What is the initial treatment for nephrotic syndrome?

Initial Treatment for Nephrotic Syndrome

Begin oral prednisone at 1 mg/kg/day (maximum 80 mg) or alternate-day dosing at 2 mg/kg (maximum 120 mg) for adults, and 60 mg/m²/day (maximum 80 mg/day) or 2 mg/kg/day for children, continuing high-dose therapy for a minimum of 4 weeks and up to 16 weeks as tolerated until complete remission is achieved. 1, 2, 3, 4

Pediatric Initial Treatment Protocol

For children presenting with their first episode of nephrotic syndrome:

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

Critical Dosing Consideration in Children

Weight-based dosing (2 mg/kg/day) delivers significantly less prednisone than BSA-based dosing (60 mg/m²/day) in children weighing <30 kg, which increases the risk of frequent relapses. 5, 6 The evidence shows that underdosing by using weight-based calculations results in a 16.6% relative underdose in frequently relapsing patients compared to 8.7% in infrequent relapsers. 6 Therefore, use BSA-based dosing (60 mg/m²/day) preferentially in smaller children to optimize outcomes. 5, 6

Duration Matters for Pediatric Outcomes

The Canadian Society of Nephrology working group supports extending initial treatment up to 6 months based on evidence showing that longer initial corticosteroid therapy reduces relapse rates. 1 A landmark study demonstrated that short-course therapy (stopping after remission) resulted in only 19% sustained remission at 2 years versus 41% with standard 8-week therapy, with mean remission duration being half as long (79 vs 169 days). 7 This evidence strongly supports completing the full 12-week minimum course rather than stopping early after remission. 7

Adult Initial Treatment Protocol

For adults with nephrotic syndrome:

• Administer prednisone at 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) 1, 2, 3
• Continue high-dose corticosteroids for a minimum of 4 weeks if complete remission is achieved 1, 3
• If remission is not achieved, continue up to a maximum of 16 weeks as tolerated 1, 3
• Adults respond more slowly than children and require longer treatment courses to achieve similar remission rates 8
• After achieving remission, taper corticosteroids slowly over a period of up to 6 months 1, 3

Steroid Resistance Definition in Adults

Steroid resistance should only be assumed after failure to respond to a 4-month (16-week) course of daily steroid therapy. 1, 8 This is critical because adults with focal segmental glomerulosclerosis can achieve remission rates up to 60% with prolonged courses, despite historically poor results with shorter treatment durations. 8

When to Defer or Modify Initial Corticosteroid Therapy

Consider alternative first-line therapy with calcineurin inhibitors (cyclosporine 3-5 mg/kg/day or tacrolimus 0.05-0.1 mg/kg/day) in patients with:

• Uncontrolled diabetes 1, 3
• Psychiatric conditions 1, 3
• Severe osteoporosis 1, 3
• Other relative contraindications to high-dose corticosteroids 1, 3

Kidney Biopsy Considerations Before Treatment

In adults, perform kidney biopsy before initiating immunosuppressive therapy to confirm the underlying pathology. 3 However, in children with typical presentation (age 1-10 years, no hematuria, normal complement, normal blood pressure), biopsy may be deferred if there is response to initial steroid therapy. 1, 3 Children younger than 1 year are more likely to have genetic causes and should undergo different evaluation before standard treatment. 4

Essential Supportive Management Alongside Immunosuppression

Initiate these measures concurrently with corticosteroid therapy:

• Restrict dietary sodium to <2.0 g/day 2
• Use loop diuretics as first-line agents for edema management 2
• Start ACE inhibitors or ARBs at maximally tolerated doses for proteinuria and blood pressure control 2
• Target systolic blood pressure <120 mmHg using standardized office measurement 2
• Administer pneumococcal and influenza vaccines 2, 3
• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose immunosuppression 2

Management of Relapses

For infrequent relapses (defined as ≥3+ protein on urine dipstick for 3 consecutive days):

• Treat with prednisone 60 mg/m²/day (maximum 60 mg/day) until remission for at least 3 days 4
• After achieving remission, switch to alternate-day prednisone (40 mg/m² or 1.5 mg/kg) for at least 4 weeks 4
• Use the same initial dose and duration as for first episodes 1

For frequent relapses or steroid-dependent nephrotic syndrome, consider steroid-sparing agents including:

• Alkylating agents (cyclophosphamide 2 mg/kg/day for 8-12 weeks or chlorambucil 0.1-0.2 mg/kg/day for 8 weeks) 1
• Levamisole at 2.5 mg/kg on alternate days for at least 12 months 1
• Calcineurin inhibitors (cyclosporine or tacrolimus) for 1-2 years 1
• Mycophenolate mofetil 500-1000 mg twice daily for 1-2 years 1
• Rituximab 4

The Canadian Society of Nephrology working group does not support low-dose daily or alternate-day maintenance corticosteroids for steroid-dependent patients when second-line agents are available, as there is higher quality evidence for steroid-sparing agents. 1

Critical Pitfalls to Avoid

Do not discontinue steroids too rapidly after remission, as this dramatically increases relapse risk—the taper should extend over 6 months. 1, 3, 4 Do not assume steroid resistance prematurely in adults; allow the full 16-week trial before declaring treatment failure. 1, 8 Do not use weight-based dosing in children <30 kg without recognizing you are delivering a lower dose than BSA-based calculations. 5, 6 Do not treat infants under 1 year with standard regimens without genetic evaluation, as they frequently have hereditary forms requiring different management. 4