What is the management of Focal Segmental Glomerulosclerosis (FSGS)?

Management of Focal Segmental Glomerulosclerosis (FSGS)

Initial Diagnostic Classification

The first critical step is to distinguish primary FSGS from secondary and genetic forms, as this fundamentally determines whether immunosuppression should be used. 1

Criteria for Primary FSGS (Immunosuppression Candidates)

• Nephrotic syndrome with proteinuria >3.5 g/day AND serum albumin <30 g/L 1
• Sudden onset of symptoms 1
• Diffuse foot process effacement on electron microscopy 1
• Absence of identifiable secondary causes (viruses, drugs, obesity, reduced nephron mass) 1

Exclude Before Starting Immunosuppression

• Secondary causes: viral infections, drug toxicity, obesity-related hyperfiltration, reduced nephron mass 1, 2
• Genetic forms: Consider genetic screening in patients with family history, early-onset disease, or atypical presentations 1, 3
• Do NOT start immunosuppression in secondary or genetic FSGS - these forms do not respond and will not recur after transplantation 2

First-Line Treatment for Primary FSGS

High-dose corticosteroids are the recommended first-line therapy for primary FSGS with nephrotic syndrome. 1, 3

Corticosteroid Protocol

• Starting dose: Prednisone 1 mg/kg/day (maximum 80 mg) as single daily dose OR 2 mg/kg alternate-day (maximum 120 mg) 1, 3
• Duration of high-dose therapy: Minimum 4 weeks, continue up to maximum 16 weeks or until complete remission, whichever comes first 1
• Patients likely to respond will show proteinuria reduction before 16 weeks - consider discontinuing if proteinuria remains persistent and unremitting, especially with significant side effects 1
• Tapering: After achieving complete remission, continue high-dose therapy for 4 weeks or after proteinuria disappears (whichever is longer), then reduce by 5 mg every 1-2 weeks to complete total 6-month course 1
• Expected response rate: Approximately 50% overall remission rate 4

Common Pitfall

Adults respond more slowly and variably than children, with higher rates of steroid resistance and greater risk of steroid-related complications 1. Do not extrapolate pediatric response expectations to adults 1.

Second-Line Treatment for Steroid-Resistant or Steroid-Dependent FSGS

For patients who fail corticosteroids or develop significant toxicity, calcineurin inhibitors (CNIs) are the next recommended therapy. 1, 3

Calcineurin Inhibitor Protocol

Cyclosporine option:

• Dose: 3-5 mg/kg/day in 2 divided doses 1
• Target trough level: 100-175 ng/mL (83-146 nmol/L) 1

Tacrolimus option:

• Dose: 0.05-0.1 mg/kg/day in 2 divided doses 1
• Target trough level: 5-10 ng/mL (6-12 nmol/L) 1

Duration and Monitoring

• Trial period: Continue at target trough levels for at least 4-6 months before declaring CNI resistance 1
• Total treatment duration: In responders, continue for at least 12 months at target levels to minimize relapses 1, 3
• Tapering: Slowly taper over 6-12 months as tolerated 1
• Monitor for nephrotoxicity: This is a significant adverse effect requiring dose adjustment 3

Efficacy in Steroid-Resistant Disease

CNIs show good efficacy in steroid-resistant FSGS, with better response rates than other alternatives 4. Systematic review data confirms proteinuria reduction with immunosuppressants, though effects on long-term kidney survival remain uncertain 5.

Alternative Immunosuppressive Options

Mycophenolate Mofetil

• More effective in steroid-dependent/multirelapsing cases than in steroid-resistant FSGS 4
• Consider as alternative when CNIs are contraindicated or poorly tolerated 4

Rituximab

• Similar to mycophenolate: better efficacy in steroid-dependent/multirelapsing disease, less effective in steroid-resistant cases 4
• May be considered in selected patients with frequent relapses 4

Alkylating Agents

• Reserved for highly resistant cases after failure of corticosteroids and CNIs 4
• Significant toxicity profile limits routine use 4

Supportive Care (Essential for ALL FSGS Types)

Regardless of FSGS type or immunosuppression status, all patients require aggressive supportive management. 1, 6

Cardiovascular Risk Reduction

• RAAS blockade: ACE inhibitors or ARBs to reduce proteinuria and control blood pressure 1, 6
• Statins: For hyperlipidemia management, particularly important given variable and prolonged response to immunosuppression in adults 1

Monitoring and Prevention

• Regular monitoring: Proteinuria, serum albumin, kidney function 1
• Thromboprophylaxis: Consider in severe nephrotic syndrome (albumin <20-25 g/L) given 29% risk of renal vein thrombosis and 17-28% risk of pulmonary embolism 7
• Infection prevention: Increased susceptibility due to immunoglobulin loss 7
• Calcium and vitamin D supplementation: Prevent hypocalcemia from urinary losses 8

Treatment Algorithm for Patients Without Nephrotic Syndrome

If proteinuria >3.5 g/day but albumin >30 g/L, OR proteinuria <3.5 g/day: 1

• Do NOT start immunosuppression 1
• Provide supportive therapy only (RAAS blockade, statins) 1
• Monitor proteinuria and serum albumin closely 1
• Only initiate immunosuppression if proteinuria worsens and albumin drops below 30 g/L 1

Prognostic Considerations

Remission of proteinuria is the most significant predictor of renal survival in FSGS - achieving complete or partial remission dramatically improves long-term kidney outcomes 7. Patients with persistent nephrotic-range proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years 7.