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.
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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
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
Columbia histologic classification of FSGS variants with clinical correlations.
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)
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)
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