Effect of B-cell Depleting Therapies on PLA2R-specific B Cells in Patients With Membranous Nephropathy

Primary Membranous Nephropathy (MN) is the most frequent cause of Nephrotic Syndrome (NS) in adults. Even though 30% of affected patients may experience spontaneous remission of the disease, MN-associated NS can severely impact on renal survival, with one third of patients invariably progressing to end-stage renal disease. In addition, NS, characterized clinically by massive proteinuria, hypoalbuminemia and generalized edema, severely affects patients' quality of life and may cause potentially life-threatening complications, including cardiovascular, thrombotic and infectious events.

MN is histologically characterized by the deposition of IgG4 and C3 on the subepithelial layer of the glomerular capillary wall, with variable degrees of glomerular basement membrane thickening. The discovery of autoantibodies directed against the M-type phospholipase A2 receptor (PLA2R) in 70% of patients finally proved MN as an autoimmune disease and provided the rationale for targeted therapies against the immune B-cell compartment.

The anti-CD20 chimeric monoclonal antibody Rituximab (RTX) is becoming the first-line therapy of MN treatment, being superior in inducing disease remission with lower incidence of adverse effects than generalized immunosuppression with glucocorticoids, alkylating agents or cyclosporine.

Binding of RTX to its molecular target results in a profound B-cell depletion in the peripheral blood, which persists for several months. In anti-PLA2R positive MN patients treated with RTX, B-cell depletion is frequently followed by a decrease in the autoantibody titer and by remission of the NS, suggesting that the drug may be active against the B-cell clones responsible for the production of anti-PLA2R antibodies.

However, the drug is effective only in 60% of cases, with the rest of patients remaining heavily proteinuric; in these patients anti-PLA2R antibodies persist after an initial transient decrease. In addition, approximately one third of patients that initially achieved clinical remission with RTX experience one or more disease relapses (usually associated with reappearance of autoantibodies), which might eventually become rituximab-dependent and spend most of their lives with nephrotic range proteinuria.