Key Facts

FSGS is a histological pattern rather than a single disease. It represents a common pathway of podocyte injury from various causes. Primary FSGS is thought to be caused by a circulating permeability factor.

Epidemiology

• Increasing incidence worldwide; now accounts for 20-25% of adult nephrotic syndrome
• Most common glomerular cause of ESRD in the US (particularly Afro-Caribbean populations)
• APOL1 gene variants (G1/G2 alleles) confer 5-15 fold increased risk in African populations
• Peak age: 25-45 years; M:F ratio 1.5:1

Aetiology

• Primary (idiopathic): circulating permeability factor (possibly suPAR, cardiotrophin-like cytokine-1)
• Secondary (adaptive): obesity, reduced nephron mass, vesicoureteric reflux, sickle cell, HIV (collapsing variant)
• Genetic: mutations in podocyte genes (NPHS1, NPHS2/podocin, ACTN4, TRPC6, INF2)
• Drug-induced: heroin, interferon, lithium, pamidronate

Pathophysiology

• Podocyte injury → foot process effacement → proteinuria
• Progressive podocyte loss → glomerular tuft adhesion → segmental sclerosis
• Sclerosed segments obstruct capillary flow → further nephron loss
• Focal and segmental distribution means lesions may be missed on biopsy (sampling error)

Presentation

• Nephrotic syndrome in 60-70%: heavy proteinuria, oedema, hypoalbuminaemia
• Subnephrotic proteinuria with haematuria in 30-40%
• Hypertension at presentation in 30-50%
• Renal impairment at presentation in 20-30%
• Microscopic haematuria in 30-50%

Variants (Columbia Classification)

• NOS (not otherwise specified): most common
• Tip variant: better prognosis, more steroid-responsive
• Collapsing variant: worst prognosis, associated with HIV and APOL1; aggressive course
• Perihilar variant: associated with secondary/adaptive FSGS
• Cellular variant: rare, intermediate prognosis

Red Flags

• Collapsing variant → screen for HIV, APOL1; poor prognosis
• Steroid resistance → check compliance, consider genetic testing
• Post-transplant recurrence → early presentation with heavy proteinuria

Bloods

• Serum albumin: low
• Urine PCR: nephrotic-range
• U&Es: may show renal impairment
• Lipid profile: hyperlipidaemia
• C3/C4: normal (distinguishes from complement-mediated GN)
• HIV test: essential (collapsing variant)
• HbA1c: exclude diabetes

Imaging

• Renal USS: normal or slightly enlarged kidneys; echogenic in advanced disease

Special Tests

• Renal biopsy (essential for diagnosis):
  • LM: segmental sclerosis in some glomeruli; may be missed if few glomeruli sampled
  • IF: IgM and C3 trapping in sclerosed segments (non-specific)
  • EM: diffuse foot process effacement (primary) or focal effacement (secondary)
• Genetic testing: NPHS2, NPHS1 mutations if familial, steroid-resistant, or childhood-onset
• Minimum 20 glomeruli recommended on biopsy to avoid sampling error

Non-pharmacological

• Sodium restriction and fluid management for oedema
• Weight loss if obesity-related (secondary FSGS)
• Treat underlying cause in secondary FSGS (e.g., antiretrovirals for HIV)

Pharmacological

Primary FSGS:

• Prednisolone 1mg/kg/day (max 80mg) for ≥16 weeks before declaring steroid resistance
• 30-50% achieve complete or partial remission
• Calcineurin inhibitors (steroid-resistant or steroid-dependent):
  • Ciclosporin 3-5mg/kg/day (target trough 100-175 ng/mL) for ≥12 months
  • Tacrolimus 0.05-0.1mg/kg/day as alternative
  • 50-60% achieve partial/complete remission
• Mycophenolate mofetil 1g BD + dexamethasone: alternative if CNI intolerant
• Rituximab: emerging evidence for steroid-dependent FSGS

Secondary FSGS:

• RAAS blockade (ACEi/ARB) to reduce proteinuria
• Treat underlying cause
• Immunosuppression generally NOT indicated

Supportive:

• ACEi/ARB for all patients with proteinuria
• Diuretics for oedema
• Statins for hyperlipidaemia
• Thromboprophylaxis if albumin <20 g/L

Referral Criteria

• All cases → nephrology
• Steroid resistance → tertiary nephrology/genetic testing
• Planning for transplantation → discuss recurrence risk

• Untreated primary FSGS: 50-70% progress to ESRD within 5-10 years
• Complete remission: <5% progress to ESRD (regardless of treatment modality)
• Partial remission: significantly better than no remission
• Steroid-resistant FSGS: ~60% reach ESRD within 6-8 years
• Collapsing variant: worst prognosis; median time to ESRD ~2-3 years
• Tip variant: best prognosis; behaves similarly to MCD
• Post-transplant recurrence: 20-40%; higher if rapid ESRD from native disease

Columbia Classification of FSGS Variants

Primary vs Secondary FSGS