Focal Segmental Glomerulosclerosis (FSGS)

Focal Segmental Glomerulosclerosis (FSGS) is a histological pattern of glomerular injury characterized by sclerosis (scarring) affecting only some (focal) glomeruli and only portions (segmental) of those glomeruli. It is a major cause of nephrotic syndrome in adults and a leading cause of ESRD in the United States. FSGS represents a heterogeneous group of disorders united by podocyte injury as the final common pathway.

Table of Contents

1. Overview
2. Epidemiology
3. Classification
4. Pathophysiology
5. Clinical Presentation
6. Diagnosis
7. Distinguishing FSGS from MCD
8. Treatment
9. Steroid-Resistant FSGS
10. Prognosis
11. Research Papers
12. References
13. Featured Videos

1. Overview

FSGS is defined by focal (affecting <50% of sampled glomeruli) and segmental (affecting part of a glomerulus) areas of sclerosis on light microscopy, with podocyte foot process effacement on electron microscopy. It can be classified as primary (idiopathic), secondary, or genetic. FSGS is the most common cause of nephrotic syndrome in Black adults in the United States and a major driver of ESRD, accounting for approximately 35% of ESRD cases attributable to glomerular disease in the US. The incidence of primary FSGS has increased 11-fold in the US over the past 25 years.

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2. Epidemiology

FSGS accounts for approximately 40% of adult nephrotic syndrome in the United States and up to 20% in Europe and Asia. Annual incidence is estimated at 7 cases per million population. Black Americans have 4-fold higher incidence than White Americans, largely attributable to APOL1 high-risk variants (G1 and G2 alleles) — present in ~13% of African Americans and associated with markedly increased FSGS risk, particularly collapsing FSGS. Male predominance is observed in most cohorts. Peak age of onset: 30–40 years for primary FSGS; genetic FSGS often presents in childhood or early adulthood.

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3. Classification: Primary, Secondary, and Genetic FSGS

Primary (Idiopathic) FSGS

Immune-mediated podocyte injury. Evidence for a circulating permeability factor — cardiotrophin-like cytokine factor 1 (CLCF1) and possibly soluble urokinase receptor (suPAR) — causing podocyte effacement. Recurrence in 30–40% of allografts suggests a circulating factor.

Secondary FSGS

Due to adaptive responses to reduced nephron mass or direct podocyte toxicity:

• Obesity-related FSGS: hyperfiltration → glomerulomegaly → perihilar FSGS variant
• Hypertension
• Reflux nephropathy (chronic vesicoureteral reflux)
• HIV-associated nephropathy (HIVAN): collapsing FSGS pattern; strongly associated with APOL1 variants
• Heroin nephropathy
• Interferon therapy (interferon-α, interferon-β)
• Anabolic steroid use, pamidronate
• Sickle cell disease, cyanotic congenital heart disease

Genetic FSGS

Mutations in podocyte structural and signaling proteins:

• NPHS1 (nephrin): congenital nephrotic syndrome of the Finnish type
• NPHS2 (podocin): autosomal recessive; most common genetic cause in children; often steroid-resistant
• ACTN4 (alpha-actinin 4): autosomal dominant; late onset; slowly progressive
• TRPC6 (transient receptor potential cation channel 6): autosomal dominant; adult onset
• WT1, INF2, CD2AP, LAMB2: additional genetic causes; often associated with extrarenal findings

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4. Pathophysiology

Podocytes are terminally differentiated cells that form interdigitating foot processes bridged by the slit diaphragm — the main filtration barrier. Podocyte injury results in:

1. Foot process effacement (fusion): increased glomerular permeability → heavy proteinuria
2. Podocyte detachment and loss: depletion below a critical threshold leads to denuded GBM, synechiae formation, and sclerosis
3. Compensatory hypertrophy of remaining podocytes: inadequate to cover expanding GBM; perpetuates injury
4. Mesangial matrix expansion and segmental sclerosis
5. Tubular damage from protein reabsorption: lipid nephrotoxicity (free fatty acids, oxidized lipids in albumin-bound form)

In primary FSGS, circulating permeability factors directly injure podocyte cytoskeleton (actin remodeling), leading to rapid-onset nephrotic syndrome. In secondary FSGS, hyperfiltration and mechanical stress drive podocyte injury more gradually.

Columbia Classification (Five Histological Variants)

• Tip variant: sclerosis at the tubular pole; best prognosis; often steroid-responsive
• Perihilar variant: sclerosis at vascular pole; most common in secondary FSGS; moderate prognosis
• Cellular variant: endocapillary hypercellularity; active injury; can mimic proliferative GN
• Collapsing variant: global or segmental capillary collapse with podocyte proliferation; seen in HIVAN, APOL1 variants, parvovirus B19, COVID-19-associated nephropathy; worst prognosis
• NOS (not otherwise specified): does not meet criteria for other variants; most common type overall

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5. Clinical Presentation

Nephrotic syndrome is the hallmark of primary FSGS:

• Heavy proteinuria: >3.5 g/day (often >10 g/day in primary FSGS); frothy urine
• Hypoalbuminemia: <3.5 g/dL (often <2.5 g/dL)
• Edema: periorbital (worse in AM), pedal, ascites; can be severe
• Hyperlipidemia: elevated LDL, VLDL; lipiduria (oval fat bodies, Maltese crosses on polarized microscopy)
• Hypertension: present in ~50% at diagnosis

Secondary FSGS often presents with subnephrotic proteinuria (1–3.5 g/day), less edema, and more slowly progressive CKD.

