What is the initial diagnostic workup for a patient presenting with nephrotic syndrome?

Diagnostic Workup for Nephrotic Syndrome

Begin with quantification of proteinuria (24-hour urine collection or spot urine protein-to-creatinine ratio), serum albumin measurement, and basic metabolic panel to confirm the diagnosis, then proceed with targeted laboratory testing and consider kidney biopsy based on age and clinical presentation. 1, 2

Initial Diagnostic Confirmation

Essential Laboratory Tests

• Quantify proteinuria: Measure 24-hour urine protein (≥3.5 g/24h in adults; ≥40 mg/h/m² or first morning UPCR ≥2 g/g in children) 1, 2
• Serum albumin: Confirm hypoalbuminemia (<3.0 g/dL in adults; ≤2.5 g/dL in children) - note that assay method matters, as bromocresol green yields values approximately 0.5 g/dL higher than bromocresol purple 1, 2
• Complete metabolic panel: Including serum creatinine, blood urea nitrogen, and electrolytes to assess kidney function 1
• Lipid profile: Document hyperlipidemia (often present but not required for diagnosis) 2

Additional Blood Work

• Complete blood count with platelets 3
• Complement levels (C3, C4) to evaluate for immune-mediated disease 3
• Antinuclear antibody testing if systemic lupus erythematosus is suspected 3
• Hepatitis B and C serologies to identify secondary causes 3
• Serum IgG level 1
• Thyroid function tests 1
• Calcium, phosphate, alkaline phosphatase, PTH, and vitamin D levels 1

Imaging Studies

• Renal ultrasound: Assess kidney size and echogenicity (particularly important before potential biopsy) 3, 1
• Abdominal ultrasound: Evaluate for ascites 1
• Cardiac ultrasound: Check for pericardial effusions and left ventricular mass 1

Age-Based Biopsy Strategy

Children <12 Years

• Do NOT perform kidney biopsy at initial presentation - minimal change disease is the most common cause and responds to empiric glucocorticoid therapy 1, 2
• Proceed directly to glucocorticoid treatment without biopsy 2
• Reserve biopsy for steroid-resistant cases (failure to respond to initial therapy) 1

Children ≥12 Years and Adults

• Kidney biopsy is recommended to determine the underlying cause before initiating immunosuppressive therapy 1, 2
• Exception: Adults with positive serum anti-phospholipase A2 receptor antibodies do not require biopsy, as this is diagnostic of membranous nephropathy 1, 2

Secondary Cause Evaluation

When to Suspect Secondary Causes

• Non-nephrotic range proteinuria (<3.5 g/day) with hypoalbuminemia 3
• Nephrotic-range proteinuria but serum albumin >3.0 g/dL 3
• Specific clinical features: Diabetes mellitus (most common secondary cause in adults), systemic lupus erythematosus, amyloidosis, malignancy, or medication exposure 4, 5

Targeted Testing Based on Clinical Suspicion

• Diabetes screening: Fasting glucose and hemoglobin A1c 5
• Serum and urine protein electrophoresis: If amyloidosis or multiple myeloma suspected 5
• HIV testing: Particularly in high-risk populations 3
• Medication review: Identify nephrotoxic agents 3

FSGS-Specific Workup (If Biopsy Shows FSGS)

• Genetic testing: Recommended for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS (11-24% of adults with steroid-resistant FSGS have disease-causing variants) 3
• Classification into categories: Primary (immunologically mediated), genetic, secondary (viral/medication/adaptive), or undetermined cause to guide treatment 3
• History of prematurity: Document as potential etiology for reduced nephron number 3

Thromboembolism Risk Assessment

• Critical when serum albumin <2.9 g/dL - particularly high risk in membranous nephropathy 1, 2
• Consider risk assessment tools: Available at http://www.med.unc.edu/gntools/ 1
• Evaluate for prophylactic anticoagulation in high-risk patients, especially those with membranous nephropathy and albumin <2.9 g/dL 1

Common Pitfalls to Avoid

• Do not perform broad, unguided laboratory workup - use targeted testing based on clinical suspicion rather than ordering every possible test 5
• Do not biopsy young children empirically - this exposes them to unnecessary procedural risk when minimal change disease is overwhelmingly likely 1, 2
• Do not overlook albumin assay methodology - results vary significantly between bromocresol green and bromocresol purple methods, affecting diagnostic thresholds 1, 2
• Do not assume nephrotic-range proteinuria is always present - patients with concurrent liver disease may have severe nephrotic syndrome with proteinuria <3.5 g/24h due to decreased albumin synthesis 6
• Do not delay genetic testing in steroid-resistant cases - early identification prevents unnecessary immunosuppression exposure and informs transplant counseling 3