages 1-2, salfi2023currentunderstandingof pages 1-2). - Genetic FSGS: monogenic podocyte/GBM disorders with variable presentations; often steroid-resistant (cos2023noveltreatmentparadigms pages 1-2, salfi2023currentunderstandingof pages 4-5). - Secondary FSGS: maladaptive (e.g., hyperfiltration) or associated with drugs/infections; secondary forms may show glomerulomegaly in contexts such as obesity, reflux nephropathy, and low birth weight (cos2023noveltreatmentparadigms pages 1-2). - FSGS of undetermined cause (FSGS-UC): diagnosis when data are insufficient for classification; immunosuppression is discouraged in non-nephrotic presentations (mirioglu2024managementofadult pages 2-3).

The KDIGO-aligned classification and initial treatment branching are summarized visually in a figure from de Cos et al. (2023) (cos2023noveltreatmentparadigms media ecc573cd).

2.2 Risk factors

  • Demographic risk: higher incidence is reported in adult males and Black individuals in a 2023 immunology-focused review (salfi2023currentunderstandingof pages 1-2).
  • Progression risk factors (clinical): high-grade proteinuria, impaired kidney function, presence of FSGS lesions on biopsy, and interstitial fibrosis/tubular atrophy are associated with progression (mirioglu2024managementofadult pages 2-3).

2.3 Protective factors

  • No specific genetic or environmental protective factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

  • The retrieved evidence strongly supports ancestry-linked genetic risk for APOL1 (see Genetics), but does not provide a mechanistically explicit gene–environment interaction model for FSGS beyond this population/ancestry association.

3. Phenotypes

3.1 Core clinical phenotypes and diagnostic features

Common phenotype cluster (nephrotic syndrome spectrum): - Proteinuria / nephrotic-range proteinuria and nephrotic syndrome are central clinical manifestations; primary FSGS often presents with abrupt marked proteinuria and overt nephrotic syndrome (cos2023noveltreatmentparadigms pages 1-2, salfi2023currentunderstandingof pages 1-2). - FSGS exhibits the lowest glucocorticoid response among idiopathic nephrotic syndrome forms; steroid resistance is commonly reported (salfi2023currentunderstandingof pages 1-2).

Biopsy and pathology phenotypes: - Light microscopy: focal/segmental glomerular scarring is required for diagnosis (cos2023noveltreatmentparadigms pages 1-2, bensink2024kidneyfailureattributed pages 1-2). - Electron microscopy: foot process effacement (FPE) extent helps distinguish etiologies; one study summarized in a 2024 ERA working group review reported primary FSGS had FPE >80%, whereas genetic/maladaptive forms had no cases with FPE >50% (mirioglu2024managementofadult pages 2-3). - Immunofluorescence: may show non-specific IgM/C3 staining in sclerotic areas (mirioglu2024managementofadult pages 2-3).

3.2 Phenotype characteristics (onset, severity, progression)

  • Course is often chronic and progressive in non-remitting disease; in adult FSGS cohorts, “Over half of the patients with nephrotic-range proteinuria progress to ESKD” (mirioglu2024managementofadult pages 2-3).

3.3 Frequencies / statistics (recent)

  • Steroid resistance in FSGS: reported 26–80% across studies (salfi2023currentunderstandingof pages 1-2); ERA review summarizes steroid resistance in FSGS as 40–60% (mirioglu2024managementofadult pages 2-3).
  • Remission/relapse: ERA review summarizes 47–66% remission and 25–36% relapse among those who remit (mirioglu2024managementofadult pages 2-3).

3.4 Suggested HPO terms (non-exhaustive, evidence-aligned)

(These are ontology suggestions; exact IDs should be validated against HPO.) - Nephrotic syndrome (cos2023noveltreatmentparadigms pages 1-2) - Proteinuria / Nephrotic-range proteinuria (cos2023noveltreatmentparadigms pages 1-2) - Podocyte foot process effacement (cos2023noveltreatmentparadigms pages 1-2, mirioglu2024managementofadult pages 2-3) - Segmental glomerulosclerosis (cos2023noveltreatmentparadigms pages 1-2, bensink2024kidneyfailureattributed pages 1-2) - Glomerulomegaly (secondary forms) (cos2023noveltreatmentparadigms pages 1-2) - Steroid resistance (cos2023noveltreatmentparadigms pages 1-2, salfi2023currentunderstandingof pages 1-2) - Progression to end-stage kidney disease (ESKD) (mirioglu2024managementofadult pages 2-3)

3.5 Quality of life impact

  • Direct quality-of-life instrument results (e.g., SF-36, EQ-5D) were not present in retrieved evidence.

