What is the treatment approach for resistant Focal Segmental Glomerulosclerosis (FSGS)?

Treatment of Resistant Focal Segmental Glomerulosclerosis (FSGS)

For steroid-resistant primary FSGS, calcineurin inhibitors (CNIs) should be used as the treatment of choice for at least 12 months to maximize chances of remission and improve renal survival. 1

First-Line Approach for Resistant FSGS

Calcineurin Inhibitors (CNIs)

• Recommended dosing:

  • Cyclosporine: 3-5 mg/kg/day in 2 divided doses 1
  • Tacrolimus: 0.05-0.1 mg/kg/day in 2 divided doses 1
  • Target trough levels:
    • Cyclosporine: 100-175 ng/ml
    • Tacrolimus: 5-10 ng/ml

• Duration of therapy:

  • Minimum trial period: 4-6 months before determining resistance 1
  • If partial or complete remission occurs: Continue for at least 12 months 1
  • Taper slowly over 6-12 months after achieving remission 1

• Monitoring:

  • Regular blood pressure measurements
  • Serum creatinine (discontinue if increases >30% from baseline and doesn't plateau)
  • CNI trough levels
  • Proteinuria response

CNIs have the strongest evidence base for steroid-resistant FSGS, with randomized controlled trials showing improved renal outcomes compared to continued glucocorticoid therapy or supportive care alone 1. Studies demonstrate remission rates of 40-50% with CNIs in steroid-resistant cases 1.

Management Algorithm for Resistant FSGS

1. Confirm steroid resistance:

   • Defined as persistent nephrotic syndrome after 16 weeks of adequate glucocorticoid therapy 1
   • Rule out secondary causes of FSGS before proceeding

2. Initiate CNI therapy:

   • First choice: Cyclosporine or tacrolimus (consider patient-specific factors)
   • Continue with low-dose alternate-day prednisone (30-40 mg/m² per 48h) for first 6 months 1

3. Assess response at 4-6 months:

   • Complete remission: Continue CNI for 12 months, then slow taper
   • Partial remission: Continue CNI for 12 months, then reassess
   • No response: Consider referral to specialized center

4. For CNI-resistant or intolerant patients:

   • Refer to specialized nephrology centers for consideration of:
     • Rebiopsy to reassess diagnosis
     • Alternative therapies
     • Clinical trial enrollment 1

Alternative Therapies for Multi-Resistant FSGS

For patients who fail or cannot tolerate both steroids and CNIs, limited evidence supports:

• Mycophenolate mofetil (MMF) with high-dose dexamethasone 1
• Plasmapheresis/plasma exchange - Consider as rescue therapy in severe cases 2
• Other agents with limited evidence: rituximab, ACTH, cyclophosphamide 1

Important Clinical Considerations

• Prognosis factors: Achieving remission (complete or partial) significantly improves long-term renal survival, with 5-year dialysis-free survival of 94% vs 53% without remission 3

• Supportive care is essential:

  • Aggressive blood pressure control
  • Renin-angiotensin system blockade (ACEi/ARBs)
  • Lipid management
  • Edema control

• Monitoring for CNI toxicity:

  • Nephrotoxicity (rising creatinine)
  • Hypertension
  • Glucose intolerance (more common with tacrolimus)
  • Dyslipidemia (more common with cyclosporine)

• Treatment duration: Prolonged therapy is often required, as relapses are common after withdrawal of CNIs 4

Common Pitfalls to Avoid

1. Premature discontinuation of CNIs - Minimum 12 months of therapy is needed to minimize relapse risk 1

2. Inadequate CNI dosing - Underdosing may lead to treatment failure; monitor drug levels

3. Failure to distinguish primary from secondary FSGS - Immunosuppression is only indicated for primary FSGS with nephrotic features 1

4. Delayed referral to specialized centers for multi-resistant cases - Early referral improves outcomes

5. Overlooking supportive therapy - Antiproteinuric and antihypertensive measures remain cornerstone of management

The treatment of resistant FSGS remains challenging, but with appropriate use of CNIs and careful monitoring, remission can be achieved in a significant proportion of patients, leading to improved renal survival and quality of life.