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

Nephrotic Syndrome Workup

Begin by confirming nephrotic syndrome with proteinuria ≥3.5 g/24 hours (or spot urine protein-to-creatinine ratio), serum albumin <3.0 g/dL, and edema in adults, then immediately perform targeted laboratory testing to exclude secondary causes before proceeding to kidney biopsy in adults or empiric corticosteroid therapy in children. 1

Diagnostic Confirmation

• Document proteinuria ≥3.5 g/24 hours using 24-hour urine collection or spot urine protein-to-creatinine ratio 1, 2
• Confirm serum albumin <3.0 g/dL in adults (or ≤2.5 g/dL in children) 1
• Verify presence of edema on physical examination 1

In children, use proteinuria ≥40 mg/h/m² or first morning urine protein-to-creatinine ratio ≥2 g/g 1

Essential Laboratory Workup to Identify Secondary Causes

Perform the following tests immediately to exclude secondary causes before initiating immunosuppressive therapy:

• Complete blood count with platelets 1
• Serum electrolytes, creatinine, and estimated GFR 1
• Fasting glucose and hemoglobin A1c to screen for diabetes mellitus (the most common secondary cause in adults) 1, 3
• Lipid profile 1
• Complement levels (C3, C4) 1
• Antinuclear antibody (ANA) and anti-dsDNA if systemic lupus erythematosus is suspected 1
• Review all medications for potential drug-induced disease 2
• Screen for infections (hepatitis B, hepatitis C, HIV) as clinically indicated 2

Imaging Studies

• Obtain renal ultrasound to assess kidney size and echogenicity, particularly before potential biopsy 1

Kidney Biopsy Decision Algorithm

The decision to perform kidney biopsy differs dramatically between adults and children:

Adults:

• Perform kidney biopsy within the first month after onset, preferably before starting immunosuppressive treatment, to establish histologic diagnosis 1
• Biopsy is essential in adults to differentiate between focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease 1, 3

Children (<12 years):

• Defer biopsy and initiate empiric corticosteroid therapy if typical presentation (age 1-10 years, no systemic symptoms, normal blood pressure, normal complement levels) 1, 2
• Perform biopsy only if steroid-resistant after 4-6 weeks of therapy 2

Genetic Testing Considerations

• Consider genetic testing in patients with:
  • Familial kidney disease 1
  • Syndromic features 1
  • Steroid-resistant FSGS 1
  • Congenital or early-onset disease (age <1 year) 1, 2
• Use massively parallel sequencing or whole-exome sequencing 2
• Assess for non-kidney manifestations including neurological status, sight, hearing, and dysmorphic features 2

Risk Stratification for Complications

Assess thromboembolism risk immediately:

• Venous thromboembolism risk is particularly high when serum albumin falls below 2.9 g/dL 1, 4
• Monitor for acute kidney injury 5, 4
• Assess infection risk, especially with immunosuppression 1, 4

Vaccination and Infection Prevention

• Administer pneumococcal and influenza vaccines before initiating immunosuppressive therapy 1, 2
• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose immunosuppression 2

Initial Supportive Management (Start Immediately)

Begin supportive therapy while awaiting biopsy results or during steroid trial:

• Restrict dietary sodium to <2.0 g/day 1, 2
• Use loop diuretics as first-line agents for edema management 1, 2
• Initiate ACE inhibitors or ARBs at maximally tolerated doses for proteinuria and blood pressure control 1, 2
• Target systolic blood pressure <120 mmHg using standardized office measurement 2

Important caveats:

• Avoid intravenous fluids and saline 2
• Use albumin infusions only based on clinical indicators of hypovolemia, not serum albumin levels 2
• Prophylactic anticoagulation is not currently recommended routinely 3

Disease-Specific Treatment Initiation

Treatment depends on histologic diagnosis in adults or steroid response in children:

Minimal Change Disease:

• Administer prednisone at 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) 1, 2
• Continue for minimum 4 weeks and up to 16 weeks until complete remission 2
• Taper slowly over 6 months after achieving complete remission 2

Focal Segmental Glomerulosclerosis:

• Confirm idiopathic FSGS before initiating immunosuppressive therapy 2
• Classify into primary, genetic, secondary, or undetermined cause to guide treatment 1

Membranous Nephropathy:

• Start immunosuppressive therapy only when urinary protein persistently exceeds 4 g/day and remains >50% of baseline despite 6 months of conservative therapy, or severe disabling symptoms are present 2

Alternative First-Line Therapy:

• Consider calcineurin inhibitors (cyclosporine 3-5 mg/kg/day divided into 2 doses, or tacrolimus 0.1-0.2 mg/kg/day divided into 2 doses) for patients with contraindications or intolerance to high-dose corticosteroids 2

Monitoring Protocol

• Assess proteinuria and kidney function every 2-4 weeks for the first 2-4 months, then every 3-6 months 1, 2
• Monitor for medication side effects, particularly with long-term immunosuppressive therapy 2

Special Populations

• Refer children with congenital nephrotic syndrome (age <1 year) immediately to specialized pediatric nephrology units due to disease complexity and high likelihood of genetic causes 1, 2
• Consider early referral to transplant center for patients with progressive disease to minimize time on dialysis 2