4. Genetic / Molecular Information

4.1 Causal genes and genetic architecture

  • Multiple recent sources emphasize genetic heterogeneity:
  • “Over 50 genes are currently known to be involved in FSGS” (xie2024precisionmedicinefor pages 1-3).
  • Monogenic causes account for roughly 20–30% of SRNS/FSGS, with detection decreasing with older age of onset; adult genetic diagnosis rates of ~11–21.3% are summarized in the 2023 review (salfi2023currentunderstandingof pages 4-5).
  • A 2024 precision-medicine review reports WES detection of pathogenic variants in 26.2% of 187 SRNS patients (xie2024precisionmedicinefor pages 1-3).

Key genes highlighted (examples): - AR/early-onset genes: NPHS1, NPHS2, PLCE1, TTC21B (xie2024precisionmedicinefor pages 1-3). - Additional genes frequently observed in cohorts: WT1, NPHS1/NPHS2 (PodoNet); adult genetic FSGS includes COL4A3–5 (reported as most common single-gene pathogenic mutation) and INF2 (xie2024precisionmedicinefor pages 1-3). - The immunology-focused 2023 review enumerates important adult/familial genes including INF2, ACTN4, TRPC6, PAX2, and core nephrotic syndrome genes NPHS1/NPHS2/WT1 (salfi2023currentunderstandingof pages 4-5).

4.2 Population differences and APOL1

  • APOL1 risk variants in people with recent African ancestry are repeatedly highlighted as major contributors to susceptibility and epidemiology (salfi2023currentunderstandingof pages 4-5).

4.3 Open Targets disease–gene associations (translation-focused)

Open Targets returned high-confidence FSGS associations for multiple genes, including APOL1, TRPC6, INF2, ACTN4, NPHS1, NPHS2, PAX2, CD2AP, MYO1E, CRB2, ANLN, LMX1B, with supporting evidence rows including genetics and curated sources (OpenTargets Search: Focal segmental glomerulosclerosis).

4.4 Variant-level details

  • Specific pathogenic variant nomenclature and allele frequencies (gnomAD/ExAC) were not present in retrieved evidence and therefore are not asserted here.

4.5 Modifier genes, epigenetics, chromosomal abnormalities

  • Not available in the retrieved evidence.

5. Environmental Information

  • Secondary FSGS mechanisms include maladaptive states (e.g., obesity-related hyperfiltration) and secondary causes such as low birth weight and reflux nephropathy-associated glomerulomegaly (cos2023noveltreatmentparadigms pages 1-2).
  • Specific toxin/occupational risk factors and explicit infectious triggers were not detailed in the retrieved 2023–2024 evidence excerpts.

6. Mechanism / Pathophysiology

6.1 Causal chain (high-level)

A consistent mechanistic chain across reviews is: 1) Upstream trigger (immune/circulating factor, genetic defect, maladaptive hyperfiltration, etc.) → 2) Podocyte injury and foot process effacement → 3) Proteinuria → 4) Podocyte depletion and progressive scarring → 5) Declining GFR and potential progression to ESKD (salfi2023currentunderstandingof pages 1-2, cos2023noveltreatmentparadigms pages 1-2).

6.2 Immune involvement and circulating factors (primary FSGS)

  • The 2023 review states “a growing body of evidence emphasizes the pivotal role of the immune system” and notes that T cells, B cells, and complement have been implicated as crucial actors, with various molecules proposed as “circulating factors” contributing to disease and post-transplant recurrence (salfi2023currentunderstandingof pages 1-2).

6.3 Suggested ontology terms (for knowledge-base annotation)

Cell types (CL suggestions): - Podocyte (inferred central cell type) (cos2023noveltreatmentparadigms pages 1-2, salfi2023currentunderstandingof pages 1-2)

Biological process (GO suggestions): - Podocyte differentiation/maintenance; regulation of glomerular filtration; actin cytoskeleton organization; regulation of cell–substrate adhesion; inflammatory response; extracellular matrix organization; fibrotic process (mechanistic categories supported broadly by the reviews emphasizing podocyte injury and inflammation/fibrosis in FSGS) (salfi2023currentunderstandingof pages 1-2).

Anatomy (UBERON suggestions): - Kidney; glomerulus; renal corpuscle; podocyte; glomerular basement membrane (cos2023noveltreatmentparadigms pages 1-2, salfi2023currentunderstandingof pages 1-2).

7. Anatomical Structures Affected

  • Primary organ: kidney, specifically the glomerulus with podocyte injury and segmental glomerular scarring (cos2023noveltreatmentparadigms pages 1-2, bensink2024kidneyfailureattributed pages 1-2).
  • The 2024 ERA update emphasizes tubulointerstitial fibrosis/tubular atrophy as prognostically relevant (mirioglu2024managementofadult pages 2-3).

