Key Facts

Childhood nephrotic syndrome results from increased glomerular permeability to protein, leading to massive proteinuria. Minimal change disease is the predominant cause in young children and typically responds well to corticosteroids.

Epidemiology

Annual incidence is approximately 2-7 per 100,000 children under 16 in the UK. Peak age of onset is 2-5 years. Male:female ratio is approximately 2:1 in younger children, equalising in adolescence. Higher incidence in South Asian and Afro-Caribbean populations.

Aetiology

• Minimal change disease (MCD): ~80% in ages 1-10; idiopathic; probable T-cell-mediated circulating permeability factor
• Focal segmental glomerulosclerosis (FSGS): ~10-15%; more common in Afro-Caribbean children; often steroid-resistant
• Membranous nephropathy: Rare in children (~5%); consider secondary causes (hepatitis B, SLE)
• Membranoproliferative GN: Rare; low complement levels
• Congenital nephrotic syndrome: Presents <3 months; Finnish type (NPHS1 mutation) most common

Pathophysiology

In MCD, electron microscopy reveals diffuse podocyte foot process effacement with normal light microscopy. A circulating permeability factor (possibly produced by dysregulated T cells) increases glomerular capillary wall permeability. Massive urinary protein loss leads to hypoalbuminaemia, reduced oncotic pressure, and oedema. The liver increases lipoprotein synthesis in response to low oncotic pressure, causing hyperlipidaemia. Loss of antithrombin III and other anticoagulant proteins creates a hypercoagulable state.

Classic Presentation

• Periorbital oedema (often first sign, worse in morning)
• Generalised oedema (ascites, scrotal/labial oedema, pleural effusions)
• Weight gain
• Frothy urine
• Reduced urine output

Complications

• Infection: Spontaneous bacterial peritonitis (Streptococcus pneumoniae), cellulitis, sepsis — due to urinary immunoglobulin loss
• Thromboembolism: Renal vein thrombosis, PE, cerebral venous sinus thrombosis
• Hypovolaemia/shock: Intravascular volume depletion despite oedema
• Acute kidney injury: Due to hypovolaemia or renal vein thrombosis

Red Flags

• Abdominal pain with fever — exclude spontaneous bacterial peritonitis
• Tachycardia, cool peripheries — hypovolaemic shock despite oedema
• Haematuria, hypertension, low C3 — suggests non-MCD pathology; biopsy indicated
• Age <1 year or >12 years at presentation — lower likelihood of MCD
• Steroid resistance after 4 weeks — refer for renal biopsy

Bedside

• Urine dipstick: 3-4+ protein; check for haematuria
• Blood pressure: Hypertension suggests non-MCD pathology
• Weight: Daily weight monitoring to track fluid balance
• Urine protein:creatinine ratio (uPCR): >200mg/mmol confirms nephrotic-range proteinuria

Bloods

• Serum albumin: <25g/L (often <20g/L in severe cases)
• U&Es: Assess renal function; hyponatraemia common
• FBC: Haemoconcentration; thrombocytosis increases thrombotic risk
• Lipid profile: Hypercholesterolaemia, raised triglycerides
• Complement (C3, C4): Normal in MCD; low in MPGN, lupus nephritis, post-streptococcal GN
• Immunoglobulins: Low IgG (urinary losses); IgM may be raised
• Hepatitis B/C, HIV serology: Exclude secondary causes

Imaging

• Renal ultrasound: Typically normal or enlarged echogenic kidneys; exclude renal vein thrombosis with Doppler
• Chest X-ray: If respiratory compromise — pleural effusions

Special Tests

• Renal biopsy: Not routinely performed in typical steroid-sensitive nephrotic syndrome (age 1-10, no haematuria, normal complement, normal renal function). Indicated for: steroid resistance, atypical features, age <1 or >12 years

Non-pharmacological

• Fluid restriction: Not routinely required unless severe hyponatraemia
• No added salt diet: Helps limit oedema
• Normal protein diet: High protein diets do not help and may worsen proteinuria
• Activity: Avoid immobilisation (thrombotic risk)
• Education: Teach parents home urine dipstick monitoring

Pharmacological

• First episode: Prednisolone 60mg/m²/day (max 80mg) for 4 weeks, then 40mg/m² alternate days (max 60mg) for 4 weeks, then wean (ISKDC regimen; extended courses of 12-16 weeks may reduce relapse — Cochrane evidence)
• Relapse: Prednisolone 60mg/m²/day until remission (3 consecutive days protein-free urine), then 40mg/m² alternate days for 4 weeks
• Frequently relapsing/steroid-dependent: Add steroid-sparing agent — levamisole 2.5mg/kg alternate days, cyclophosphamide 2mg/kg/day for 8-12 weeks, ciclosporin 4-5mg/kg/day in 2 divided doses, mycophenolate mofetil 600mg/m² BD, or rituximab 375mg/m² × 1-2 doses
• Steroid-resistant: Ciclosporin or tacrolimus (KDIGO 2021); consider rituximab
• Albumin infusion: 20% albumin 1g/kg IV over 4-6h for symptomatic hypovolaemia or severe oedema
• Furosemide: 1-2mg/kg IV ONLY with albumin co-infusion (risk of AKI if given alone)
• Penicillin V prophylaxis: 12.5mg/kg BD during oedematous phase (pneumococcal infection risk)

Surgical/Interventional

• Not typically required; paracentesis for tense symptomatic ascites rarely needed

Referral Criteria

• All children with first presentation of nephrotic syndrome — paediatric nephrology
• Steroid resistance — urgent nephrology for biopsy
• Frequently relapsing or steroid-dependent disease — nephrology for steroid-sparing agents

• Steroid-sensitive MCD: Excellent long-term prognosis; rarely progresses to CKD
• Relapse rate: Approximately 70-80% will have at least one relapse; 50% become frequently relapsing
• Frequently relapsing disease: May continue relapsing into adulthood in ~30% of cases
• Steroid-resistant FSGS: Approximately 50% progress to ESRD within 5-10 years
• Mortality: <2% in developed countries; infection and thromboembolism are main causes
• Most children with MCD become relapse-free by late adolescence/early adulthood

Definitions in Childhood Nephrotic Syndrome

Steroid-Sparing Agents Comparison