What is the initial treatment for nephrotic syndrome?

Initial Treatment for Nephrotic Syndrome

Begin oral prednisone at 60 mg/m²/day (maximum 60 mg) as a single daily dose for 4-6 weeks in children, or 1 mg/kg/day (maximum 80 mg) in adults, followed by a prolonged tapering regimen to minimize relapse risk. 1, 2

Diagnostic Confirmation Before Treatment

• Confirm nephrotic-range proteinuria using 24-hour urine collection or spot urine protein-to-creatinine ratio before initiating therapy 1
• In children with typical presentation (age 1-10 years, edema, proteinuria), kidney biopsy may be deferred if there is response to initial steroid therapy 1, 2
• Critical caveat: Children younger than 1 year require different management as they are more likely to have genetic forms of nephrotic syndrome and should not receive standard corticosteroid protocols without further evaluation 2
• Adults generally require kidney biopsy before starting immunosuppressive therapy to establish the underlying histologic diagnosis 1

Corticosteroid Protocol for Children

Daily Phase:

• Administer prednisone 60 mg/m²/day or 2 mg/kg/day (maximum 60 mg/day) as a single daily dose for 4-6 weeks 2, 3, 4
• Important dosing consideration: Weight-based dosing (2 mg/kg/day) may result in underdosing compared to BSA-based dosing (60 mg/m²/day) in children weighing less than 30 kg, which can increase the risk of frequent relapses 5, 6
• Use BSA-based dosing (60 mg/m²/day) rather than weight-based dosing to optimize outcomes, particularly in smaller children 5, 6

Alternate-Day Phase:

• After the daily phase, transition to alternate-day prednisone at 40 mg/m² or 1.5 mg/kg (maximum 40 mg on alternate days) 2, 3
• Continue alternate-day dosing for 2-5 months with gradual tapering 2, 3

Total Duration:

• The total initial treatment duration should be at least 12 weeks, with strong evidence supporting prolonged therapy up to 6 months to significantly reduce relapse rates 7, 2, 8
• Meta-analysis demonstrates an inverse linear relationship between treatment duration and relapse risk, with benefit extending up to 7 months of therapy 8
• In populations with 60% baseline relapse risk after 2 months of prednisone, extending treatment to 6 months reduces relapses by approximately 40% 8

Corticosteroid Protocol for Adults

• Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) 1, 3
• Continue high-dose therapy for a minimum of 4 weeks if complete remission is achieved 1, 3
• If remission is not achieved, continue up to 16 weeks before declaring steroid resistance 1, 3
• After achieving remission, taper slowly over up to 6 months 1

Alternative First-Line Therapy

For patients with contraindications to high-dose corticosteroids (uncontrolled diabetes, severe psychiatric conditions, severe osteoporosis, or morbid obesity with elevated HbA1c), consider calcineurin inhibitors as first-line therapy: 3

• Cyclosporine: 3-5 mg/kg/day in divided doses 3
• Tacrolimus: 0.05-0.1 mg/kg/day in divided doses (adults) or 0.1-0.2 mg/kg/day (children) 3

Supportive Management of Edema/Anasarca

• Loop diuretics (furosemide) are first-line for managing severe edema 3
• Restrict dietary sodium to <2.0 g/day 3
• Avoid routine intravenous albumin infusions; use only if clinical indicators of hypovolemia are present (hypotension, tachycardia, poor perfusion), not based on serum albumin levels alone 3
• Avoid intravenous saline administration, which can worsen edema 3

Infection Prevention (Critical During Immunosuppression)

• Administer pneumococcal vaccination (23-valent or conjugate vaccine) before or early in immunosuppressive therapy 1, 3
• Provide annual influenza vaccination to patients and household contacts 1, 3
• Live vaccines are contraindicated in children receiving immunosuppressive agents 1

Monitoring Treatment Response

• Monitor urine protein daily using dipstick or spot urine protein-to-creatinine ratio 3
• Complete remission is defined as urine protein <200 mg/g (<20 mg/mmol) or trace/negative on dipstick for 3 consecutive days 1, 3
• Do not declare steroid resistance until at least 8 weeks of adequate corticosteroid therapy has been completed 1, 3
• Regularly assess for corticosteroid side effects including obesity, poor growth, hypertension, diabetes, and osteoporosis 2, 9

Management of Relapses

Relapse is defined as ≥3+ protein on urine dipstick for 3 consecutive days or uPCR ≥2000 mg/g (≥200 mg/mmol) 2

For infrequent relapses:

• Treat with prednisone 60 mg/m²/day (maximum 60 mg/day) until remission for at least 3 days 2, 3
• Switch to alternate-day prednisone (40 mg/m² per dose) for at least 4 weeks 2, 3

For frequent relapses or steroid-dependent disease:

• Treat relapses with daily prednisone until remission, followed by alternate-day prednisone for at least 3 months 3
• Consider steroid-sparing agents including alkylating agents (cyclophosphamide or chlorambucil), levamisole, calcineurin inhibitors, mycophenolate mofetil, or rituximab 7, 2, 3
• The Canadian Society of Nephrology recommends calcineurin inhibitors or alkylating agents over low-dose maintenance corticosteroids for steroid-dependent nephrotic syndrome, given higher quality evidence for second-line agents 7

Common Pitfalls to Avoid

• Do not discontinue steroids too rapidly, as this significantly increases relapse risk 2
• Do not use weight-based dosing in children under 30 kg without recognizing the risk of underdosing; BSA-based dosing is preferred 5, 6
• Do not stop therapy prematurely if partial response is occurring; continue up to 16 weeks in adults 3
• Approximately 80% of children will experience at least one relapse, and 50% will have frequent relapses or become steroid-dependent, so counsel families accordingly 2
• Monitor growth velocity in children on prolonged corticosteroid therapy, as it may be a more sensitive indicator of systemic exposure than HPA axis testing 9