8. Temporal Development

  • Presentation may be abrupt in primary FSGS with sudden nephrotic syndrome (cos2023noveltreatmentparadigms pages 1-2).
  • Progression: in patients with nephrotic-range proteinuria, “Over half… progress to ESKD” (mirioglu2024managementofadult pages 2-3).
  • For kidney failure attributed to FSGS in USRDS, downstream kidney replacement pathways show prolonged morbidity (dialysis, transplant) (bensink2024kidneyfailureattributed pages 1-2).

9. Inheritance and Population

9.1 Epidemiology (recent statistics)

  • Pediatric vs adult nephrotic syndrome: FSGS ~20% in children and 40% in adults (salfi2023currentunderstandingof pages 1-2).
  • Incidence (review-level estimate): 0.2–2.5 per 100,000/year (salfi2023currentunderstandingof pages 1-2).
  • USRDS kidney failure attributable to FSGS (2008–2018): mean annual prevalence 87.6/million and incidence 7.5/million, with prevalence increasing from 76.5/million (2008) to 96.0/million (2018) (bensink2024kidneyfailureattributed pages 2-3).
  • Demographic disparities in USRDS: highest prevalence in Native Hawaiian/Pacific Islander 262.9/million and Black/African American 256.3/million, and higher in males vs females (bensink2024kidneyfailureattributed pages 2-3).

9.2 Inheritance patterns

  • Autosomal recessive early-onset forms (NPHS1/NPHS2/PLCE1/TTC21B) and autosomal dominant later-onset forms (COL4A3–5, INF2) are emphasized in the 2024 precision-medicine review (xie2024precisionmedicinefor pages 1-3).

10. Diagnostics

10.1 Clinical testing and biopsy

  • Kidney biopsy remains foundational and is central to classification/prognosis in contemporary reviews (salfi2023currentunderstandingof pages 1-2, mirioglu2024managementofadult pages 2-3).
  • The Columbia histologic lesion patterns do not reliably discriminate etiologies; therefore, clinical context + EM + genetics are required (mirioglu2024managementofadult pages 2-3).

10.2 Electron microscopy criterion supporting etiology

  • Extent of FPE supports classification: >80% FPE supports primary FSGS, while <50% FPE is more typical for genetic/maladaptive forms (mirioglu2024managementofadult pages 2-3).

10.3 Genetic testing strategy

  • Genetic testing is recommended when early onset, family history, extrarenal features, consanguinity, or early progression suggest a monogenic disorder; and in steroid-resistant presentations (mirioglu2024managementofadult pages 2-3, salfi2023currentunderstandingof pages 4-5).

10.4 Differential diagnosis

  • FSGS is frequently considered along a spectrum with minimal change disease in idiopathic nephrotic syndrome; biopsy and response patterns help distinguish (salfi2023currentunderstandingof pages 1-2, mirioglu2024managementofadult pages 2-3).

11. Outcome / Prognosis

  • Registry and review estimates converge on high progression risk:
  • “Over half of the patients with nephrotic-range proteinuria progress to ESKD” (mirioglu2024managementofadult pages 2-3).
  • In USRDS kidney failure attributable to FSGS, 7-year kidney survival is reported as 69% (bensink2024kidneyfailureattributed pages 2-3).
  • Response to therapy is prognostic: remission/relapse rates and steroid resistance rates are summarized in Section 3 (mirioglu2024managementofadult pages 2-3, salfi2023currentunderstandingof pages 1-2).

12. Treatment

A structured treatment summary (with MAXO and NCT mapping) is provided in the artifact table below.

