What is the treatment for Primary Membranous Nephropathy with worsening Albumin-to-Creatinine Ratio (ACR) and proteinuria?

Treatment for Primary Membranous Nephropathy with Worsening ACR and Proteinuria

For primary membranous nephropathy (PMN) with worsening albumin-to-creatinine ratio (ACR) and proteinuria, a 6-month course of alternating monthly cycles of oral and intravenous corticosteroids with oral cyclophosphamide is recommended as the initial immunosuppressive therapy. 1

Initial Assessment and Management

• Start with supportive care for all PMN patients from the time of diagnosis to minimize protein excretion 2
• Use ACE inhibitors or ARBs at maximally tolerated doses as first-line therapy for proteinuria reduction 3
• Target systolic blood pressure <120 mmHg using standardized office BP measurement 1
• Restrict dietary sodium to <2.0 g/day to enhance antiproteinuric effects 4

Criteria for Starting Immunosuppressive Therapy

Immunosuppressive therapy should be initiated when at least one of the following conditions is met:

• Urinary protein excretion persistently exceeds 4 g/day AND remains at >50% of baseline value despite 6 months of conservative therapy 1
• Presence of severe, disabling, or life-threatening symptoms related to nephrotic syndrome 1
• Serum creatinine has risen by ≥30% within 6-12 months (but eGFR remains >30 ml/min/1.73m²) 1

Recommended Immunosuppressive Regimen

• First-line immunosuppressive therapy: 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide (modified Ponticelli regimen) 1
• Cyclophosphamide is preferred over chlorambucil due to better safety profile 1
• Adjust cyclophosphamide dose according to patient age and eGFR to minimize toxicity 1

Monitoring and Follow-up

• Monitor patients for at least 6 months following completion of immunosuppressive therapy before considering treatment failure 1
• Perform repeat kidney biopsy only if patient has rapidly deteriorating kidney function (doubling of serum creatinine over 1-2 months) in the absence of massive proteinuria (≥15 g/day) 1
• Monitor labs frequently when on ACE inhibitor or ARB therapy, including serum creatinine, potassium levels, and proteinuria 4
• Counsel patients to temporarily discontinue ACE inhibitors/ARBs and diuretics during periods of volume depletion (illness, diarrhea) 3

Management of Treatment Resistance

• For patients not responding to initial therapy, consider intensifying dietary sodium restriction 4
• Consider using mineralocorticoid receptor antagonists in refractory cases (monitor for hyperkalemia) 4
• Use potassium-wasting diuretics and/or potassium-binding agents to manage hyperkalemia when using RAS blockers 3

Important Caveats

• Do not use immunosuppressive therapy in patients with serum creatinine persistently ≥3.5 mg/dl (or eGFR ≤30 ml/min/1.73m²) AND reduced kidney size on ultrasound OR those with severe/life-threatening infections 1
• Do not stop ACE inhibitor or ARB with modest and stable increase in serum creatinine (up to 30%) unless kidney function continues to worsen or refractory hyperkalemia develops 1
• Higher serum albumin levels and treatment with cyclophosphamide are associated with faster proteinuria reduction and/or serum albumin normalization 5
• Advanced age is a risk factor for eGFR decline in patients with PMN 5

Prognosis

With proper management including immunosuppressive therapy when indicated, only about 10% of patients with PMN will develop end-stage renal disease over the subsequent 10 years 2