What is the diagnostic algorithm for nephrotic syndrome?

Diagnostic Algorithm for Nephrotic Syndrome

The diagnosis of nephrotic syndrome requires the triad of proteinuria exceeding 3.5 g/24 hours, hypoalbuminemia (<3.0 g/dL in adults, ≤2.5 g/dL in children), and edema, often accompanied by hyperlipidemia and lipiduria. 1

Core Diagnostic Criteria

• Adults: Proteinuria >3.5 g/24h, serum albumin <3.0 g/dL, and edema 1, 2
• Children: Proteinuria ≥40 mg/h/m² or first morning UPCR of ≥2 g/g, serum albumin ≤2.5 g/dL, and edema 3, 1
• Hyperlipidemia (hypertriglyceridemia and hypercholesterolemia) is a common associated finding 4

Initial Diagnostic Evaluation

• Quantify proteinuria: Measure urine protein-to-creatinine ratio (uPCR) or albumin-to-creatinine ratio (uACR) 2

  • Nephrotic-range proteinuria: uPCR >300-350 mg/mmol or >3.5 g/24h 2
  • According to KDIGO, severely increased albuminuria (A3) is defined as uACR ≥300 mg/g (≥30 mg/mmol) 3

• Laboratory assessment:

  • Serum albumin (note assay type - bromocresol green vs. bromocresol purple) 3
  • Complete blood count, serum electrolytes, kidney function tests 1
  • Lipid profile (total cholesterol, LDL, HDL, triglycerides) 1
  • Serum IgG level 1
  • Calcium, phosphate, alkaline phosphatase, PTH, and vitamin D levels 1

• Imaging:

  • Renal ultrasound to assess kidney size and echogenicity 1
  • Consider abdominal ultrasound to evaluate for ascites 1
  • Consider cardiac ultrasound to check for effusions 1

Differential Diagnosis by Age Group

• Children <12 years:

  • Most common cause is minimal change disease 3, 5
  • Initial treatment with glucocorticoids without biopsy is standard 3
  • If no response after 4-6 weeks, proceed to genetic testing and kidney biopsy 3

• Children ≥12 years and Adults:

  • Kidney biopsy and/or genetic testing recommended 3
  • Most common primary causes in adults: focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN) 5
  • Most common secondary cause in adults: diabetes mellitus 5, 6

Evaluation for Secondary Causes

• Diabetes mellitus: Check HbA1c, fasting glucose 5
• Systemic lupus erythematosus: ANA, anti-dsDNA, complement levels 2
• Amyloidosis: Consider serum and urine protein electrophoresis, free light chains 2
• Infections: Consider hepatitis B, hepatitis C, HIV testing 5
• Malignancies: Age-appropriate cancer screening 5

Kidney Biopsy Indications

• Adults: Generally indicated for diagnosis except in cases with positive serum anti-phospholipase A2 receptor antibodies (diagnostic of membranous nephropathy) 5
• Children <12 years: Not initially indicated if response to steroids is observed 3
• Children ≥12 years: Recommended at initial presentation 3
• Children with steroid resistance: Indicated regardless of age 3, 1

FSGS-Specific Evaluation

For patients with FSGS on biopsy, classify into one of four categories to guide treatment 3:

1. Primary FSGS: Diffuse foot process effacement and nephrotic syndrome (often sudden onset)
2. Genetic FSGS: Familial, syndromic, or sporadic
3. Secondary FSGS: Viral, drug-induced, or related to glomerular hyperfiltration
4. FSGS of undetermined cause: Segmental foot process effacement with proteinuria without nephrotic syndrome

Risk Assessment for Complications

• Venous thromboembolism risk assessment:

  • Higher risk when serum albumin falls below 2.9 g/dL 3
  • Membranous nephropathy carries higher VTE risk than other causes 3
  • Consider risk assessment tools (e.g., http://www.med.unc.edu/gntools/) 3
  • Note that albumin assay type affects interpretation: 2.5 g/dL with bromocresol green equals approximately 2.0 g/dL with bromocresol purple 3

• Arterial thrombosis risk assessment:

  • Consider Framingham risk score plus additional risk from proteinuria and reduced eGFR 3

Management Algorithm

1. Initial management:

   • Fluid and sodium restriction 6
   • Diuretics (oral or intravenous) 6
   • Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers 6
   • Consider anticoagulation for high-risk patients, particularly those with membranous nephropathy 5

2. Disease-specific therapy:

   • Based on biopsy findings and underlying cause
   • For primary causes, immunosuppressive therapy according to specific disease guidelines
   • For secondary causes, treat the underlying condition

3. Monitoring:

   • Regular assessment of proteinuria, serum albumin, and kidney function
   • Monitoring for complications (thromboembolism, infections)

Special Considerations

• Bromocresol green (BCG) albumin assays overestimate serum albumin in nephrotic syndrome compared to bromocresol purple (BCP) 3
• Consider prophylactic anticoagulation in high-risk patients, particularly those with membranous nephropathy and serum albumin <2.9 g/dL 3
• Direct oral anticoagulants are not recommended for prophylactic treatment of VTE in nephrotic syndrome based on current evidence 3