Therapy/Approach MAXO term suggestion Indication/Patient subgroup Key evidence and quantitative outcomes Key trial IDs (NCT) Source (author year) URL Evidence type
Supportive care: RAAS blockade, blood-pressure control, salt restriction MAXO: angiotensin receptor antagonist treatment; angiotensin-converting enzyme inhibitor treatment; blood pressure control; dietary sodium restriction All FSGS categories as baseline care; especially supportive strategy for secondary and genetic FSGS KDIGO-aligned supportive care includes RAAS blockade, BP control, and salt restriction; de Cos notes these as core background therapy for FSGS. Figure-based treatment algorithm shows RAAS blockade first, with etiology-specific escalation. No quantitative effect size for FSGS-specific remission provided in the gathered excerpt (cos2023noveltreatmentparadigms pages 1-2, cos2023noveltreatmentparadigms media ecc573cd) — de Cos 2023 https://doi.org/10.1016/j.ekir.2022.10.004 Review/guideline summary
SGLT2 inhibitors as adjunct supportive therapy MAXO: sodium-glucose cotransporter 2 inhibitor treatment Proteinuric FSGS as adjunct supportive care; not established as disease-specific immunologic therapy Discussed as supportive option in FSGS; de Cos reports dapagliflozin showed non-significant benefit in the FSGS substudy. Endothelin-review notes concomitant SGLT2i may help optimize ERA safety, but no definitive FSGS-specific efficacy estimate is given in the extracted text (cos2023noveltreatmentparadigms pages 1-2, ma2025theroleof pages 8-9) NCT02585804 (dapagliflozin trial listed in ClinicalTrials.gov search) (OpenTargets Search: Focal segmental glomerulosclerosis) de Cos 2023; ClinicalTrials.gov search https://doi.org/10.1016/j.ekir.2022.10.004 Review; trial registry
High-dose glucocorticoids MAXO: corticosteroid treatment Presumed primary FSGS with nephrotic syndrome; first-line for immune-mediated/primary disease KDIGO-referenced first-line therapy for primary FSGS. Mirioglu reports FSGS remission in 47–66% with 25–36% relapse and steroid resistance in 40–60%; Salfi reports steroid resistance across studies in 26–80%. Not recommended for non-nephrotic FSGS-UC/secondary forms (mirioglu2024managementofadult pages 2-3, salfi2023currentunderstandingof pages 1-2) — Mirioglu 2024; Salfi 2023 https://doi.org/10.1093/ndt/gfae025; https://doi.org/10.3389/fimmu.2023.1247606 Review/guideline update
Calcineurin inhibitors (cyclosporine, tacrolimus) MAXO: calcineurin inhibitor treatment Steroid-resistant primary FSGS; steroid-intolerant patients; generally not for clear genetic/secondary disease unless another indication Salfi states evidence most strongly supports CNIs for steroid-resistant primary FSGS for at least 6 months. de Cos lists CNIs as KDIGO-recommended for steroid-resistant or steroid-intolerant primary disease. No pooled remission percentage for CNIs alone was extracted from the gathered text (salfi2023currentunderstandingof pages 1-2, cos2023noveltreatmentparadigms pages 1-2) — Salfi 2023; de Cos 2023 https://doi.org/10.3389/fimmu.2023.1247606; https://doi.org/10.1016/j.ekir.2022.10.004 Review/guideline summary
Sparsentan vs irbesartan (pooled RCT evidence) MAXO: endothelin receptor antagonist treatment; angiotensin II receptor antagonist treatment Proteinuric FSGS, including primary FSGS populations enrolled in DUET/DUPLEX Meta-analysis of randomized trials: greater UP/C reduction with sparsentan (ratio of percentage reduction 0.66, 95% CI 0.58–0.74, P<0.001); complete remission RR 2.57 (95% CI 1.73–3.81); partial remission RR 1.63 (95% CI 1.40–1.91); no significant eGFR difference (MD 1.98 mL/min/1.73 m2, 95% CI -1.05 to 5.01); hypotension increased (RR 2.02, 95% CI 1.30–3.16) (elnaga2024safetyandefficacy pages 1-2) NCT01613118; NCT03493685 (OpenTargets Search: Focal segmental glomerulosclerosis) Elnaga 2024 https://doi.org/10.1186/s12882-024-03713-9 Meta-analysis
