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.
Ask a research question about Focal Segmental Glomerulosclerosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: Focal Segmental Glomerulosclerosis
creation_date: "2026-04-13T17:56:50Z"
updated_date: "2026-05-08T23:53:01Z"
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.
disease_term:
preferred_term: Focal Segmental Glomerulosclerosis
term:
id: MONDO:0100313
label: focal segmental glomerulosclerosis
parents:
- Glomerular Diseases
- Nephrotic Syndrome
has_subtypes:
- name: Primary FSGS
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
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.
- 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.
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
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.
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
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.
cell_types:
- preferred_term: podocyte
term:
id: CL:0000653
label: podocyte
genes:
- preferred_term: NPHS2
term:
id: hgnc:13394
label: NPHS2
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.
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.
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.
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.
- 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
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
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.
treatment_term:
preferred_term: kidney transplantation
term:
id: MAXO:0010039
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: Genetic FSGS
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: Genetic FSGS
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: Genetic FSGS
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
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
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.
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.
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.
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).
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).
(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)
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).
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).
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).
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).
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.
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.
A KDIGO-aligned classification and management flow is available as a figure from de Cos et al. 2023 (cos2023noveltreatmentparadigms media ecc573cd).
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).
References
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.