What is the diagnostic approach for nephrotic syndrome?

Diagnosing Nephrotic Syndrome

Nephrotic syndrome is definitively diagnosed by the triad of proteinuria exceeding 3.5 g/24 hours (or urine protein:creatinine ratio >300-350 mg/mmol), hypoalbuminemia (<3.0 g/dL in adults, ≤2.5 g/dL in children), and edema, often accompanied by hyperlipidemia. 1, 2

Core Diagnostic Criteria

• Proteinuria: Adults require >3.5 g/24 hours; children need ≥40 mg/h/m² or first morning UPCR of ≥2 g/g 1
• Hypoalbuminemia: Serum albumin <3.0 g/dL in adults; ≤2.5 g/dL in children 1
• Edema: Typically periorbital (morning) or dependent pitting edema (later in day) 2
• Hyperlipidemia: Often present but not required for diagnosis 1, 3

Diagnostic Approach

First-Line Evaluation

• Clinical assessment: Evaluate for edema, hypertension, and signs of volume status 4
• Urinalysis: Quantify proteinuria with urine protein:creatinine ratio (PCR) or albumin:creatinine ratio (ACR) 1, 2
• Blood biochemistry:
  • Complete blood count
  • Serum albumin (note assay type - bromocresol green vs. purple)
  • Electrolytes, creatinine, urea
  • Lipid profile (cholesterol, triglycerides)
  • Glucose 4, 1

Extended Evaluation

• Thyroid function: TSH and free T4 4
• Immunological assessment: Serum IgG level 4
• Bone metabolism: Calcium, phosphate, alkaline phosphatase, PTH, vitamin D 4
• Imaging: Renal ultrasound to assess kidney size and echogenicity 4
• Cardiac assessment: Echocardiogram to evaluate for effusions 4

Age-Based Diagnostic Approach

Children <12 Years

• Minimal change disease is most common cause 1
• Initial treatment with glucocorticoids without biopsy is standard 1
• If no response to steroids after 4-6 weeks, proceed to genetic testing and kidney biopsy 4

Children ≥12 Years and Adults

• Kidney biopsy is recommended to determine underlying cause 1
• Exception: Positive serum anti-phospholipase A2 receptor antibodies (diagnostic of membranous nephropathy) 1

Differential Diagnosis

Primary (Idiopathic) Causes

• Children: Minimal change disease (most common) 4, 1
• Adults:
  • Membranous nephropathy (most common in white adults)
  • Focal segmental glomerulosclerosis (most common in populations of African ancestry) 2, 5

Secondary Causes

• Systemic diseases: Diabetes mellitus, systemic lupus erythematosus, amyloidosis 2, 6
• Infections: Various bacterial, viral, and parasitic infections 5
• Medications: Certain drugs can induce nephrotic syndrome 6

Complications Assessment

• Thromboembolism risk: Higher risk when serum albumin <2.9 g/dL, particularly in membranous nephropathy 1
• Infection risk: Evaluate for signs of infection due to increased susceptibility 7
• Acute kidney injury: Monitor kidney function 6

Important Considerations

• The albumin assay method affects results: 2.5 g/dL with bromocresol green equals approximately 2.0 g/dL with bromocresol purple 4, 1
• Urgent referral to nephrology (within 2 weeks) is necessary for most newly diagnosed cases 2
• Kidney biopsy is essential in adults and children with steroid resistance to guide management 4, 1

Pitfalls to Avoid

• Don't rely solely on dipstick tests for proteinuria; quantitative measurement is required 2
• Don't delay nephrology referral, especially for steroid-resistant cases 4
• Don't overlook secondary causes, which may require specific treatment 6, 5
• Don't forget to assess for complications, particularly thromboembolism risk 1