What is the initial workup and treatment for secondary membranous nephropathy?

Workup for Secondary Membranous Nephropathy

The initial workup for secondary membranous nephropathy must include a comprehensive evaluation to identify the underlying cause, as this will determine the specific treatment approach and improve outcomes by addressing the primary disease process rather than just the glomerular manifestation. 1

Diagnostic Evaluation

Initial Laboratory Tests

• Complete blood count
• Comprehensive metabolic panel including renal function (serum creatinine, eGFR)
• 24-hour urine collection for protein quantification
• Serum and urine protein electrophoresis
• Serum free light chain measurement
• Anti-PLA2R antibodies (to distinguish primary from secondary MN)

Serologic Testing for Secondary Causes

1. Autoimmune diseases (account for 73.3% of secondary MN cases) 2

   • Antinuclear antibodies (ANA)
   • Anti-double stranded DNA antibodies
   • Complement levels (C3, C4)
   • Rheumatoid factor
   • Anti-SSA/SSB antibodies

2. Infections (account for 17.7% of secondary MN cases) 2

   • Hepatitis B surface antigen and core antibody
   • Hepatitis C antibody and RNA
   • HIV serology
   • H. pylori testing (especially with gastrointestinal symptoms) 3

3. Malignancy screening (accounts for 4.5% of secondary MN cases) 2

   • Age-appropriate cancer screening
   • Serum tumor markers
   • Chest imaging
   • Consider PET-CT in patients with high suspicion

4. Drug or toxin exposure (accounts for 4.5% of secondary MN cases) 2

   • Detailed medication history (NSAIDs, gold, penicillamine)
   • Environmental/occupational exposure history

Kidney Biopsy

• Essential for diagnosis of MN
• Evaluate for features suggesting secondary causes:
  • Full house pattern of immune deposits
  • Mesangial deposits
  • Endothelial tubuloreticular inclusions
  • IgG subclass predominance (IgG1 and IgG3 more common in secondary MN)
  • Absence of PLA2R staining in tissue (suggests secondary MN)

Treatment Approach

1. Treat the Underlying Cause

• Autoimmune diseases: Appropriate immunosuppression based on the specific disease
• Infections: Antimicrobial therapy (e.g., triple therapy for H. pylori) 3
• Malignancy: Cancer-directed therapy
• Drug-induced: Discontinuation of offending agent

2. Supportive Care for All Patients

• Optimal blood pressure control (target <130/80 mmHg)
• ACE inhibitors or ARBs for antiproteinuric effect
• Dietary sodium restriction
• Diuretics for edema management
• Statins for hyperlipidemia

3. Thrombosis Prevention

• Consider prophylactic anticoagulation in patients with:
  • Serum albumin <2.5 g/dL (by bromocresol purple) or <2.0 g/dL (by bromocresol green) 1
  • Additional risk factors for thrombosis

4. Immunosuppressive Therapy

• Indications for immunosuppression: 1

  • Persistent proteinuria >4 g/day despite 6 months of supportive care
  • Severe, disabling, or life-threatening symptoms related to nephrotic syndrome
  • Serum creatinine rise ≥30% within 6-12 months (with eGFR >30 ml/min/1.73m²)

• Contraindications to immunosuppression: 1

  • Serum creatinine persistently ≥3.5 mg/dL or eGFR ≤30 ml/min/1.73m²
  • Reduced kidney size on ultrasound
  • Severe or potentially life-threatening infections

• Treatment options (if underlying cause treatment is insufficient):

  • Rituximab (preferred in younger patients or those concerned about fertility) 1, 4
  • Cyclophosphamide with alternate month glucocorticoids for 6 months 1
  • Calcineurin inhibitors (tacrolimus or cyclosporine) for ≥6-12 months 1, 4

Monitoring and Follow-up

• Regular monitoring of proteinuria, serum albumin, and kidney function
• For anti-PLA2R positive patients, monitor antibody levels every 3 months 1, 4
• Consider treatment failure if no substantial reduction in proteinuria (30-50%) after 4-6 months 4
• Monitor for complications of nephrotic syndrome and medication side effects

Common Pitfalls to Avoid

1. Failing to thoroughly investigate for secondary causes before diagnosing primary MN
2. Initiating immunosuppression without addressing the underlying cause
3. Using immunosuppression in patients with advanced kidney disease (serum creatinine >3.5 mg/dL)
4. Prematurely declaring treatment failure (remission may take 12-18 months) 1
5. Inadequate thromboprophylaxis in high-risk patients with severe hypoalbuminemia

By systematically evaluating for secondary causes and addressing the underlying disease process, outcomes can be significantly improved in patients with secondary membranous nephropathy.