What is the recommended first‑line management for an adult with focal segmental glomerulosclerosis presenting with edema, nephrotic‑range proteinuria (>3.5 g/24 h), hypoalbuminemia, and an estimated glomerular filtration rate ≥30 mL/min/1.73 m²?

First-Line Management of Primary Focal Segmental Glomerulosclerosis with Nephrotic Syndrome

High-dose oral corticosteroids (prednisone 1 mg/kg/day, maximum 80 mg daily, or 2 mg/kg alternate-day, maximum 120 mg) should be initiated as first-line therapy for at least 4 weeks and continued up to 16 weeks or until complete remission, followed by a slow taper over 6 months. 1

Initial Conservative Management (Start Immediately)

Before or concurrent with immunosuppression, all patients require optimal supportive care:

• ACE inhibitor or ARB to reduce proteinuria and target blood pressure ≤125/75 mmHg 1, 2
• Loop diuretics (furosemide) for edema control 2
• Statin therapy for persistent hyperlipidemia, particularly with cardiovascular risk factors 2
• Assess thromboembolism risk: Consider prophylactic anticoagulation if albumin <2.0-2.5 g/dL (20-25 g/L) AND additional risk factors present (proteinuria >10 g/day, BMI >35 kg/m², immobilization, heart failure) 2

Corticosteroid Protocol (First-Line Therapy)

Dosing and Duration

• 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
• High-dose duration: Continue for minimum 4 weeks up to maximum 16 weeks, or until complete remission is achieved, whichever comes first 1
• Early assessment: Patients likely to respond typically show some proteinuria reduction within 4-8 weeks 1
• Consider early switch: If proteinuria remains persistent and unremitting by 8-12 weeks, especially with significant steroid side effects, consider transitioning to calcineurin inhibitor rather than continuing to 16 weeks 1

Tapering Strategy

• After complete remission: Continue high-dose therapy for 2 weeks after proteinuria disappears, then reduce prednisone by 5 mg every 1-2 weeks to complete total treatment duration of 6 months 1
• After partial remission (achieved at 8-12 weeks): Continue until 16 weeks to assess for further improvement, then taper by 5 mg every 1-2 weeks over 6 months 1

Second-Line Therapy: Calcineurin Inhibitors

Indications for CNI Use

Switch to CNI therapy if: 1

• Steroid resistance (no response after 16 weeks)
• Steroid intolerance or contraindications
• Unacceptable steroid toxicity developing during treatment

CNI Dosing Protocols

Cyclosporine: 1

• Start at 2-3 mg/kg/day in 2 divided doses
• Gradually increase to maximum 4-5 mg/kg/day based on response
• Target trough level (C0): 100-175 ng/mL (83-146 nmol/L)
• Alternative target C2 level: <500 ng/mL

Tacrolimus: 1

• Start at 0.05-0.1 mg/kg/day in 2 divided doses
• Target trough level: 5-10 ng/mL (6-12 nmol/L)
• May be preferred over cyclosporine due to lower risk of precipitating diabetes 2

CNI Treatment Duration

• Efficacy assessment period: Continue at target trough levels for minimum 4-6 months before declaring treatment failure 1
• Total treatment duration: If partial or complete remission achieved, continue for at least 12 months total 1
• Tapering: After remission, slowly taper by 0.5 mg/kg/month to minimum effective dose, then maintain for 1-2 years 1

Critical Monitoring and Pitfalls

Steroid Toxicity Monitoring

• High-dose prednisone (1 mg/kg/day) carries substantial toxicity risk requiring close supervision for hyperglycemia, hypertension, weight gain, psychiatric effects, and infection 1
• Maximum 16-week duration is essential to limit cumulative toxicity 1

CNI Nephrotoxicity

• Monitor serum creatinine closely: If creatinine increases >30% from baseline and does not plateau, reduce CNI dose 1
• If creatinine remains elevated after dose reduction, discontinue CNI 1
• Perform renal biopsy if CNI toxicity versus disease progression is unclear 1

Response Assessment

• Complete remission (proteinuria <0.3 g/day) is the strongest predictor of renal survival and should be the treatment goal 4, 5
• Partial remission (≥50% reduction in proteinuria) may still provide clinical benefit and should be maintained with lowest effective CNI dose 1
• No response after 6 months of CNI therapy (failure to achieve ≥50% proteinuria reduction) warrants consideration of alternative agents or referral to expert center 1

Treatment-Resistant Disease

If no response to both corticosteroids and CNI after appropriate trials: 1

• Consider adding or switching to cytotoxic agents (cyclophosphamide) or mycophenolic acid
• Refer to expert center for consideration of experimental therapies
• Accept partial remission if clinically beneficial rather than escalating to more toxic regimens

Key Algorithmic Decision Points

1. Week 0: Start prednisone 1 mg/kg/day + supportive care
2. Week 4-8: Assess proteinuria response
   • Improving → Continue to week 16 or complete remission
   • No improvement + toxicity → Switch to CNI
3. Week 16: If still on steroids
   • Complete remission → Begin 6-month taper
   • Partial remission → Continue 2 more weeks, then taper
   • No response → Switch to CNI
4. Month 6 on CNI: Assess response
   • Remission → Continue total 12 months, then slow taper
   • No response → Consider alternative agents or expert referral

The KDIGO 2021 guidelines represent the most current evidence-based approach, superseding older 2007 and 2012 recommendations, though the core principle of corticosteroids first-line followed by CNI for resistant disease remains consistent across all guideline iterations. 1, 3