What is the initial approach to treating secondary membranous disease?

Initial Approach to Treating Secondary Membranous Nephropathy

The initial approach to treating secondary membranous nephropathy should focus on identifying and treating the underlying cause while providing optimal supportive care, with immunosuppressive therapy decisions based on disease severity and kidney function stability.1

Identification and Treatment of Underlying Cause

• Secondary membranous nephropathy can be associated with various conditions including infections, autoimmunity, drugs, and malignancies - addressing the underlying cause is the primary treatment approach 2
• A thorough evaluation to identify the underlying etiology should be performed before initiating specific therapy for the glomerular disease 3
• Treatment of the underlying condition may lead to resolution of the secondary membranous nephropathy without specific immunosuppressive therapy 4

Supportive Care

• All patients with secondary membranous nephropathy and proteinuria should receive optimal supportive care, including RAS blockade (ACEi/ARB), blood pressure control, and management of nephrotic syndrome complications 1, 5
• Immunosuppressive therapy is not required in patients with proteinuria < 3.5 g/d, serum albumin > 30 g/L, and eGFR > 60 ml/min per 1.73 m² 1
• Prophylactic anticoagulation should be considered in patients with severe hypoalbuminemia (<25 g/L by bromocresol purple or <20 g/L by bromocresol green) due to increased thromboembolism risk 1, 5

Immunosuppressive Therapy Based on Disease Severity

For Stable Kidney Function (eGFR stable)

• If immunosuppressive therapy is indicated (proteinuria >3.5 g/d or complications of nephrotic syndrome), consider calcineurin inhibitors (CNIs) as first-line therapy 1
• Rituximab may be considered as an alternative first-line agent in patients with stable kidney function 1
• Monitor treatment response by assessing proteinuria, serum albumin, and kidney function at regular intervals 5

For Declining Kidney Function (eGFR decreasing)

• Cyclophosphamide with glucocorticoids is recommended as first-line therapy when kidney function is declining 1
• The cumulative dose of cyclophosphamide should not exceed 36 g (preferably limited to 25 g) to minimize the risk of malignancy 1
• Lower doses (maximum 10 g) must be used in patients who wish to preserve fertility 1

Treatment Monitoring and Adjustment

• In patients with primary membranous nephropathy, anti-PLA2R antibody levels are monitored to guide therapy, but this may not be applicable in all cases of secondary membranous nephropathy 6
• If proteinuria persists while serum albumin has increased, consider secondary focal segmental glomerulosclerosis (FSGS) 1
• In patients with persistent proteinuria despite appropriate treatment of the underlying cause, a repeat kidney biopsy may be considered to document active disease 1

Management of Resistant Disease

• For patients resistant to initial therapy with stable eGFR, consider switching from CNIs to rituximab or vice versa 1
• For resistant disease with declining eGFR, cyclophosphamide with glucocorticoids is recommended 1
• Patients who do not respond to rituximab or cyclophosphamide should be referred to an expert center for consideration of experimental therapies or higher doses of conventional immunosuppressive therapy 1

Special Considerations for Lupus Membranous Nephropathy

• For patients with lupus nephritis Class V (membranous) with or without proliferative components, treatment with glucocorticoids plus one of the following is recommended: mycophenolic acid analogs, low-dose intravenous cyclophosphamide, belimumab combined with either mycophenolic acid or cyclophosphamide, or mycophenolic acid with a calcineurin inhibitor 1

Common Pitfalls to Avoid

• Failing to identify and treat the underlying cause of secondary membranous nephropathy 3
• Initiating immunosuppressive therapy before ruling out secondary causes 4
• Using cyclophosphamide at doses that exceed the recommended cumulative limits, increasing the risk of malignancy and infertility 1
• Continuing immunosuppression unnecessarily when disease is in remission 6
• Interpreting persistent proteinuria alone as treatment failure, as proteinuria may persist for months after immunologic remission 6