What is the recommended diagnostic workup and initial treatment for an adult with nephrotic-range proteinuria?

Workup for Nephrotic Range Proteinuria

All adults with nephrotic-range proteinuria require kidney biopsy to establish the underlying diagnosis, except when serum anti-phospholipase A2 receptor antibodies are positive, which is diagnostic of membranous nephropathy. 1

Immediate Laboratory Evaluation

Obtain the following tests before nephrology referral:

• Quantify proteinuria using spot urine protein-to-creatinine ratio (PCR >300-350 mg/mmol confirms nephrotic range) or 24-hour urine collection (>3.5 g/24 hours) 1, 2
• Complete metabolic panel including serum creatinine, estimated GFR, electrolytes, glucose, and albumin (expect albumin <30 g/L) 1, 2
• Urinalysis with microscopy to assess for hematuria, pyuria, and cellular casts that suggest glomerulonephritis 1
• Lipid panel as hyperlipidemia is commonly associated 2, 3

Serologic Workup to Identify Secondary Causes

These tests determine whether nephrotic syndrome is primary (kidney-specific) or secondary to systemic disease:

• Serum anti-phospholipase A2 receptor antibodies - positive results are diagnostic of membranous nephropathy and can avoid unnecessary biopsy 1
• Antinuclear antibody (ANA) to screen for systemic lupus erythematosus 1
• Complement levels (C3, C4) to evaluate for complement-mediated glomerular disease 1
• Hepatitis B and C serology to exclude viral-associated glomerular disease 1
• HIV testing to exclude HIV-associated nephropathy, particularly in high-risk populations 1, 4

Imaging

• Renal ultrasound to evaluate kidney size, structural abnormalities, and exclude obstruction 1

Nephrology Referral and Kidney Biopsy

Urgent referral to nephrology is mandatory (ideally within 2 weeks) as kidney biopsy and immunosuppressive medications may be indicated 5, 2. The biopsy establishes the specific diagnosis—whether membranous nephropathy, IgA nephropathy, focal segmental glomerulosclerosis, lupus nephritis, or another glomerular disease—which is essential for determining the appropriate treatment approach 5, 2.

Kidney biopsy should be performed in nearly all cases because:

• Treatment varies dramatically by underlying pathology 1
• Even with nephrotic-range proteinuria and low CD4 count in HIV patients, 33% have diagnoses other than HIV-associated nephropathy 4
• The distinction between primary and secondary causes is critical for treatment decisions 6

The only exception to biopsy: Positive anti-phospholipase A2 receptor antibodies establish membranous nephropathy diagnosis without tissue confirmation 1.

Immediate Conservative Management (Start While Awaiting Biopsy)

Begin these interventions immediately, regardless of the underlying diagnosis:

• ACE inhibitor or ARB therapy as first-line treatment to reduce proteinuria and slow disease progression 5, 1, 3
• Target blood pressure <125/75 mmHg in nephrotic-range proteinuria to reduce cardiovascular risk and slow kidney disease progression 5, 1
• Loop diuretics (furosemide) for edema control 1, 3
• Sodium restriction to <2 g/day to enhance the antiproteinuric effect of renin-angiotensin system blockade 7
• Statin therapy for hyperlipidemia with target LDL-cholesterol <100 mg/dL 1

Monitoring Strategy

• Recheck UPCR and serum creatinine every 4-6 weeks initially to assess response to ACE inhibitor/ARB therapy 5
• Monitor serum potassium and creatinine 1-2 weeks after initiating or uptitrating RAS blockade 5
• Assess for thrombotic complications as nephrotic syndrome carries increased thromboembolism risk 2, 3
• Evaluate need for anticoagulation based on albumin level and other risk factors 3

Critical Pitfalls to Avoid

Never initiate immunosuppressive therapy without tissue diagnosis, as the specific glomerular disease determines whether immunosuppression is beneficial or harmful 5, 1. For example:

• Membranous nephropathy typically warrants 6 months of observation on conservative therapy before considering immunosuppression 6, 1
• Lupus nephritis requires immediate immunosuppression 6, 1
• Secondary FSGS (obesity-related) requires aggressive conservative management, not immunosuppression 1

Do not delay RAS blockade while awaiting biopsy, as continued proteinuria causes tubular injury and interstitial inflammation that accelerates progression 5.