Complications of nephrotic syndrome in FSGS: hypercoagulability (renal vein thrombosis, DVT/PE — from loss of antithrombin III and protein C/S), infection (encapsulated bacteria — loss of immunoglobulins and complement), acute kidney injury (from severe hypoalbuminemia reducing effective circulating volume), and cardiovascular disease from hyperlipidemia.

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6. Diagnosis

Kidney Biopsy (Essential)

• Light microscopy: focal (<50% glomeruli) and segmental sclerosis; ± hyalinosis, synechia (adhesion to Bowman's capsule); tubular atrophy in proportion to sclerosis; Columbia classification
• Immunofluorescence: nonspecific IgM and C3 trapping in sclerotic areas (no immune deposits); helps distinguish from immune-complex GN
• Electron microscopy: diffuse podocyte foot process effacement (>80% of capillary surface area) in primary FSGS; less extensive effacement (<50%) in secondary FSGS (key distinction); no immune deposits; no GBM thickening (distinguishes from membranous nephropathy)

Laboratory Workup

• 24h urine protein or spot urine protein/creatinine ratio: quantify proteinuria
• Serum creatinine, eGFR, BUN
• Serum albumin, total protein
• Lipid panel: elevated LDL, triglycerides
• CBC: normocytic anemia from hypoalbuminemia
• Coagulation: elevated fibrinogen, reduced antithrombin III
• Serum electrophoresis: exclude paraprotein/myeloma
• Complement (C3, C4): normal in FSGS; low in MPGN, lupus, MPGN
• ANA, anti-dsDNA, ANCA, hepatitis B/C, HIV serology
• APOL1 genotyping: in patients of African ancestry
• Genetic testing: if childhood onset, family history, or steroid-resistant (NPHS2/NPHS1/ACTN4/TRPC6 panel)
• suPAR level: elevated in primary FSGS; research use

Urinalysis: heavy proteinuria; oval fat bodies (lipiduria); RBC casts uncommon (unlike proliferative GN).

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7. Distinguishing FSGS from Minimal Change Disease (MCD)

Both FSGS and MCD present with nephrotic syndrome and diffuse foot process effacement on EM, making distinction critical since they require different treatment approaches:

• Biopsy: FSGS has sclerotic lesions (may be missed on small biopsy — "sampling error"); MCD has normal light microscopy and IF, only EM changes
• Electron microscopy: both show diffuse FPE; FSGS has additional sclerotic segments and occasional mesangial deposits; MCD is "minimal change" on EM
• Foot process effacement extent: >80% in primary FSGS; >90% in MCD (less helpful as discriminator)
• Age: MCD more common in children (90% of childhood nephrotic syndrome); primary FSGS peaks in adults
• Response to steroids: MCD responds rapidly (1–2 weeks) in >90% of children, >80% of adults; primary FSGS responds in ~30–40% with prolonged course (16–24 weeks)
• Recurrence post-transplant: FSGS 30–40%; MCD rare
• HIV/APOL1 association: FSGS collapsing; MCD not associated

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8. Treatment

Supportive Therapy

• ACEi or ARB: reduce proteinuria and slow CKD progression via glomerular pressure reduction; first-line for all FSGS with proteinuria
• SGLT2 inhibitors: indicated for proteinuria reduction and CKD protection (DAPA-CKD/EMPA-KIDNEY evidence)
• Statins: for hyperlipidemia; also anti-proteinuric effects via HECT-domain and RCC1-like domain protein (HERC2)-dependent pathway
• Anticoagulation: low-molecular-weight heparin or warfarin if albumin <2.5 g/dL or thromboembolic event
• Dietary sodium restriction (<2 g/day), fluid restriction in severe hypoalbuminemia
• Loop diuretics for edema (furosemide); IV albumin + furosemide for severe refractory edema

Primary FSGS Immunosuppression

• Corticosteroids: prednisone 1 mg/kg/day (max 80 mg) for 16–24 weeks with slow taper; first-line for primary FSGS. Complete remission rate ~30–40%; partial remission ~25%
• Calcineurin inhibitors (cyclosporine/tacrolimus): first-line for steroid-resistant FSGS; cyclosporine 3–5 mg/kg/day with blood level monitoring; tacrolimus 0.05–0.1 mg/kg/day. Response rate 50–70%
• Mycophenolate mofetil (MMF): second-line; less effective than CNI but fewer nephrotoxic side effects
• Rituximab: anti-CD20; beneficial for idiopathic FSGS with circulating permeability factor; evidence strongest for recurrent FSGS post-transplant
• Sparsentan (DUPLEX trial): dual endothelin/AT1 receptor antagonist; Phase 3 DUPLEX trial in primary FSGS showed significant proteinuria reduction; FDA breakthrough therapy designation

Secondary FSGS

Treat underlying cause (weight loss in obesity-FSGS, antiretrovirals for HIVAN, stop offending drug). ACEi/ARB + SGLT2i; lower threshold for disease control vs. aggressive immunosuppression.

