What is the initial workup and treatment for a patient presenting 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

Confirm Nephrotic Range Proteinuria

• Obtain spot urine protein-to-creatinine ratio (PCR) to quantify proteinuria 2, 3
• Nephrotic range is defined as PCR >300-350 mg/mmol (or >3.5 g/24 hours) 4
• For diabetic patients, equivalent threshold is urine albumin >2.2 g/day or albumin-creatinine ratio >2.2 g/g 5
• Document the classic triad: substantial proteinuria (>3.5 g/24 hours), hypoalbuminemia (<30 g/L), and edema 4

Initial Laboratory Workup

Complete the following tests before nephrology referral:

• Complete metabolic panel including serum creatinine, estimated GFR, electrolytes, glucose, and albumin 1
• Lipid panel (hyperlipidemia is commonly present) 4, 6
• Urinalysis with microscopic examination for hematuria, pyuria, and cellular casts (suggests glomerulonephritis) 1
• Hepatitis B and C serology to exclude viral-associated glomerular disease 1
• HIV testing to exclude HIV-associated nephropathy 1
• Antinuclear antibody (ANA) to screen for systemic lupus erythematosus 1
• Complement levels (C3, C4) to assess for complement-mediated glomerular disease 1
• Serum anti-phospholipase A2 receptor antibodies (if positive, this is diagnostic of membranous nephropathy and may obviate need for biopsy) 1, 6

Imaging

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

Urgent Nephrology Referral

• Refer within 2 weeks for nephrotic-range proteinuria 4
• Kidney biopsy is typically required unless anti-phospholipase A2 receptor antibodies are positive 1, 6
• For lupus nephritis, use ISN/RPS 2003 classification with assessment of activity and chronicity indices 1

Immediate Supportive Management

Initiate these interventions while awaiting nephrology evaluation:

• Start ACE inhibitor or ARB for all patients with nephrotic-range proteinuria, regardless of blood pressure 1
• Target blood pressure <125/75 mmHg in nephrotic-range proteinuria 1
• Dietary sodium restriction to manage edema 6
• Consider thromboembolism prophylaxis for high-risk patients, particularly those with membranous nephropathy 6
• Statin therapy for hyperlipidemia with target LDL-cholesterol <100 mg/dL 7

Special Populations

Children younger than 12 years:

• Most cases are minimal change disease, which is steroid-responsive 6
• Start glucocorticoid therapy empirically without biopsy 6
• If no improvement with steroids, proceed with genetic testing and kidney biopsy 6

Infants with congenital nephrotic syndrome (onset within first 3 months):

• Perform whole-exome sequencing as first-line diagnostic 1
• Immediate referral to specialized tertiary pediatric nephrology center 1

Common Pitfalls

• Do not delay nephrology referral while completing the workup—refer urgently within 2 weeks 4
• Do not skip anti-phospholipase A2 receptor antibody testing in adults, as positive results can avoid unnecessary biopsy 1, 6
• Do not withhold ACE inhibitor/ARB therapy while awaiting biopsy results—start immediately 1
• Do not overlook thromboembolism risk, especially in membranous nephropathy where prophylaxis may be warranted 6