In a 4‑year‑old boy with proteinuria and a family history of focal segmental glomerulosclerosis, should I be concerned that he has early FSGS?

Yes, you should be highly concerned about FSGS in this 4-year-old with proteinuria and a positive family history

Given the combination of proteinuria and a family history of FSGS in a young child, genetic FSGS is a strong possibility and warrants immediate evaluation, as patients with disease onset before age 25 and positive family history have a substantially higher prevalence of genetic forms of FSGS. 1

Why This Combination is Concerning

High-Risk Features Present

• Age of onset: Disease presentation before age 25 years significantly increases the likelihood of genetic FSGS 1
• Family history: A positive family history is one of the three key indicators for genetic FSGS (along with early onset and extrarenal manifestations) 1
• Proteinuria: This is the hallmark clinical manifestation of FSGS and indicates active podocyte injury 2, 3

Genetic FSGS Considerations

The presence of both early onset and family history makes this a high-probability scenario for inherited disease. Genetic testing should be strongly considered, starting with the affected family member first, followed by cascade testing of this child if a causative variant is identified. 1 This approach is critical because:

• Identifying a genetic cause predicts substantially lower likelihood of disease recurrence if kidney transplantation becomes necessary 1
• It provides prognostic information and may influence treatment decisions 1
• Multiple genes encoding podocyte structural proteins can cause familial FSGS 4, 2

Immediate Diagnostic Workup Required

Essential Laboratory Evaluation

• First morning spot urine protein-to-creatinine ratio (PCR): This is the preferred method in children rather than 24-hour collections 5

  • Normal PCR is <0.2 g/g 5
  • Nephrotic-range proteinuria is PCR >2 g/g 5
  • Obtain three separate specimens to confirm persistent proteinuria 5

• Complete metabolic panel: To assess kidney function (serum creatinine) and albumin levels 5

• Serum albumin: Hypoalbuminemia (<2.5 g/dL) combined with heavy proteinuria and edema defines nephrotic syndrome 5

Imaging

• Renal ultrasound: First-line imaging to assess kidney size, echogenicity, and structural abnormalities 5

Nephrology Referral Criteria

Immediate pediatric nephrology referral is indicated based on the following:

• Nephrotic syndrome features (heavy proteinuria, hypoalbuminemia, edema) require prompt specialist evaluation 5
• Family history of FSGS combined with proteinuria warrants genetic counseling and specialized evaluation 1
• The presence of significant proteinuria (PCR ≥0.2 g/g on three specimens) in a young child with family history necessitates expert management 5

Prognostic Implications

Why Early Identification Matters

• Proteinuria magnitude predicts outcomes: The amount of proteinuria at presentation has consistently been identified as a significant predictor of progression to end-stage renal disease 6
• Nephrotic patients have worse prognosis: Those with massive proteinuria have 50% progression to ESRD over 3-8 years 6
• Remission is protective: Achievement of proteinuria remission is the only significant negative predictor of progression to ESRD 6
• Spontaneous remissions are rare: Occurring in ≤6% of patients, making treatment consideration important 6

Treatment Considerations After Diagnosis

If FSGS is confirmed by biopsy (typically performed if steroid-resistant after 4 weeks), treatment options in children include:

• Corticosteroids: Initial therapy once nephrotic syndrome is confirmed (prednisone 60 mg/m²/day) 5
• Calcineurin inhibitors: For steroid-resistant cases, cyclosporin at 100 mg/m²/day in divided doses, gradually increased to maximum 150 mg/m²/day, combined with alternate-day prednisone 1
• ACE inhibitors or ARBs: For proteinuria reduction and renoprotection 5, 7

Common Pitfalls to Avoid

• Delaying genetic evaluation: In children with early onset and family history, genetic testing should be pursued early rather than waiting for disease progression 1
• Assuming all proteinuria is benign: While transient proteinuria is common in children, persistent proteinuria with family history of FSGS requires thorough investigation 5
• Using dipstick alone: Laboratory measurement of PCR is essential as dipstick testing is less sensitive and specific 5
• Inadequate monitoring: If proteinuria is confirmed, monthly PCR monitoring for 3 months, then every 3-6 months is recommended 5

The combination of proteinuria and family history of FSGS in a 4-year-old represents a high-risk scenario that demands prompt, comprehensive evaluation by a pediatric nephrologist with consideration of genetic testing. Early identification allows for appropriate treatment initiation, prognostic counseling, and family planning discussions. 1, 5, 6