Genetic FSGS

NPHS2/NPHS1 mutations: generally steroid-resistant; avoid prolonged steroid courses; ACEi/ARB supportive; CNI in selected cases; genetic counseling; kidney transplant has low recurrence risk.

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9. Steroid-Resistant FSGS

Defined as failure to achieve complete or partial remission after 16–24 weeks of adequate corticosteroid therapy. Affects ~60–70% of primary FSGS patients. Workup: reassess biopsy (Columbia variant, degree of fibrosis), APOL1 genotyping, genetic panel (NPHS2, ACTN4, TRPC6, INF2), suPAR level.

Management: Calcineurin inhibitor (cyclosporine or tacrolimus) + MMF combinations; rituximab; investigational agents (BI 764198 — anti-TRPC6; atrasentan; LNP023 — complement factor B inhibitor). Sparsentan Phase 3 DUPLEX data maturing. ESRD preparation: manage CKD complications, list for transplant, living donor evaluation, APOL1 testing of potential living donors of African ancestry.

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10. Prognosis

Without treatment: 50% reach ESRD within 10 years. Collapsing FSGS: worst prognosis (~50% ESRD within 2–5 years). Tip variant: best prognosis (>80% remission with steroids; low risk of ESRD). Primary vs. secondary: secondary FSGS generally progresses more slowly to ESRD.

Remission status is the strongest predictor:

• Complete remission (urine protein <0.3 g/day): excellent renal survival >90% at 10 years
• Partial remission (50% reduction and protein <3.5 g/day): good, ~60–70% renal survival at 10 years
• No remission: poor, ~50% ESRD at 5–10 years

Post-transplant recurrence: 30–40% (up to 80% in children with primary FSGS recurrence in prior transplant); can cause rapid graft loss; treatment: plasmapheresis/immunoadsorption to remove circulating factor, rituximab.

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11. Research Papers

• focal segmental glomerulosclerosis treatment
• FSGS podocyte injury pathogenesis
• APOL1 FSGS African Americans
• FSGS steroid resistant calcineurin inhibitor
• sparsentan FSGS DUPLEX trial
• FSGS recurrence kidney transplant
• Columbia classification FSGS prognosis

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12. References

1. D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011;365(25):2398–2411. PMID: 22187987. https://doi.org/10.1056/NEJMra1106556
2. Kopp JB, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011;22(11):2129–2137. PMID: 21997394. https://doi.org/10.1681/ASN.2011040388
3. Trachtman H, et al. A phase 2, randomized, placebo-controlled, dose-finding clinical trial of sparsentan in patients with primary FSGS. Kidney Int. 2018;94(6):1190–1202. PMID: 30343855. https://doi.org/10.1016/j.kint.2018.07.037
4. Cattran DC, et al. The Columbia classification of focal segmental glomerulosclerosis. Am J Kidney Dis. 2004;43(2):368–382. PMID: 14750106. https://doi.org/10.1053/j.ajkd.2003.10.024
5. Gipson DS, et al. Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int. 2011;80(8):868–878. PMID: 21734641. https://doi.org/10.1038/ki.2011.195
6. Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD). N Engl J Med. 2020;383(15):1436–1446. PMID: 32970396. https://doi.org/10.1056/NEJMoa2024816
7. Mathieson PW. The podocyte as a target for therapies: new and old. Nat Rev Nephrol. 2012;8(2):77–84. PMID: 22207202. https://doi.org/10.1038/nrneph.2011.162
8. Ponticelli C, et al. Rituximab in idiopathic nephrotic syndrome: does it make sense? Nephrol Dial Transplant. 2020;35(6):906–915. PMID: 30395268. https://doi.org/10.1093/ndt/gfy356
9. Iijima K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome. Lancet. 2014;384(9946):1273–1281. PMID: 25012351. https://doi.org/10.1016/S0140-6736(14)60541-9
10. Sampson MG, et al. Integration of genomic information and kidney disease classification for nephrotic syndrome. Clin J Am Soc Nephrol. 2014;9(5):946–961. PMID: 24627342. https://doi.org/10.2215/CJN.07410713
11. Kitiyakara C, et al. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis. 2004;44(5):815–825. PMID: 15492947. https://doi.org/10.1016/j.ajkd.2004.07.022
12. Vincenti F, et al. A phase 2 trial of sparsentan for steroid-resistant, primary focal segmental glomerulosclerosis. Kidney Int Rep. 2023. [DUPLEX Phase 3 ongoing; preliminary data presented at ASN 2022]. PMID: 36866080. https://doi.org/10.1016/j.ekir.2023.01.012

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Connections

• Nephrotic Syndrome
• Glomerulonephritis
• IgA Nephropathy
• Rapidly Progressive GN
• Chronic Kidney Disease
• Acute Kidney Injury
• Lupus Nephritis
• HIV/AIDS
• Kidney Function Tests
• Creatinine
• Urinalysis
• Hypertension

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