Sparsentan DUET phase 2 + open-label extension MAXO: proteinuria-reducing therapy; endothelin receptor antagonist treatment; angiotensin II receptor antagonist treatment FSGS with UP/C ≥1.0 g/g and eGFR >30 mL/min/1.73 m2; long-term treatment follow-up DUET/OLE analysis: 108 patients received sparsentan; median follow-up 47.0 months; 46/108 (43%) achieved at least one complete remission (UP/C ≤0.3 g/g), and 61% of complete remissions occurred within 12 months. OLE report: 52.8% achieved FSGS partial remission within 9 months; remission associated with slower eGFR decline vs nonresponders (overall slope -2.70 vs -6.56 mL/min/1.73 m2/year, P=0.03; first 2 years -1.69 vs -6.46, P=0.03). Common TEAEs included headache, peripheral edema, URI, hyperkalemia, hypotension; no heart failure events or deaths reported (trachtman2023implicationsofcomplete pages 1-2, campbell2024sparsentanforfocal pages 1-2) NCT01613118 (OpenTargets Search: Focal segmental glomerulosclerosis) Trachtman 2023; Campbell 2024 https://doi.org/10.1016/j.ekir.2023.07.022; https://doi.org/10.1016/j.xkme.2024.100833 Phase 2 RCT extension / open-label follow-up
Sparsentan DUPLEX phase 3 MAXO: endothelin receptor antagonist treatment; angiotensin II receptor antagonist treatment Primary FSGS / proteinuric FSGS enrolled in pivotal phase 3 study Extracted review summary reports DUPLEX randomized sparsentan 800 mg vs irbesartan 300 mg over 108 weeks in 371 participants; partial remission endpoint favored sparsentan (UPCR ≤1.5 g/g and >40% reduction; p=0.0094). Review/meta-analysis materials note strong antiproteinuric effect; detailed AE frequencies not fully extracted from the gathered snippet (rakotoarison2024endothelininhibitorsin pages 8-9, ma2025theroleof pages 8-9) NCT03493685 (OpenTargets Search: Focal segmental glomerulosclerosis) Rakotoarison 2024; Ma 2025 review of trial https://doi.org/10.3390/jcm13206056; https://doi.org/10.1080/0886022x.2025.2465810 Phase 3 RCT summary / review
Immunosuppression avoidance in non-primary disease MAXO: avoidance of immunosuppressive therapy; supportive care FSGS of undetermined cause without nephrotic syndrome, and many genetic/secondary forms ERA Immunonephrology review emphasizes unmet need to identify who should receive immunosuppression vs supportive care; immunosuppression is generally reserved for presumed primary FSGS, and patients with FSGS-UC without nephrotic syndrome should not receive immunosuppression (mirioglu2024managementofadult pages 2-3) — Mirioglu 2024 https://doi.org/10.1093/ndt/gfae025 Review/guideline update
Genetic testing / precision medicine MAXO: genetic testing; precision medicine approach Suspected monogenic FSGS, steroid-resistant disease, unclear etiology, biopsy-contraindicated/high-risk settings de Cos and Mirioglu recommend integrating genetic testing into diagnosis/classification; genetic testing is especially recommended when steroid resistance suggests a genetic form. Precision-medicine review highlights clinical significance of next-generation sequencing and biomarker-guided stratification to avoid unnecessary immunosuppression, but no diagnostic yield percentage was present in extracted snippets (mirioglu2024managementofadult pages 2-3, salfi2023currentunderstandingof pages 1-2, cos2023noveltreatmentparadigms pages 1-2) — Mirioglu 2024; Salfi 2023; de Cos 2023 https://doi.org/10.1093/ndt/gfae025; https://doi.org/10.3389/fimmu.2023.1247606; https://doi.org/10.1016/j.ekir.2022.10.004 Review / precision-medicine framework
Rituximab / other targeted or adjunct therapies under study MAXO: anti-CD20 monoclonal antibody treatment; B-cell depletion therapy Selected relapsing/refractory podocytopathies; role in primary FSGS remains less established than in MCD Mirioglu notes rituximab is highlighted particularly for MCD and discusses ongoing trials in podocytopathies; clinical trial registry search identified FSGS-focused rituximab and abatacept studies, but gathered evidence did not provide robust 2023–2024 quantitative efficacy estimates for routine FSGS use (mirioglu2024managementofadult pages 2-3, OpenTargets Search: Focal segmental glomerulosclerosis) NCT00550342; NCT01573533; NCT00981838; NCT04369183; NCT02592798 (OpenTargets Search: Focal segmental glomerulosclerosis) Mirioglu 2024; ClinicalTrials.gov search https://doi.org/10.1093/ndt/gfae025 Review; trial registry
Real-world implementation / care burden in kidney failure attributed to FSGS MAXO: kidney replacement therapy; kidney transplantation; hemodialysis Advanced FSGS progressing to kidney failure USRDS cohort: 72.1% initiated in-center hemodialysis; 7.3% had an initial transplant; transplant rates were 15% at 1 year and 34% at 5 years; about one-third died during follow-up. These data reflect real-world downstream management burden rather than disease-modifying therapy efficacy (bensink2024kidneyfailureattributed pages 1-2) — Bensink 2024 https://doi.org/10.1016/j.xkme.2023.100760 Registry/observational

