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 typical pediatric cases. 1

Diagnostic Confirmation

Adults:

• 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 1
• Assess for edema on physical examination 1

Children:

• Use proteinuria ≥40 mg/h/m² or first morning urine protein-to-creatinine ratio ≥2 g/g 1
• Confirm serum albumin ≤2.5 g/dL 1

Essential Laboratory Workup to Exclude Secondary Causes

Perform the following tests systematically to identify treatable secondary causes 1, 2:

Metabolic screening:

• Fasting glucose and hemoglobin A1c (diabetes mellitus is the most common secondary cause in adults) 1
• Lipid profile 1

Autoimmune evaluation:

• Complement levels (C3, C4) 1
• Antinuclear antibody (ANA) and anti-dsDNA if systemic lupus erythematosus is suspected 1

Baseline renal and hematologic assessment:

• Complete blood count with platelets 1
• Serum electrolytes, creatinine, and estimated GFR 1

Medication review:

• Systematically review all medications as potential causes 2

Imaging Studies

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

Kidney Biopsy Decision Algorithm

Adults:

• Perform kidney biopsy within the first month after onset, preferably before starting immunosuppressive treatment, to establish histologic diagnosis 1
• This is critical because focal segmental glomerulosclerosis and membranous nephropathy are the most common primary causes in adults, each requiring different treatment approaches 1, 2

Children <12 years:

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

Genetic Testing Considerations

Consider genetic testing in specific scenarios 1:

• Familial kidney disease
• Syndromic features (neurological abnormalities, hearing/vision loss, dysmorphic features) 2
• Steroid-resistant focal segmental glomerulosclerosis
• Congenital or early-onset disease (age <1 year)

Use massively parallel sequencing or whole-exome sequencing when indicated 2

Risk Stratification for Complications

Thromboembolism risk:

• Assess venous thromboembolism risk, particularly when serum albumin falls below 2.9 g/dL 1
• This is a critical complication given the hypercoagulable state from urinary loss of anticoagulant proteins 3

Infection prevention:

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

Initial Supportive Management

Edema control:

• Restrict dietary sodium to <2.0 g/day 1, 2
• Use loop diuretics as first-line agents for edema 1, 2
• Avoid routine intravenous albumin infusions; use only based on clinical indicators of hypovolemia, not serum albumin levels 2

Proteinuria and blood pressure management:

• Initiate ACE inhibitors or ARBs at maximally tolerated doses 1, 2
• Target systolic blood pressure <120 mmHg in adults using standardized office BP measurement 2

Disease-Specific Treatment Initiation

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 high-dose corticosteroids for minimum 4 weeks and up to 16 weeks as tolerated or 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 initial 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

Special Populations

Congenital nephrotic syndrome:

• Immediately refer to specialized pediatric nephrology units due to disease complexity and need for specialized management 1, 2
• Consider early referral to transplant center for patients with progressive disease 2

Monitoring Protocol

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

Common Pitfalls to Avoid

• Do not delay biopsy in adults attempting empiric steroid therapy, as this obscures histologic diagnosis and delays appropriate treatment 1
• Do not use intravenous fluids and saline routinely; concentrate oral fluid intake if necessary 2
• Do not prescribe prophylactic anticoagulation routinely; individualize based on albumin level and additional risk factors 1
• Avoid performing broad, unguided laboratory workups; use targeted testing based on clinical suspicion 1