What is the treatment for a patient experiencing a relapse of nephrotic syndrome, considering their previous treatment response and underlying cause?

Treatment of Relapse Nephrotic Syndrome

For patients experiencing a relapse of nephrotic syndrome, restart the same therapy that successfully induced the original remission, using daily prednisone at 60 mg/m² (maximum 60 mg/day) until remission for at least 3 consecutive days, followed by alternate-day prednisone at 40 mg/m² for at least 3 months. 1, 2

Initial Management of Relapse

Corticosteroid Reinduction Protocol

• Administer daily prednisone at 60 mg/m² or 2 mg/kg (maximum 60 mg/day) as a single morning dose until complete remission is achieved for at least 3 consecutive days 2, 3

• Complete remission is defined as urine protein <200 mg/g or trace/negative on dipstick for 3 consecutive days 4

• After achieving remission, transition to alternate-day prednisone at 40 mg/m² or 1.5 mg/kg (maximum 40 mg on alternate days) for at least 3 months 2, 3

• For infrequent relapsers (≤2 relapses in 6 months), a minimum 4-week course of alternate-day prednisone after remission induction is acceptable 1

Return to Previously Successful Therapy

• If the patient achieved remission with a specific immunosuppressive agent previously, restart that same agent rather than trying a new approach 1

• This principle applies to calcineurin inhibitors, cyclophosphamide, or other steroid-sparing agents that were effective 1

• Important caveat: If the original therapy was cyclophosphamide and resuming it would exceed safe cumulative lifetime exposure (>168 mg/kg in children, >200 mg/kg in adults), choose an alternative non-cyclophosphamide regimen 1, 2

Management Based on Relapse Frequency

Frequent Relapsers (≥2 relapses in 6 months)

• After achieving remission with daily prednisone, continue alternate-day prednisone for at least 3 months rather than the shorter 4-week course used for infrequent relapsers 2, 3

• Consider adding corticosteroid-sparing agents if the patient develops steroid-related adverse effects or continues to have frequent relapses despite optimal prednisone therapy 2

• First-line steroid-sparing options include:

  • Levamisole 2.5 mg/kg on alternate days for at least 12 months 2
  • Cyclophosphamide 2 mg/kg/day for 8-12 weeks (maximum cumulative dose 168 mg/kg) 2
  • Calcineurin inhibitors: cyclosporine 3-5 mg/kg/day or tacrolimus, continued for minimum 12 months 1, 2
  • Mycophenolate mofetil 1200 mg/m²/day in two divided doses for at least 12 months 2

Steroid-Dependent Patients

• For patients who relapse during steroid tapering or within 2 weeks of stopping steroids, consider rituximab if they have continuing frequent relapses despite optimal combinations of prednisone and steroid-sparing agents, or have serious adverse effects from therapy 2

• Calcineurin inhibitors are particularly effective in steroid-dependent cases, producing complete remissions in 85% of children and 79% of adults 5

Special Clinical Scenarios

Infection-Triggered Relapses

• For children on alternate-day prednisone who have a history of infection-triggered relapses, consider increasing to daily prednisone during episodes of upper respiratory tract infections to prevent relapse 2, 3

• Specifically, increase prednisone to 0.5 mg/kg/day for 5-7 days during respiratory infections 3

Pregnancy-Related Relapses

• If relapse occurs during pregnancy, treat with corticosteroids as first-line therapy 1

• Depending on severity, add azathioprine rather than mycophenolate mofetil, cyclophosphamide, ACE inhibitors, or ARBs, which are contraindicated in pregnancy 1

• Do not taper corticosteroids or azathioprine during pregnancy or for at least 3 months after delivery 1

When to Consider Repeat Kidney Biopsy

• Perform repeat kidney biopsy if there is suspicion that the histological pattern has changed, uncertainty whether rising creatinine or worsening proteinuria represents active disease versus chronic scarring, or late failure to respond following initial response 1

• Consider biopsy if kidney function is decreasing in patients receiving calcineurin inhibitors 1

• Biopsy is particularly important if the diagnosis of relapse remains uncertain, as this informs whether to proceed with immunosuppression 1

Monitoring During Relapse Treatment

• Monitor urine protein daily using dipstick or spot urine protein-to-creatinine ratio to assess treatment response 4

• Regular assessment of kidney function is essential, especially in patients receiving calcineurin inhibitors 2

• Do not declare treatment failure until at least 8 weeks of adequate corticosteroid therapy has been completed; adults may require up to 16 weeks to respond 4, 5

Critical Pitfalls to Avoid

• Never start cyclophosphamide until the patient has achieved remission with corticosteroids first 2

• Avoid second courses of alkylating agents due to cumulative gonadal and oncogenic toxicity; if a second course is absolutely necessary, ensure total lifetime cyclophosphamide dose remains below 200 mg/kg 2, 5

• Do not abruptly stop alternate-day prednisone; taper gradually over the recommended 3-month period to minimize relapse risk 2, 6

• Relapses are common following withdrawal of calcineurin inhibitors (occurring in 67-85% of patients), so plan for slow tapering over several months rather than abrupt discontinuation 3, 5

• Verify medication adherence before escalating therapy or declaring treatment failure 1

• Ensure adequate dosing by measuring plasma drug levels when applicable (mycophenolic acid levels, calcineurin inhibitor trough levels) 1