Table: This table summarizes current FSGS treatment approaches, emphasizing 2023-2024 evidence, patient subgroups, quantitative outcomes, and implementation details. It is useful for mapping supportive care, immunosuppression, sparsentan trial data, and precision-medicine strategies to a knowledge base.

12.1 Sparsentan (dual endothelin–angiotensin receptor antagonist)

  • Efficacy (2024 meta-analysis): sparsentan improved proteinuria compared with irbesartan (ratio of percentage reduction 0.66, 95% CI 0.58–0.74) and increased complete and partial remission probabilities (CR RR 2.57; PR RR 1.63). Kidney function effects were not significantly different in pooled eGFR change (MD 1.98 mL/min/1.73m², P=0.20), and hypotension was more frequent (RR 2.02) (elnaga2024safetyandefficacy pages 1-2).
  • Long-term extension (DUET OLE): partial remission achieved by 52.8% within 9 months, with slower eGFR decline in responders (overall slope −2.70 vs −6.56 mL/min/1.73m²/year; P=0.03) and no heart failure events or deaths reported (campbell2024sparsentanforfocal pages 1-2).

12.2 Immunosuppression and supportive care selection

  • High-dose glucocorticoids are standard first-line for presumed primary FSGS, with CNIs for steroid-resistant or intolerant patients; immunosuppression is not recommended for FSGS-UC without nephrotic syndrome (cos2023noveltreatmentparadigms pages 1-2, mirioglu2024managementofadult pages 2-3).

12.3 Real-world implementation downstream

  • USRDS kidney failure attributable to FSGS: 72.1% started in-center hemodialysis; 7.3% had an initial transplant; transplant rates 15% at 1 year and 34% at 5 years (bensink2024kidneyfailureattributed pages 1-2).

13. Prevention

  • Primary prevention strategies are not well-defined for primary FSGS; secondary prevention focuses on early detection of proteinuria and implementation of renoprotective strategies (RAAS blockade, BP control). Specific guideline-grade prevention programs were not present in retrieved evidence.

14. Other Species / Natural Disease

  • Not available in the retrieved evidence.

15. Model Organisms

  • Specific model-organism details were not extracted from the 2023–2024 evidence presented here.

Key Epidemiology & Prognosis Snapshot (2023–2024)

The following table consolidates identifiers and key statistics (registry + recent reviews).

Category Data Source (first author year) PMID URL Evidence type
Identifiers/Synonyms FSGS = focal segmental glomerulosclerosis; described as a histologic pattern of glomerular injury / podocytopathy, not a single disease entity; classified into primary, genetic, secondary, and FSGS of undetermined cause (cos2023noveltreatmentparadigms pages 1-2, mirioglu2024managementofadult pages 2-3) de Cos 2023; Mirioglu 2024 https://doi.org/10.1016/j.ekir.2022.10.004; https://doi.org/10.1093/ndt/gfae025 Review
Identifiers/Synonyms Histologic lesion defined by segmental sclerosis in some glomeruli with variable podocyte foot-process effacement on EM; primary FSGS often presents with abrupt nephrotic syndrome (cos2023noveltreatmentparadigms pages 1-2) de Cos 2023 https://doi.org/10.1016/j.ekir.2022.10.004 Review
Epidemiology FSGS accounts for about 20% of nephrotic syndrome in children and 40% in adults; annual incidence estimated 0.2–2.5 per 100,000 (salfi2023currentunderstandingof pages 1-2) Salfi 2023 https://doi.org/10.3389/fimmu.2023.1247606 Review
Epidemiology In the USRDS 2008–2018 cohort, mean annual prevalence of FSGS-attributed kidney failure was 87.6 per 1,000,000 US persons and incidence was 7.5 per 1,000,000; prevalence rose from 76.5/million (2008) to 96.0/million (2018) (bensink2024kidneyfailureattributed pages 1-2, bensink2024kidneyfailureattributed pages 2-3) Bensink 2024 https://doi.org/10.1016/j.xkme.2023.100760 Registry/retrospective cohort
Epidemiology Historical U.S. incidence of FSGS (all disease, 2004–2013) reported as about 3.2 per 100,000 person-years, a 41% increase vs 1994–2003 (bensink2024kidneyfailureattributed pages 1-2) Bensink 2024 https://doi.org/10.1016/j.xkme.2023.100760 Registry/retrospective cohort
Progression/Prognosis “Over half of the patients with nephrotic-range proteinuria progress to ESKD” (mirioglu2024managementofadult pages 2-3) Mirioglu 2024 https://doi.org/10.1093/ndt/gfae025 Review
Progression/Prognosis FSGS remission rates: 47–66% remit; among those, 25–36% relapse; steroid resistance encountered in 40–60% of patients (mirioglu2024managementofadult pages 2-3) Mirioglu 2024 https://doi.org/10.1093/ndt/gfae025 Review
Progression/Prognosis Across studies, steroid resistance reported in 26–80% of patients; adults respond less favorably than children, and <50% of initially steroid-sensitive patients maintain stable remission (salfi2023currentunderstandingof pages 1-2) Salfi 2023 https://doi.org/10.3389/fimmu.2023.1247606 Review
Progression/Prognosis In USRDS, 7-year kidney survival for FSGS was 69% (vs 88% membranous nephropathy; 82% IgA nephropathy); >50% progress to kidney failure within 5–10 years (bensink2024kidneyfailureattributed pages 2-3) Bensink 2024 https://doi.org/10.1016/j.xkme.2023.100760 Registry/retrospective cohort
Transplant recurrence Small series: anti-nephrin antibodies identified in 11/14 (79%) patients with recurrence of primary FSGS after kidney transplantation (mirioglu2024managementofadult pages 2-3) Mirioglu 2024 https://doi.org/10.1093/ndt/gfae025 Review
Demographics Incidence/prevalence are higher in male adults and Black individuals (salfi2023currentunderstandingof pages 1-2) Salfi 2023 https://doi.org/10.3389/fimmu.2023.1247606 Review
Demographics USRDS prevalence lower in children <18 y: 31.4/million vs adults ≥18 y: 104.9/million; higher in males 108.0/million vs females 67.9/million (bensink2024kidneyfailureattributed pages 2-3) Bensink 2024 https://doi.org/10.1016/j.xkme.2023.100760 Registry/retrospective cohort
Demographics Highest prevalence of FSGS-attributed kidney failure in Native Hawaiian/Pacific Islander: 262.9/million and Black/African American: 256.3/million groups (bensink2024kidneyfailureattributed pages 2-3) Bensink 2024 https://doi.org/10.1016/j.xkme.2023.100760 Registry/retrospective cohort

