What is the initial treatment for nephrotic syndrome?

Initial Treatment for Nephrotic Syndrome

Begin oral prednisone at 60 mg/m²/day (or 2 mg/kg/day, maximum 60 mg/day) as a single daily dose for 4-6 weeks, followed by alternate-day prednisone at 40 mg/m² (or 1.5 mg/kg, maximum 40 mg) for 2-5 months with gradual tapering, for a total treatment duration of at least 12 weeks. 1, 2

Age-Specific Considerations Before Starting Treatment

• Children younger than 1 year require different management as they are more likely to have genetically definable causes of nephrotic syndrome and should not receive standard corticosteroid protocols without further evaluation 1, 2
• Adults generally require kidney biopsy before initiating immunosuppressive therapy to identify the specific histopathologic subtype 3, 2
• In children with typical presentation (age >1 year, no atypical features), biopsy may be deferred if there is response to initial steroid therapy 3, 2

Initial Corticosteroid Protocol

Daily Phase (Weeks 1-6)

• Administer prednisone 60 mg/m²/day or 2 mg/kg/day (maximum 60 mg/day) as a single daily dose 1, 4
• Continue daily dosing for 4-6 weeks, or until remission is achieved for at least 3 consecutive days 1, 2
• Important dosing caveat: Weight-based dosing (2 mg/kg/day) may result in underdosing in children weighing <30 kg compared to BSA-based dosing (60 mg/m²/day), which can increase the risk of frequent relapses 5, 6

Alternate-Day Phase (Weeks 7-24)

• After the daily phase, transition to alternate-day prednisone at 40 mg/m² or 1.5 mg/kg (maximum 40 mg on alternate days) 1, 4
• Continue alternate-day dosing for 2-5 months with gradual tapering 1, 4
• Total treatment duration should be at least 12 weeks to reduce relapse risk, with some evidence supporting up to 6 months for initial episodes 3, 1

Monitoring Treatment Response

• Remission is defined as: urine protein <1+ on dipstick for 3 consecutive days or urine protein-to-creatinine ratio <200 mg/g (<20 mg/mmol) 1, 7
• Approximately 80% of children will achieve remission with initial corticosteroid therapy 1
• Continue high-dose corticosteroids for a minimum of 4 weeks if complete remission is achieved, and up to a maximum of 16 weeks if complete remission is not achieved 3, 2

Alternative First-Line Therapy for Steroid-Intolerant Patients

• For patients with relative contraindications or intolerance to high-dose corticosteroids (uncontrolled diabetes, psychiatric conditions, severe osteoporosis), consider calcineurin inhibitors as first-line therapy 3, 7
• Cyclosporine: 3-5 mg/kg/day in divided doses 3, 7
• Tacrolimus: 0.05-0.1 mg/kg/day in divided doses 3

Management of Relapses

Defining Relapse

• Relapse is defined as: ≥3+ protein on urine dipstick for 3 consecutive days or urine protein-to-creatinine ratio ≥2000 mg/g (≥200 mg/mmol) 1, 7

Treatment of Infrequent Relapses

• Treat with prednisone 60 mg/m²/day (maximum 60 mg/day) until remission for at least 3 days 1, 4
• After achieving remission, switch to alternate-day prednisone (40 mg/m² or 1.5 mg/kg) for at least 4 weeks 1

Infection-Related Relapse Prevention

• During episodes of upper respiratory tract infections in children with frequent relapses, daily prednisone at 0.5 mg/kg/day for 5-7 days may reduce relapse risk 1

When to Consider Steroid-Sparing Agents

• Frequent relapses (≥2 relapses within 6 months of initial response) or steroid-dependent nephrotic syndrome (relapse during steroid taper or within 14 days of stopping steroids) warrant consideration of steroid-sparing agents 3, 1

Second-Line Agent Options

• Alkylating agents (cyclophosphamide 2 mg/kg/day for 8-12 weeks or chlorambucil 0.1-0.2 mg/kg/day for 8 weeks) are recommended for frequently relapsing steroid-sensitive nephrotic syndrome 3
• Levamisole at 2.5 mg/kg on alternate days for at least 12 months is recommended as a corticosteroid-sparing agent 3
• Calcineurin inhibitors (cyclosporine 3-5 mg/kg/day or tacrolimus 0.05-0.1 mg/kg/day) for 1-2 years for patients who have relapsed despite cyclophosphamide or wish to preserve fertility 3
• Rituximab should be considered for steroid-dependent or frequently relapsing nephrotic syndrome 1
• Mycophenolate mofetil 500-1000 mg twice daily for 1-2 years for patients intolerant of corticosteroids, cyclophosphamide, and calcineurin inhibitors 3

Supportive Management During Initial Treatment

• Restrict dietary sodium to <2.0 g/day to reduce edema 7
• Use loop diuretics as first-line agents for edema management 7
• Initiate ACE inhibitors or ARBs at maximally tolerated doses for proteinuria and blood pressure control 7
• Administer pneumococcal and influenza vaccines (live vaccines are contraindicated in children receiving immunosuppressive agents) 2, 7

Critical Pitfalls to Avoid

• Do not discontinue steroids too rapidly, as this significantly increases relapse risk 1, 7
• Do not use weight-based dosing exclusively in children <30 kg without verifying equivalence to BSA-based dosing, as this may result in underdosing and increased relapse rates 5, 6
• Do not treat infants <1 year with standard protocols without genetic evaluation and specialized pediatric nephrology consultation 1, 2
• Monitor for steroid side effects including growth suppression in children, which may occur even without laboratory evidence of HPA axis suppression 8
• Avoid intravenous fluids and saline in nephrotic patients; concentrate oral fluid intake if necessary 7
• Approximately 80% of children will experience at least one relapse, and 50% will have frequent relapses or become steroid-dependent, so anticipate this trajectory 1