Management of Pediatric Nephrotic Syndrome
For children under 12 years presenting with new-onset nephrotic syndrome without syndromic features or family history, immediately initiate oral prednisone/prednisolone for either 8 weeks (4 weeks daily + 4 weeks alternate-day) or 12 weeks (6 weeks daily + 6 weeks alternate-day). 1
Initial Evaluation and Risk Stratification
Age-Based Approach
Children < 12 years old:
- If no syndromic features (skeletal abnormalities, neurodevelopmental delays, ocular abnormalities, deafness, genital ambiguity, facial dysmorphisms) or family history: Start glucocorticoids empirically without biopsy 1
- Approximately 85-90% will achieve complete remission (steroid-sensitive nephrotic syndrome) 2
Children ≥ 12 years old OR any age with syndromic features/family history:
- Proceed directly to kidney biopsy and/or genetic testing
- Refer to specialty center 1
Clinical Presentation to Document
- Heavy proteinuria (nephrotic-range)
- Hypoalbuminemia
- Edema (periorbital, facial, peripheral, ascites)
- Assess for complications: hypovolemia, infections, thromboembolism risk 3
Initial Treatment Protocol
Glucocorticoid Regimen (First Episode)
Two acceptable regimens with equal efficacy 1:
- 8-week protocol: 4 weeks daily prednisone/prednisolone, then 4 weeks alternate-day
- 12-week protocol: 6 weeks daily prednisone/prednisolone, then 6 weeks alternate-day
Dosing: Calculate based on body surface area for accurate dosing during relapses 4
Response Assessment
Complete response (steroid-sensitive):
- Continue monitoring for relapses
- 70-80% will experience at least one relapse 2
No response after 4-6 weeks (steroid-resistant):
- Initiate genetic testing
- Perform kidney biopsy
- Start calcineurin inhibitor (cyclosporine or tacrolimus) 1
- Add renin-angiotensin-aldosterone system blockade
Management of Relapsing Disease
Frequent Relapses Without Glucocorticoid Toxicity
First-line options:
- Low-dose alternate-day oral prednisone/prednisolone may be continued 1
- Preferred steroid-sparing agents: Cyclophosphamide or levamisole 1
Frequent Relapses WITH Glucocorticoid Toxicity or Steroid-Dependent Disease
Glucocorticoid-sparing agents are mandatory 1:
For steroid-dependent nephrotic syndrome, preferred agents:
- Mycophenolate mofetil
- Rituximab (1-4 doses, though optimal dosing unclear)
- Calcineurin inhibitors (cyclosporine or tacrolimus)
- Cyclophosphamide (to lesser extent)
Critical implementation points:
- Achieve remission with glucocorticoids before starting steroid-sparing agent
- Continue glucocorticoids for 2 weeks after initiating the new agent 1
- In complicated cases: Consider mycophenolate mofetil after rituximab to decrease treatment failure risk 1
Important Update on Infection-Associated Relapses
Do NOT routinely give daily glucocorticoids during upper respiratory tract infections or other infections to prevent relapses in children with frequently relapsing or steroid-dependent nephrotic syndrome 1. This represents a significant change from prior practice based on the PREDNOS2 study showing no benefit.
Exception: In select patients already on low-dose alternate-day prednisolone with history of repeated infection-associated relapses AND significant prednisone-related morbidity, consider 3 extra doses of low-dose (0.5 mg/kg/day) prednisone at infection onset 1
Steroid-Resistant Nephrotic Syndrome
Initial second-line therapy: Cyclosporine or tacrolimus 1
If calcineurin inhibitor-resistant:
- Rituximab achieves remission in approximately 30% of children 1
- Mycophenolate mofetil has very limited evidence 1
Supportive Care During Relapses
Edema Management
- Assess intravascular volume status carefully before diuretics 4
- Progressive edema with weight gain: Escalate to IV furosemide with 20% human albumin 4
- Monitor for hypovolemia despite edema
Infection Prophylaxis
- Penicillin V for spontaneous bacterial peritonitis prophylaxis during severe hypoalbuminemia 4
- Monitor for leukocytosis, fever during relapses
Monitoring During Calcineurin Inhibitor Therapy
- Regular blood pressure monitoring
- Renal function assessment
- Therapeutic drug monitoring (trough concentrations)
- Assess for calcineurin inhibitor toxicity with prolonged use 4
Common Pitfalls to Avoid
- Underdosing prednisolone during relapses: Use body surface area-based calculations, not just weight 4
- Premature diuretic use: Can precipitate hypovolemic crisis; assess volume status first 4
- Routine steroids during infections: No longer recommended based on recent evidence 1
- Delaying steroid-sparing agents: Mandatory in steroid-dependent disease and frequent relapses with toxicity 1
- Continuing calcineurin inhibitors indefinitely without monitoring: Regular toxicity assessment required 4
Key Definitions for Treatment Decisions
The 2025 KDIGO guidelines refined definitions to guide therapy changes 5:
- Relapse: Return of significant proteinuria after remission
- Frequently-relapsing: Pattern requiring steroid-sparing consideration
- Steroid-dependent: Relapse during steroid taper or within period after discontinuation
- Steroid-resistant: No complete remission after 4-6 weeks of glucocorticoids
The KDIGO 2025 guidelines eliminated the formal distinction between "first-line" and "alternative" steroid-sparing agents, instead recommending agent selection based on relapse pattern and steroid-dependence status 1.