Nephrotic Syndrome in Children: Diagnostic Criteria and First-Line Treatment
Diagnostic Criteria
Pediatric nephrotic syndrome is diagnosed by the presence of nephrotic-range proteinuria (first morning urine protein-to-creatinine ratio ≥2 g/g) plus hypoalbuminemia (serum albumin ≤2.5 g/dL). 1
Key Diagnostic Parameters:
- Proteinuria threshold: First morning spot urine protein-to-creatinine ratio (UPCR) ≥2 g/g, which has replaced 24-hour urine collections (≥40 mg/h/m²) due to ease of collection and good correlation 1
- Albumin cutoff: ≤2.5 g/dL (not <3 g/dL as suggested in some newer guidelines, since evidence for the higher threshold is lacking) 1
- Associated findings: Edema, hyperlipidemia, and elevated cholesterol are typical but not required for diagnosis 2, 3
Clinical Presentation:
- Typical age: 2-7 years, though can occur from age 1-10 years 2, 3
- Presenting symptoms: Sudden onset of edema (periorbital, scrotal, or generalized), foamy urine 2, 4
- Red flags requiring kidney biopsy: Age <1 year or >12 years at onset, macroscopic hematuria, hypertension, low C3 complement, persistent renal failure, or steroid resistance after 8 weeks 1, 2
First-Line Treatment: Oral Glucocorticoids
All children with newly diagnosed nephrotic syndrome should receive oral prednisone 60 mg/m²/day (maximum 60 mg/day) as a single morning dose for 4-6 weeks, followed by 40 mg/m² on alternate days for another 4-6 weeks. 1, 5
Standard Treatment Protocols:
Two evidence-based regimens are recommended:
8-week protocol:
- 60 mg/m²/day for 4 weeks daily
- Then 40 mg/m² on alternate days for 4 weeks 1
12-week protocol:
Rationale for Protocol Selection:
- Choose 8-week regimen for children who achieve rapid remission (within 7 days) or those at high risk for steroid complications (obesity, diabetes, psychiatric illness) 1
- Choose 12-week regimen for typical presentations to potentially reduce relapse risk, though evidence for superiority beyond 12 weeks is lacking 1
Expected Response:
- Remission definition: Urine dipstick trace/negative for proteinuria for at least 3 consecutive days 1, 5, 6
- Response rate: 85-90% of children achieve remission with initial steroid therapy 2, 7, 3
- Steroid resistance: Defined as failure to achieve remission after 8 weeks of corticosteroid therapy 1, 5
Treatment Algorithm Based on Response
For Steroid-Sensitive Nephrotic Syndrome (SSNS):
Relapse Management:
- Relapse definition: Urine dipstick ≥3+ protein for 3 consecutive days after previous remission 6
- Treatment: Resume prednisone 60 mg/m²/day until remission (≥3 consecutive days trace/negative), then switch to 40 mg/m² alternate days for 4 weeks 1
Frequent Relapses or Steroid Dependence:
- Indications for steroid-sparing agents: ≥2 relapses in 6 months (frequently relapsing) or relapse during steroid taper/within 14 days of stopping steroids (steroid-dependent) 6, 4
- First-line steroid-sparing agent: Levamisole 2.5 mg/kg on alternate days (maximum 150 mg) for minimum 12 months 6
- Alternative agents (if levamisole unavailable or fails): Oral cyclophosphamide 2 mg/kg/day for 12 weeks (cumulative maximum 168 mg/kg, never repeat due to gonadal toxicity), or calcineurin inhibitors (cyclosporine 4-5 mg/kg/day or tacrolimus 0.1 mg/kg/day) 1, 6
For Steroid-Resistant Nephrotic Syndrome (SRNS):
After 8 weeks without remission:
- Mandatory kidney biopsy to confirm diagnosis and guide therapy (unless genetic/familial cause known) 1, 8
- First-line immunosuppression: Calcineurin inhibitors—cyclosporine 4-5 mg/kg/day (target trough 60-150 ng/mL) or tacrolimus 0.1 mg/kg/day (target trough 5-10 ng/mL) for minimum 6 months 1, 6, 8
- Continue CNI for 12-24 months if partial or complete remission achieved by 6 months 1, 6
- Second-line options if CNI fails: Mycophenolate mofetil 1200 mg/m²/day divided twice daily, or rituximab 375 mg/m² IV for 1-4 doses 6, 8
Critical Pitfalls to Avoid
During Initial Treatment:
- Never start steroid-sparing agents during active relapse—always achieve remission with prednisone first 6, 8
- Avoid premature steroid discontinuation—complete the full 8-12 week initial course even if remission occurs early 1, 5
- Do not perform kidney biopsy in typical presentations (age 1-10 years, no red flags, steroid-responsive)—biopsy is reserved for atypical features or steroid resistance 1, 2
With Steroid-Sparing Agents:
- Never give a second course of cyclophosphamide—cumulative gonadal toxicity is irreversible 6, 8
- Monitor for levamisole neutropenia—check complete blood count every 2-3 months and stop immediately if neutropenia develops 6
- Assess CNI nephrotoxicity—monitor serum creatinine regularly and perform kidney biopsy if renal function declines 1, 6
- Maintain adequate treatment duration—most steroid-sparing agents require minimum 12 months; shorter courses lead to higher relapse rates 6, 8
Acute Complications:
- Infection risk is highest in initial nonresponders and early relapsers—nearly one-fifth of initial nonresponders with minimal change disease died in historical cohorts, primarily from infection 9
- Monitor for hypovolemia, thrombosis, and peritonitis—these are life-threatening complications requiring immediate recognition 2, 3, 4
- Restrict fluids to insensible losses plus urine output during severe edema/oliguria to prevent volume overload 5, 8
Supportive Care Measures
During Active Nephrotic Syndrome:
- Salt restriction and fluid restriction only when serum sodium <125 mEq/L 2
- Diuretics (furosemide) reserved for severe edema after correcting hypovolemia; consider albumin 0.5-1 g/kg IV before diuretic doses in severely hypoalbuminemic patients 1, 8, 2
- Calcium and vitamin D supplementation to prevent steroid-induced bone disease 2
- Pneumococcal vaccination (if not already given) due to increased infection risk 1, 2
- Daily urine dipstick monitoring by parents to detect early relapse 6