How should a relapse of nephrotic syndrome be managed?

Management of Nephrotic Syndrome Relapse in Children

For a relapse of nephrotic syndrome in children, treat with oral prednisone/prednisolone for 8-12 weeks: either 4 weeks daily followed by 4 weeks alternate-day, or 6 weeks daily followed by 6 weeks alternate-day glucocorticoids 1.

Initial Treatment of Relapse

The 2025 KDIGO guidelines provide clear direction on relapse management:

• Start oral glucocorticoids immediately when relapse is confirmed (proteinuria for 3 consecutive days)
• Two acceptable regimens exist with equivalent efficacy:
  • 8-week course: 4 weeks daily + 4 weeks alternate-day
  • 12-week course: 6 weeks daily + 4 weeks alternate-day
• Both regimens carry a 1B recommendation strength 1

Dosing Considerations

While the guidelines specify duration, standard dosing is typically:

• Daily phase: 60 mg/m² or 2 mg/kg/day (maximum 60 mg)
• Alternate-day phase: Same dose given every other day
• Single daily dosing is as effective as divided doses and improves compliance 2

Key Management Decisions Based on Relapse Pattern

For Infrequently Relapsing Nephrotic Syndrome

• Use the standard 8-12 week glucocorticoid regimen for each relapse
• No steroid-sparing agents needed unless glucocorticoid toxicity develops
• Monitor for progression to frequently relapsing pattern

For Frequently Relapsing Nephrotic Syndrome (FRNS)

Without glucocorticoid toxicity:

• Continue using standard glucocorticoid regimens for relapses 1
• Consider low-dose alternate-day prednisone/prednisolone for relapse prevention (Practice Point) 1
• Preferred steroid-sparing agents: oral cyclophosphamide or levamisole 1

With serious glucocorticoid toxicity:

• Initiate glucocorticoid-sparing agents (1B recommendation) 1
• Consider shorter tapers for subsequent relapses 1
• Options include: cyclophosphamide, levamisole, calcineurin inhibitors, mycophenolate mofetil, or rituximab

For Steroid-Dependent Nephrotic Syndrome (SDNS)

All children with SDNS should receive glucocorticoid-sparing agents to prevent relapses rather than continuing glucocorticoids alone (1B recommendation) 1.

Preferred steroid-sparing agents for SDNS:

• Mycophenolate mofetil
• Rituximab
• Calcineurin inhibitors (cyclosporine or tacrolimus)
• Oral cyclophosphamide (to lesser extent)

Critical Practice Changes from 2025 Guidelines

What NOT to Do

Do not routinely give daily glucocorticoids during upper respiratory tract infections to prevent relapses in children with FRNS or SDNS (1C recommendation) 1. This represents a significant change based on the PREDNOS2 study showing no benefit of prophylactic steroids during infections.

Exception: For children already on low-dose alternate-day prednisolone with history of repeated infection-associated relapses or significant steroid morbidity, consider 3 extra doses of low-dose prednisolone (0.5 mg/kg/day) at infection onset 1.

Steroid-Sparing Agent Implementation

When initiating glucocorticoid-sparing agents:

• Achieve remission with glucocorticoids first before starting the agent
• Continue glucocorticoids for 2 weeks after initiating the steroid-sparing medication 1
• No formal hierarchy of "first-line" vs "alternative" agents exists—choice depends on relapse pattern and individual factors

Agent Selection Algorithm

For FRNS: Cyclophosphamide or levamisole preferred

For SDNS: Mycophenolate mofetil, rituximab, or calcineurin inhibitors preferred

For complicated FRNS/SDNS: Consider mycophenolate mofetil after rituximab to decrease treatment failure risk 1

Common Pitfalls to Avoid

1. Underdosing during relapse: Ensure proper weight/BSA-based dosing, not arbitrary fixed doses
2. Premature discontinuation: Complete the full 8-12 week course even if remission occurs quickly
3. Delaying steroid-sparing agents: Don't wait for multiple relapses if glucocorticoid toxicity is already present
4. Routine infection prophylaxis with steroids: This practice is no longer recommended based on recent evidence 1
5. Ignoring quality of life: Glucocorticoid toxicity significantly impacts QOL and should prompt earlier use of steroid-sparing agents 3

Monitoring During Relapse Treatment

• Daily urine protein monitoring (dipstick) until 3 consecutive days of nil proteinuria
• Monitor for complications: severe edema, infections, acute kidney injury, thromboembolism
• Assess for glucocorticoid toxicity: weight gain, hypertension, behavioral changes, hyperglycemia
• For children on calcineurin inhibitors: regular blood pressure, renal function, and therapeutic drug monitoring 4