Table: This table summarizes how recent 2023-2024 sources define and classify FSGS and compiles key epidemiology, prognosis, recurrence, and demographic statistics directly from the available evidence snippets.

Visual Evidence: Classification and Treatment Algorithm

A KDIGO-aligned classification and management flow is available as a figure from de Cos et al. 2023 (cos2023noveltreatmentparadigms media ecc573cd).

Direct abstract-supported statements (quotes)

The following direct statements come from abstracts of retrieved peer-reviewed papers: - “The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system…” (Frontiers in Immunology, 2023-09) (salfi2023currentunderstandingof pages 1-2). - “Kidney biopsy remains central to diagnosis…” in the ERA Immunonephrology Working Group update on podocytopathies (Nephrology Dialysis Transplantation, 2024-02) (mirioglu2024managementofadult pages 2-3). - In the sparsentan meta-analysis abstract: “Sparsentan was superior to irbesartan in improving urine protein to creatinine ratio…” and hypotension was higher (BMC Nephrology, 2024-09) (elnaga2024safetyandefficacy pages 1-2).

Limitations / Evidence Gaps for Knowledge Base Completion

  • ICD-10/ICD-11, MeSH, OMIM, and Orphanet identifiers were not available in retrieved texts; additional ontology lookups are needed.
  • Variant-level details (HGVS nomenclature, allele frequency in gnomAD), epigenetic mechanisms, and quality-of-life instrument results were not present in the retrieved evidence.
  • Environmental/toxin and infectious triggers for secondary FSGS were only partially represented in retrieved excerpts.

References

  1. (cos2023noveltreatmentparadigms pages 1-2): Marina de Cos, Kristin Meliambro, and Kirk N. Campbell. Novel treatment paradigms: focal segmental glomerulosclerosis. Kidney International Reports, 8:30-35, Jan 2023. URL: https://doi.org/10.1016/j.ekir.2022.10.004, doi:10.1016/j.ekir.2022.10.004. This article has 41 citations and is from a peer-reviewed journal.

  2. (salfi2023currentunderstandingof pages 1-2): Giuseppe Salfi, Federica Casiraghi, and Giuseppe Remuzzi. Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis. Frontiers in Immunology, Sep 2023. URL: https://doi.org/10.3389/fimmu.2023.1247606, doi:10.3389/fimmu.2023.1247606. This article has 45 citations and is from a peer-reviewed journal.

  3. (mirioglu2024managementofadult pages 2-3): Safak Mirioglu, Lisa Daniel-Fischer, Ilay Berke, Syed Hasan Ahmad, Ingeborg M Bajema, Annette Bruchfeld, Gema M Fernandez-Juarez, Jürgen Floege, Eleni Frangou, Dimitrios Goumenos, Megan Griffith, Sarah M Moran, Cees van Kooten, Stefanie Steiger, Kate I Stevens, Kultigin Turkmen, Lisa C Willcocks, and Andreas Kronbichler. Management of adult patients with podocytopathies: an update from the era immunonephrology working group. Nephrology Dialysis Transplantation, 39:569-580, Feb 2024. URL: https://doi.org/10.1093/ndt/gfae025, doi:10.1093/ndt/gfae025. This article has 33 citations and is from a domain leading peer-reviewed journal.

  4. (OpenTargets Search: Focal segmental glomerulosclerosis): Open Targets Query (Focal segmental glomerulosclerosis, 19 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  5. (bensink2024kidneyfailureattributed pages 1-2): Mark E. Bensink, Deborah Goldschmidt, Zheng-Yi Zhou, Kaijun Wang, Richard Lieblich, and C. Martin Bunke. Kidney failure attributed to focal segmental glomerulosclerosis: a usrds retrospective cohort study of epidemiology, treatment modalities, and economic burden. Kidney Medicine, 6:100760, Feb 2024. URL: https://doi.org/10.1016/j.xkme.2023.100760, doi:10.1016/j.xkme.2023.100760. This article has 11 citations.

