What is the appropriate workup and treatment for a patient with nephrotic syndrome?

Nephrotic Syndrome Workup

The workup for nephrotic syndrome should begin with confirmation of the diagnosis through laboratory testing (proteinuria >3.5 g/day, serum albumin <3.0 g/dL), followed by systematic evaluation to distinguish primary from secondary causes, assessment for complications, and kidney biopsy in most adults to guide immunosuppressive therapy. 1, 2

Initial Diagnostic Confirmation

Laboratory Confirmation

• Measure 24-hour urine protein or spot urine protein-to-creatinine ratio to confirm nephrotic-range proteinuria (≥3.5 g/day in adults) 2, 3
• Obtain serum albumin level to confirm hypoalbuminemia (<3.0 g/dL in adults) 2, 3
• Complete blood count, comprehensive metabolic panel including sodium, chloride, creatinine, urea, and glucose 1, 4
• Fasting lipid panel (cholesterol and triglycerides) to document hyperlipidemia 1

Exclude Secondary Causes

• Screen for diabetes mellitus with hemoglobin A1c and fasting glucose 2, 5
• Test for systemic lupus erythematosus with ANA, anti-dsDNA, and complement levels (C3, C4) 2, 3
• Obtain hepatitis B and C serologies, HIV testing 1, 2
• Review medication history for NSAIDs, gold, penicillamine, and other nephrotoxic drugs 2, 5
• Consider serology for syphilis in appropriate clinical contexts 1

Additional Essential Testing

Assess Complications and Risk Stratification

• Measure serum IgG levels to assess infection risk 1, 4
• Obtain thyroid function tests (TSH, free T4) as hypothyroidism commonly occurs 1, 4
• Assess calcium-phosphate metabolism: ionized calcium, phosphate, alkaline phosphatase, PTH, and 25-OH vitamin D 1, 4
• Calculate eGFR to assess kidney function and ASCVD risk 1

Imaging Studies

• Perform renal ultrasound to evaluate kidney size, echogenicity, and exclude structural abnormalities 1, 4
• Obtain abdominal ultrasound to assess for ascites, pleural effusions, and renal vein thrombosis if clinically indicated 1, 4
• Consider cardiac ultrasound to evaluate for pericardial effusion and left ventricular mass 1, 4

Kidney Biopsy Indications

When to Perform Biopsy

• Kidney biopsy is recommended in adults to establish histologic diagnosis and guide immunosuppressive therapy 2, 3
• Biopsy is particularly indicated when secondary causes have been excluded and primary glomerular disease is suspected 2, 3
• In children with typical presentation (age 1-10 years, no hematuria, normal complement), biopsy may be deferred if there is response to initial corticosteroid therapy 2
• Biopsy is mandatory in steroid-resistant nephrotic syndrome in children 2
• Biopsy should be performed before initiating immunosuppression in adults to distinguish primary FSGS from secondary forms 1, 2

Biopsy Processing Requirements

• Ensure tissue is processed with light microscopy, immunofluorescence/immunohistochemistry, and electron microscopy 1
• Electron microscopy is essential to assess for diffuse foot process effacement (suggests primary disease) versus segmental effacement (suggests secondary FSGS) 1

Genetic Testing Considerations

When to Order Genetic Testing

• Consider genetic testing in congenital or early-onset nephrotic syndrome (onset <1 year of age) 1, 2
• Order genetic testing in familial cases, consanguinity, or syndromic features 6
• Test adults with steroid-resistant FSGS, as 11-24% will have disease-causing variants 6
• Use massively parallel sequencing or whole-exome sequencing panels 2
• Common mutations include NPHS1, NPHS2, WT1, PLCE1, and type IV collagen genes 6

Critical caveat: Do not initiate immunosuppressive therapy in genetic forms of nephrotic syndrome, as they will not respond 4, 6

Risk Assessment for Complications

Thromboembolism Risk Stratification

• Assess for high-risk features requiring prophylactic anticoagulation: serum albumin <20-25 g/L AND any of the following: 1
  • Proteinuria >10 g/day
  • BMI >35 kg/m²
  • NYHA class III or IV heart failure
  • Recent orthopedic or abdominal surgery
  • Prolonged immobilization
• Note that membranous nephropathy carries particularly high thrombotic risk (29% renal vein thrombosis, 17-28% pulmonary embolism) 1, 6

Infection Risk Assessment

• Patients with serum IgG <600 mg/dL are at highest infection risk 1, 4
• Administer pneumococcal and influenza vaccines 2
• Consider prophylactic trimethoprim-sulfamethoxazole during high-dose immunosuppression 2

Cardiovascular Risk

• Recognize that reduced eGFR (<60 mL/min/1.73 m²) and albuminuria (ACR >30 mg/g) independently increase ASCVD risk 1
• Measure fasting lipids 4-12 weeks after statin initiation and every 3-12 months thereafter 1

Special Populations

Congenital Nephrotic Syndrome (Age <3 Months)

• Refer immediately to specialized pediatric nephrology center 1, 4, 2
• Obtain prenatal history: enlarged nuchal translucency, increased amniotic fluid alpha-fetoprotein, placental weight >25% of birth weight 1
• Perform extended evaluation for dysmorphic features, neurological status, ophthalmologic and hearing assessment 1, 2
• Order genetic testing as first-line diagnostic measure 1, 4

Adults with Suspected Primary Disease

• Distinguish primary FSGS (diffuse foot process effacement, sudden-onset nephrotic syndrome) from secondary FSGS (segmental foot process effacement, proteinuria without full nephrotic syndrome) 1
• This distinction is critical because immunosuppression should NOT be used in secondary FSGS 6

Common Pitfalls to Avoid

• Do not perform broad, unguided serologic workup; use blood tests selectively based on clinical suspicion 5, 3
• Do not defer biopsy in adults with unexplained nephrotic syndrome, as histology guides therapy 2, 3
• Do not start immunosuppression before excluding genetic causes in young patients or those with family history 4, 6
• Do not use serum albumin levels alone to guide albumin infusions; base decisions on clinical indicators of hypovolemia 4, 2
• Do not routinely prescribe prophylactic anticoagulation or antibiotics without risk stratification 1, 5
• Do not overlook medication review, as drug-induced nephrotic syndrome is a reversible secondary cause 2, 5