Focal Segmental Glomerulosclerosis (FSGS)
Podocyte injury causing nephrotic-range proteinuria with segmental sclerosis on biopsy.
Also known as: FSGS, focal segmental glomerulosclerosis, collapsing glomerulopathy, primary FSGS, secondary FSGS
Overview
A pattern of glomerular injury characterized by focal (involving some glomeruli) and segmental (involving part of the glomerular tuft) sclerosis on light microscopy, accompanied by podocyte foot-process effacement on electron microscopy. Clinically presents most often as nephrotic syndrome and is a leading cause of steroid-resistant nephrotic syndrome in adults.
Epidemiology
Most common primary cause of nephrotic syndrome in adults in the United States, with higher incidence in Black patients (linked to APOL1 risk variants). Incidence has risen over several decades. Accounts for ~20-25% of adult nephrotic syndrome and a substantial fraction of ESKD attributable to primary glomerular disease.
Keep reading — start your free trial
You've read your 2 free diagnosis previews. Create your free account to unlock the full Focal Segmental Glomerulosclerosis (FSGS) outline — plus all 514 diagnoses, 5,500+ board-style questions, flashcards, and an AI tutor. Your 7-day free trial includes everything, and there's no credit card required.
Risk factors
- African ancestry (APOL1 G1/G2 high-risk genotype)
- HIV infection (collapsing variant — HIVAN)
- Obesity and reduced nephron mass (unilateral renal agenesis, reflux nephropathy, low birth weight)
- Chronic viral infections: parvovirus B19, CMV, EBV, SARS-CoV-2
- Medications and toxins: pamidronate, interferon, anabolic steroids, heroin, lithium
- Sickle cell disease, vesicoureteral reflux, prior nephrectomy
Pathophysiology
FSGS is best understood as a podocytopathy. Primary (idiopathic) FSGS is thought to result from a circulating permeability factor (candidates include suPAR, anti-CD40 antibodies, cardiotrophin-like cytokine-1) that injures podocytes, causing foot-process effacement, detachment, and progressive segmental sclerosis. Secondary FSGS arises from adaptive hyperfiltration (obesity, reduced nephron mass), direct toxic injury (heroin, pamidronate), or viral infection. Genetic forms involve mutations in podocyte structural proteins (NPHS1/nephrin, NPHS2/podocin, ACTN4, TRPC6, INF2). APOL1 high-risk variants accelerate podocyte injury under inflammatory or viral 'second hits.'
Clinical presentation
Symptoms
- Foamy urine, dependent edema (periorbital and pretibial), weight gain
- Fatigue, dyspnea on exertion if anasarca or pleural effusions develop
- Often asymptomatic until proteinuria is detected incidentally
Signs / physical exam
- Peripheral and periorbital edema, sometimes ascites
- Hypertension in ~50% at presentation (especially secondary forms)
- Hyperlipidemia-related findings (xanthelasma in chronic cases)
Classic findings
Nephrotic-range proteinuria with relatively preserved or modestly reduced GFR; collapsing variant presents with rapid GFR decline and very heavy proteinuria.
Differential diagnosis
- Minimal change disease — Abrupt onset, more common in children; normal light microscopy with foot-process effacement on EM; usually steroid-responsive within 8-12 weeks
- Membranous nephropathy — Subepithelial immune deposits, anti-PLA2R antibody positive in ~70% of primary cases; thickened GBM with spikes
- Diabetic nephropathy — Long-standing diabetes, retinopathy, gradual proteinuria, mesangial expansion and Kimmelstiel-Wilson nodules — biopsy usually unnecessary
- HIV-associated nephropathy (HIVAN) — Collapsing FSGS variant; rapid progression, large echogenic kidneys, low CD4 count; treat with ART
- Amyloidosis — Older patient, monoclonal gammopathy or chronic inflammation; Congo red apple-green birefringence; SPEP/UPEP/free light chains
- Obesity-related glomerulopathy — BMI >35, sub-nephrotic proteinuria, normal albumin; weight loss and RAAS blockade improve disease
- Lupus nephritis (membranous class V) — Positive ANA, anti-dsDNA, low complements, extrarenal SLE features
Diagnostic workup
Diagnostic criteria
Definitive diagnosis requires kidney biopsy showing focal (some glomeruli) and segmental (part of tuft) sclerosis on light microscopy with diffuse foot-process effacement on EM. Columbia classification recognizes five variants: not-otherwise-specified (NOS), perihilar, cellular, tip, and collapsing. Tip lesion has the best prognosis; collapsing the worst.
