What are the latest treatment guidelines for pediatric patients with nephrotic syndrome?

Latest Guidelines for Pediatric Nephrotic Syndrome

The most recent 2025 KDIGO guidelines recommend treating children with their first episode of nephrotic syndrome with oral prednisone 60 mg/m²/day (or 2 mg/kg/day, maximum 60 mg) for 4-6 weeks, followed by alternate-day prednisone 40 mg/m² for 2-5 months, with a total treatment duration of 8-12 weeks minimum instead of the previously recommended 24 weeks. 1, 2

Initial Episode Management

Corticosteroid Regimen

• Start with oral prednisone 60 mg/m²/day or 2 mg/kg/day (maximum 60 mg/day) as a single morning dose for 4-6 weeks 1, 2
• After the initial daily phase, switch to alternate-day prednisone 40 mg/m² for 2-5 months 1, 2
• Total minimum treatment duration should be 8-12 weeks (this represents a major change from the 2012 guidelines which recommended up to 24 weeks) 1, 2
• The shorter duration reduces glucocorticoid toxicity while maintaining comparable efficacy 1

Important Considerations for Initial Treatment

• Children under 1 year of age likely have genetic causes and should be managed differently with early genetic testing 1, 3
• Most children (approximately 85%) will respond within 4 weeks and are classified as steroid-sensitive 4
• Despite high initial response rates, 80% will experience at least one relapse, and 50% will become frequent relapsers or steroid-dependent 1

Relapse Management

Infrequent Relapses

• Treat with prednisone 60 mg/m²/day or 2 mg/kg (maximum 60 mg/day) until complete remission for 3 consecutive days 1, 2, 3
• Then switch to alternate-day prednisone 40 mg/m² or 1.5 mg/kg (maximum 40 mg on alternate days) for at least 4 weeks 1, 2, 3

Frequently Relapsing and Steroid-Dependent Disease

• Treat relapses with daily prednisone until remission for 3 days, followed by alternate-day prednisone for at least 3 months 1, 3
• During upper respiratory infections, give 0.5 mg/kg/day of prednisone for one week to reduce relapse risk in children already on alternate-day therapy 1, 3
• For children with serious glucocorticoid-related adverse effects (frequently relapsing) or all children with steroid-dependent disease, glucocorticoid-sparing agents should be prescribed rather than continuing corticosteroids alone 1, 2, 3

Glucocorticoid-Sparing Agents

The 2025 KDIGO guidelines removed the formal distinction between first-line and alternative agents, instead recommending agent selection based on disease pattern 1:

For Frequently Relapsing Disease (Preferred Options)

• Oral cyclophosphamide: 2 mg/kg/day for 8-12 weeks (maximum cumulative dose 168 mg/kg) 1, 2, 3
  • Must achieve remission with glucocorticoids before starting 1, 3
  • Monitor CBC weekly during treatment 1
  • Do not give second courses of alkylating agents due to cumulative toxicity 3
• Levamisole: 2.5 mg/kg on alternate days for at least 12 months 1, 2, 3
  • Monitor CBC every 2-3 months and liver enzymes every 3-6 months 1
  • Check ANCA titers every 6 months if possible 1

For Steroid-Dependent Disease (Preferred Options)

• Mycophenolate mofetil: 1200 mg/m²/day in two divided doses for at least 12 months 2, 3
• Rituximab: 1-4 doses (specific dosing varies by protocol) 1, 2
  • Consider in complicated cases with continuing frequent relapses despite optimal combinations of prednisone and other agents 3
  • Mycophenolate mofetil after rituximab can decrease risk of treatment failure 1
• Calcineurin inhibitors (cyclosporine or tacrolimus) 1, 2, 3
  • Regular monitoring of kidney function is essential 3
• Oral cyclophosphamide (to a lesser extent than in frequently relapsing disease) 1

Key Principles for Glucocorticoid-Sparing Agents

• Patients should ideally be in remission with glucocorticoids before initiating these agents 1
• Continue glucocorticoids for 2 weeks following initiation of glucocorticoid-sparing agents 1
• Treatment duration typically requires at least 12 months 3

Steroid-Resistant Nephrotic Syndrome (SRNS)

Diagnostic Evaluation

• Kidney biopsy is required for all children with SRNS 1
• Genetic testing should be performed 1
• Evaluate kidney function by GFR or eGFR 1
• Quantify urine protein excretion 1

Treatment Approach

• Use cyclosporine or tacrolimus as initial second-line therapy 1, 2
• Continue CNI therapy for minimum 6 months; stop if no partial or complete remission achieved 1
• If at least partial remission achieved by 6 months, continue CNI for minimum 12 months 1
• Combine with low-dose corticosteroid therapy 1
• Add ACE inhibitors or ARBs for all children with SRNS 1

For CNI Failure

• Consider mycophenolate mofetil, high-dose corticosteroids, or combination of these agents 1
• Recent evidence suggests rituximab may achieve remission in approximately 30% of children with CNI-resistant SRNS 1
• Do not give cyclophosphamide to children with SRNS 1
• Genetic testing may clarify whether immunosuppression will be beneficial, as most podocyte mutations will not respond 1

For Patients Who Switch to MMF

• Consider switching from CNI to MMF to maintain remission and avoid long-term CNI toxicity 1

Indications for Kidney Biopsy

Perform kidney biopsy in the following situations: 1, 3

• Late failure to respond following initial response to corticosteroids
• High index of suspicion for different underlying pathology
• Decreasing kidney function in children receiving CNIs
• Steroid resistance (defined as failure to respond after minimum 8 weeks of corticosteroid treatment) 1

Common Pitfalls to Avoid

• Do not use shorter than 8-week initial treatment courses, as this increases relapse rates despite the goal of reducing glucocorticoid exposure 1
• Transition to alternate-day therapy as soon as remission is achieved to minimize adrenocortical suppression and other adverse effects 3
• Never start cyclophosphamide until remission is achieved with glucocorticoids 1, 3
• Avoid second courses of alkylating agents due to cumulative gonadal and malignancy risks 3
• Do not use azathioprine as a corticosteroid-sparing agent in frequently relapsing or steroid-dependent disease 1
• Monitor kidney function closely in all patients on CNIs, as decreasing function is an indication for biopsy 1, 3