What is the initial treatment for primary membranous nephropathy?

Initial Treatment for Primary Membranous Nephropathy

For patients with primary membranous nephropathy and nephrotic syndrome with risk factors for disease progression, the initial treatment should be rituximab or cyclophosphamide with alternate month glucocorticoids for 6 months, or tacrolimus-based therapy for ≥6 months, depending on the estimated risk profile. 1

Patient Assessment and Risk Stratification

Before initiating immunosuppressive therapy, patients should be evaluated for:

1. Risk factors for disease progression:

   • Persistent proteinuria >4 g/day despite 6 months of supportive care
   • Severe, disabling, or life-threatening symptoms related to nephrotic syndrome
   • Serum creatinine rise by ≥30% within 6-12 months (but eGFR not less than 25-30 ml/min/1.73m²) 1

2. Contraindications to immunosuppressive therapy:

   • 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 1

3. Anti-PLA2R antibody status:

   • Positive antibodies suggest primary MN and can be used to monitor treatment response 1

Initial Treatment Algorithm

Step 1: Supportive Care for All Patients

• Optimal blood pressure control
• RAS blockade (ACE inhibitors/ARBs)
• Dietary sodium restriction
• Diuretics for edema management
• Statins for dyslipidemia

Step 2: Observe for 6 Months Unless:

• Severe, disabling symptoms are present
• Rapidly declining kidney function
• Life-threatening complications of nephrotic syndrome 1

Step 3: Initiate Immunosuppressive Therapy if Indicated

First-line options (choose one based on risk profile):

1. Rituximab:

   • Better safety profile compared to cyclophosphamide
   • Preferred in younger patients or those concerned about fertility
   • Dosing: 375 mg/m² weekly for 4 weeks or 1 g × 2 doses given 2 weeks apart 1

2. Cyclical Corticosteroid/Alkylating Agent Regimen:

   • 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide
   • Cyclophosphamide preferred over chlorambucil due to better safety profile
   • Dose adjustment needed based on age and eGFR
   • Maximum cumulative cyclophosphamide dose: 10g if fertility preservation needed, 36g to limit malignancy risk 1

3. Calcineurin Inhibitors (CNIs):

   • Tacrolimus or cyclosporine for at least 6 months
   • Target tacrolimus levels: 8-10 ng/mL
   • Monitor CNI blood levels regularly
   • Continue for at least 12 months if remission occurs
   • Higher relapse rates compared to other options 1

Monitoring Treatment Response

• Regular monitoring of proteinuria, serum albumin, and kidney function
• For anti-PLA2R positive patients: monitor antibody levels every 3 months
• Continue therapy for at least 6-12 months before considering treatment failure 1
• Consider treatment failure if no substantial reduction in proteinuria (30-50%) after 4-6 months of adequate therapy 1

Important Caveats and Pitfalls

1. Avoid monotherapy with:

   • Corticosteroids alone (ineffective) 1
   • Mycophenolate mofetil alone (insufficient evidence) 1

2. Thrombosis prevention:

   • Consider prophylactic anticoagulation with warfarin in patients with:
     • Serum albumin <2.5 g/dl
     • Additional risk factors for thrombosis 1

3. Treatment duration considerations:

   • CNIs: Continue for at least 12 months if remission occurs
   • Do not discontinue CNIs at 6 months if showing partial response 1
   • Taper CNI dose only after remission is achieved 1

4. Secondary causes:

   • Always rule out secondary causes of membranous nephropathy before initiating treatment

Treatment-Resistant Disease

If no response to initial therapy:

• If failed alkylating agent/steroid therapy → switch to CNI
• If failed CNI therapy → switch to alkylating agent/steroid therapy 1
• Consider referral to specialized center for experimental therapies in refractory cases 1

The 2021 KDIGO guidelines represent the most recent evidence-based approach to primary membranous nephropathy treatment, emphasizing individualized therapy based on risk stratification and offering multiple first-line options with different safety and efficacy profiles.