Labs
- 24-hour urine protein or spot urine protein-to-creatinine ratio (typically >3.5 g/day in primary FSGS)
- Serum albumin (low), lipid panel (elevated LDL and triglycerides), BMP/Cr/eGFR
- Hepatitis B, hepatitis C, and HIV serologies
- ANA, complements C3/C4, SPEP/UPEP/serum free light chains, anti-PLA2R (to exclude alternative causes)
- Consider APOL1 genotyping in patients of African ancestry; targeted podocyte-gene panel if congenital or familial
Imaging
- Renal ultrasound — kidney size and echogenicity, exclude obstruction; large echogenic kidneys raise concern for HIVAN/collapsing FSGS
Diagnostic algorithm
| Variant | Histologic clue | Clinical hallmark | Prognosis |
|---|---|---|---|
| Tip lesion | Sclerosis at tubular pole | Acute nephrotic syndrome, often white patients | Best — steroid responsive |
| NOS (classic) | Segmental sclerosis, no other features | Most common pattern | Intermediate |
| Perihilar | Sclerosis near vascular pole | Obesity, reduced nephron mass | Slow progression, secondary |
| Cellular | Endocapillary hypercellularity | Heavy proteinuria | Intermediate |
| Collapsing | Capillary collapse, podocyte hypertrophy | HIVAN, APOL1, rapid GFR loss | Worst |
Treatment
First-line
- RAAS blockade for all patients with proteinuria — ACE inhibitor (lisinopril, enalapril, ramipril) or ARB (losartan, valsartan, irbesartan); titrate to maximally tolerated dose
- Blood pressure target systolic <120 mmHg by standardized office measurement in most adults (KDIGO 2021)
- Dietary sodium restriction (<2 g/day), moderate protein intake (~0.8 g/kg/day)
- Statin therapy for nephrotic hyperlipidemia — atorvastatin, rosuvastatin
- Diuretics for edema — loop diuretic (furosemide, torsemide, bumetanide), often combined with thiazide (metolazone) for diuretic resistance
- Anticoagulation considered if serum albumin <2.0-2.5 g/dL and additional thrombotic risk
Primary (idiopathic) FSGS with nephrotic syndrome
- High-dose corticosteroids — prednisone 1 mg/kg/day (max 80 mg) for 8-16 weeks, then taper
- Calcineurin inhibitor (cyclosporine, tacrolimus) for steroid-resistant or relapsing disease
- Mycophenolate mofetil or rituximab as additional options in refractory cases
- Plasmapheresis considered in post-transplant recurrence
Secondary (adaptive) FSGS
- Treat underlying cause: weight loss, sleep apnea therapy, ART for HIV, discontinue offending drug
- Maximize RAAS blockade
- Avoid immunosuppression — does not address mechanism and adds harm
Collapsing FSGS / HIVAN
- Antiretroviral therapy is mainstay for HIVAN
- RAAS blockade
- Limited and conflicting data for steroids in non-HIV collapsing variant
Second-line / adjunct
- Sparsentan — dual endothelin and angiotensin II receptor antagonist approved for FSGS proteinuria reduction (FDA accelerated approval, DUPLEX trial 2023)
- SGLT2 inhibitor (dapagliflozin, empagliflozin) for CKD with residual proteinuria
- Kidney transplantation for ESKD; primary FSGS recurs in ~30% of grafts
Complications
- Progression to ESKD (~50% within 5-10 years in untreated primary FSGS)
- Thromboembolism — DVT, PE, renal vein thrombosis (loss of antithrombin III)
- Infection from urinary loss of IgG and complement; pneumococcal vaccination indicated
- Acute kidney injury from intravascular volume depletion or interstitial edema
- Cardiovascular disease from chronic dyslipidemia and hypertension
- Post-transplant recurrence, particularly in pediatric and young adult primary FSGS
PANCE pearls
- APOL1 high-risk genotypes (G1, G2) are present in ~13% of Black Americans and dramatically increase risk for FSGS, HIVAN, and hypertension-attributed CKD.
- Tip lesion variant is the most steroid-responsive and has the best prognosis; collapsing variant the worst.
- Differentiating primary from secondary FSGS hinges on degree of foot-process effacement (diffuse in primary, segmental in secondary) and presence/absence of nephrotic syndrome.
- Sparsentan (Filspari) is the first targeted therapy approved specifically to reduce FSGS proteinuria.
- Always exclude HIV before initiating immunosuppression for FSGS.
References
- KDIGO 2021 — KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases (Kidney Int 2021;100:S1-S276)
- Columbia Classification — D'Agati VD et al. Pathologic classification of focal segmental glomerulosclerosis: a working proposal (AJKD 2004;43:368-382)
- DUPLEX Trial — Rheault MN et al. Sparsentan versus irbesartan in focal segmental glomerulosclerosis (NEJM 2023;389:2436-2445)
- APOL1 — Genovese G et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans (Science 2010;329:841-845)
Practice Renal/Urology questions on FirstPassPA
Turn this outline into retention. 5,500+ board-style questions with an AI tutor that explains every answer — free to start, no card required.
Start studying free → Browse all 514 diagnosesEducational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.