What investigations are needed to rule out nephrotic syndrome?

Diagnostic Investigations for Nephrotic Syndrome

To rule out nephrotic syndrome, a 24-hour urine collection for protein quantification is the gold standard investigation, accompanied by measurement of serum albumin, lipid profile, and kidney function tests. 1

Initial Diagnostic Tests

Essential First-line Investigations

• 24-hour urine collection for total protein excretion

  • Gold standard for diagnosing abnormal proteinuria 1
  • Nephrotic range proteinuria defined as ≥3.5g/24 hours 2
  • Collection should include measurement of creatinine excretion to assess adequacy 1

• Serum albumin measurement

  • Hypoalbuminemia (<30 g/L) is a key diagnostic criterion 2
  • Critical for confirming the diagnosis alongside proteinuria

• Spot urine protein/creatinine ratio (PCR)

  • Alternative when 24-hour collection is not feasible
  • PCR ≥300-350 mg/mmol indicates nephrotic range proteinuria 2
  • Values ≥30 mg/mmol (0.3 mg/mg) are considered abnormal 1

• Blood biochemistry panel

  • Complete blood count
  • Serum creatinine and urea (to assess kidney function)
  • Electrolytes (sodium, chloride, potassium)
  • Fasting lipid profile (total cholesterol, triglycerides) 1

Second-line Investigations

• Kidney biopsy
  • Indicated in adults with nephrotic syndrome to determine underlying pathology 1
  • May be deferred in children with typical presentation who respond to steroids 3
  • Should meet standards of biopsy adequacy (8-10 glomeruli) 1
  • Analysis should include:
    • Light microscopy
    • Immunofluorescence
    • Electron microscopy 1

Special Considerations

For Children

• First morning urine PCR is preferred over 24-hour collection (more practical) 1
• Nephrotic syndrome defined as:
  • Proteinuria (UPCR ≥2 g/g)
  • Hypoalbuminemia (≤2.5 g/dL) 1
  • Edema

For Adults with Specific Presentations

• For suspected membranous nephropathy:

  • Test for anti-phospholipase A2 receptor (anti-PLA2R) antibodies
  • Positive result may obviate need for kidney biopsy 3

• For suspected secondary causes:

  • Antinuclear antibodies, complement levels (C3, C4) for lupus nephritis
  • Serum and urine protein electrophoresis for multiple myeloma
  • Blood glucose and HbA1c for diabetic nephropathy 2

Monitoring Tests

• Regular assessment of kidney function (serum creatinine)
• Monitoring of serum albumin levels
• Repeat urine protein quantification to assess response to treatment 4
• Serum electrolytes, particularly in patients on diuretic therapy 5

Common Pitfalls to Avoid

1. Relying solely on dipstick testing

   • Dipstick testing alone is insufficient for diagnosis
   • False negatives can occur in some proteinuric cases 1
   • Positive dipstick (≥1+) should be followed by quantitative PCR 1

2. Overlooking nephrotic syndrome with sub-nephrotic proteinuria

   • Some patients may have all features of nephrotic syndrome with <3.5g/24h proteinuria
   • This can occur with concurrent liver disease affecting albumin synthesis 6

3. Confusing nephrotic with nephritic syndrome

   • Nephritic syndrome presents with hematuria, proteinuria, hypertension, and often acute kidney injury 7
   • Nephrotic syndrome is characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia 2

4. Missing orthostatic proteinuria

   • First morning urine collections may underestimate 24-hour protein excretion in orthostatic proteinuria 1

Remember that prompt diagnosis and referral to a nephrologist (ideally within 2 weeks) is necessary for patients with suspected nephrotic syndrome to establish the underlying cause and initiate appropriate treatment 2.