  6. (elnaga2024safetyandefficacy pages 1-2): Ahmed A. Abo Elnaga, Mohamed A. Alsaied, Abdelrahman M. Elettreby, Alaa Ramadan, Mohamed Abouzid, Raghda Shetta, and Yazan A. Al-Ajlouni. Safety and efficacy of sparsentan versus irbesartan in focal segmental glomerulosclerosis and iga nephropathy: a systematic review and meta-analysis of randomized controlled trials. BMC Nephrology, Sep 2024. URL: https://doi.org/10.1186/s12882-024-03713-9, doi:10.1186/s12882-024-03713-9. This article has 4 citations and is from a peer-reviewed journal.

  7. (salfi2023currentunderstandingof pages 4-5): Giuseppe Salfi, Federica Casiraghi, and Giuseppe Remuzzi. Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis. Frontiers in Immunology, Sep 2023. URL: https://doi.org/10.3389/fimmu.2023.1247606, doi:10.3389/fimmu.2023.1247606. This article has 45 citations and is from a peer-reviewed journal.

  8. (cos2023noveltreatmentparadigms media ecc573cd): Marina de Cos, Kristin Meliambro, and Kirk N. Campbell. Novel treatment paradigms: focal segmental glomerulosclerosis. Kidney International Reports, 8:30-35, Jan 2023. URL: https://doi.org/10.1016/j.ekir.2022.10.004, doi:10.1016/j.ekir.2022.10.004. This article has 41 citations and is from a peer-reviewed journal.

  9. (xie2024precisionmedicinefor pages 1-3): Yi Xie and Fei Liu. Precision medicine for focal segmental glomerulosclerosis. Kidney Research and Clinical Practice, 43:709-723, Nov 2024. URL: https://doi.org/10.23876/j.krcp.23.227, doi:10.23876/j.krcp.23.227. This article has 3 citations.

  10. (bensink2024kidneyfailureattributed pages 2-3): Mark E. Bensink, Deborah Goldschmidt, Zheng-Yi Zhou, Kaijun Wang, Richard Lieblich, and C. Martin Bunke. Kidney failure attributed to focal segmental glomerulosclerosis: a usrds retrospective cohort study of epidemiology, treatment modalities, and economic burden. Kidney Medicine, 6:100760, Feb 2024. URL: https://doi.org/10.1016/j.xkme.2023.100760, doi:10.1016/j.xkme.2023.100760. This article has 11 citations.

  11. (ma2025theroleof pages 8-9): Xiaoting Ma, Yuyang Liang, Wenmin Chen, Lingqian Zheng, Haishan Lin, and Tianbiao Zhou. The role of endothelin receptor antagonists in kidney disease. Renal Failure, Feb 2025. URL: https://doi.org/10.1080/0886022x.2025.2465810, doi:10.1080/0886022x.2025.2465810. This article has 13 citations and is from a peer-reviewed journal.

  12. (trachtman2023implicationsofcomplete pages 1-2): Howard Trachtman, Ulysses Diva, Edward Murphy, Kaijun Wang, Jula Inrig, and Radko Komers. Implications of complete proteinuria remission at any time in focal segmental glomerulosclerosis: sparsentan duet trial. Kidney International Reports, 8:2017-2028, Oct 2023. URL: https://doi.org/10.1016/j.ekir.2023.07.022, doi:10.1016/j.ekir.2023.07.022. This article has 13 citations and is from a peer-reviewed journal.

  13. (campbell2024sparsentanforfocal pages 1-2): Kirk N. Campbell, Loreto Gesualdo, Edward Murphy, Michelle N. Rheault, Tarak Srivastava, Vladimir Tesar, Radko Komers, and Howard Trachtman. Sparsentan for focal segmental glomerulosclerosis in the duet open-label extension: long-term efficacy and safety. Kidney Medicine, 6:100833, Jun 2024. URL: https://doi.org/10.1016/j.xkme.2024.100833, doi:10.1016/j.xkme.2024.100833. This article has 14 citations.

  14. (rakotoarison2024endothelininhibitorsin pages 8-9): Agata Rakotoarison, Marta Kepinska, Andrzej Konieczny, Karolina Władyczak, Dariusz Janczak, Agnieszka Hałoń, Piotr Donizy, and Mirosław Banasik. Endothelin inhibitors in chronic kidney disease: new treatment prospects. Journal of Clinical Medicine, 13:6056, Oct 2024. URL: https://doi.org/10.3390/jcm13206056, doi:10.3390/jcm13206056. This article has 15 citations.