What is the treatment approach for a patient presenting with nephrotic range proteinuria?

Treatment Approach for Nephrotic Range Proteinuria

All adults with nephrotic-range proteinuria require kidney biopsy to establish the underlying diagnosis before initiating immunosuppressive therapy, with the sole exception being positive serum anti-phospholipase A2 receptor antibodies, which is diagnostic of membranous nephropathy and can avoid biopsy. 1, 2

Immediate Diagnostic Workup

Before nephrology referral, obtain the following essential tests:

• Quantify proteinuria using spot urine protein-to-creatinine ratio (PCR), where PCR >300-350 mg/mmol confirms nephrotic range 1, 3
• Complete metabolic panel including serum creatinine, estimated GFR, electrolytes, glucose, and albumin 1, 2
• Urinalysis with microscopy to assess for hematuria, pyuria, and cellular casts that suggest glomerulonephritis 1, 2
• Serological testing including hepatitis B and C, HIV, antinuclear antibody (ANA), complement levels (C3, C4), and serum anti-phospholipase A2 receptor antibodies 1, 2
• Renal ultrasound to evaluate kidney size, structural abnormalities, and exclude obstruction 1, 2

The anti-phospholipase A2 receptor antibody test is critical because positive results establish membranous nephropathy diagnosis without biopsy, fundamentally altering the diagnostic pathway. 1, 2

Immediate Supportive Management (Start Before Biopsy)

While awaiting nephrology evaluation and biopsy, initiate the following:

• ACE inhibitor or ARB for all patients with nephrotic-range proteinuria, regardless of baseline blood pressure 1, 2, 4
• Target blood pressure <125/75 mmHg using additional antihypertensive agents as needed 1, 2
• Statin therapy for hyperlipidemia with target LDL-cholesterol <100 mg/dL 1

These interventions reduce proteinuria and cardiovascular risk independent of the underlying glomerular pathology and should not be delayed. 1, 4

Immunosuppressive Treatment Strategy (Post-Biopsy)

Do not start immunosuppressive therapy before establishing the histological diagnosis, as treatment varies dramatically by underlying pathology. 1

For Membranous Nephropathy:

• Observe for 6 months with conservative therapy (ACE inhibitor/ARB, blood pressure control, statin) before starting immunosuppression, as one-third will have spontaneous remission 1
• Start immunosuppression earlier than 6 months if any of the following are present: urinary protein excretion persistently exceeds 4 g/day, severe symptoms, serum creatinine rises by ≥30%, or high thrombotic risk 1
• First-line immunosuppression: 6-month course of alternating monthly cycles of oral and IV corticosteroids plus oral alkylating agents (cyclophosphamide or chlorambucil) 1
• Alternative regimen: cyclosporine or tacrolimus for ≥6 months if contraindications to corticosteroids exist or patient refuses alkylating agents 1

For Lupus Nephritis (Class III or IV):

• Immunosuppressive treatment is mandatory for active class III or IV lupus nephritis, with or without coexisting histological chronicity 5
• For pure class V lupus nephritis, immunosuppression is recommended for patients with nephrotic-range proteinuria, which is associated with worse prognosis 5
• Alternative indication for class V: proteinuria >1 g/24 hours despite optimal use of renin-angiotensin-aldosterone system blockers for at least 3 months 5

The distinction between membranous nephropathy and lupus nephritis is critical because lupus nephritis requires immediate immunosuppression while membranous nephropathy typically warrants a 6-month observation period. 5, 1

Special Population: Congenital Nephrotic Syndrome (Infants <3 Months)

• Whole-exome sequencing as first-line diagnostic rather than kidney biopsy 1, 2
• Immediate referral to specialized tertiary pediatric nephrology center with multidisciplinary teams 1, 2

Common Pitfalls to Avoid

• Do not delay kidney biopsy in adults with nephrotic-range proteinuria unless anti-phospholipase A2 receptor antibodies are positive 1, 2
• Do not start immunosuppression empirically without histological diagnosis, as this can worsen outcomes in certain conditions 1
• Do not assume diabetic nephropathy in diabetic patients without biopsy confirmation, as 5.5% of nephrotic syndrome cases may be due to hypertensive nephrosclerosis, particularly in African-American patients 6
• Do not withhold ACE inhibitor/ARB while awaiting biopsy, as these provide immediate renoprotection 1, 2, 4

Monitoring Response to Treatment

For patients on immunosuppression:

• At 3 months: expect evidence of proteinuria improvement with GFR stabilization 7
• At 6 months: anticipate ≥50% reduction in proteinuria 7
• At 12 months: target complete or partial remission, though only 50% achieve this by 12 months 7
• Consider repeat kidney biopsy before changing therapy if inadequate response, to distinguish active inflammation from chronic scarring 7

If ≥50% worsening of proteinuria or creatinine occurs at 3 months, consider changing induction regimens immediately. 7