Contemporary review of primary membranous nephropathy.

Primary membranous nephropathy (PMN) is a single-organ autoimmune disease caused by autoantibodies targeting podocyte-associated antigens, most commonly phospholipase A2-receptor (PLA2R). Although 14 other antigens have been identified, the target remains unidentified in 5 - 10%. Specific secondary causes have been associated with each antigen with much overlap. PMN usually presents as nephrotic syndrome. About one-third spontaneously remit, one-third progress to ESKD, and the rest maintain non-remitting proteinuria. Treatment includes supportive anti-proteinuric therapy. Immunosuppression is guided by KDIGO-based risk stratification. Low-risk cases can be watched expectantly. Very high-risk cases (declining eGFR, complications of nephrosis) should receive alternating steroids/cyclophosphamide. Moderate to high-risk cases should receive rituximab, expecting 60 - 80% response. PLA2R-titers can be followed to assess response in positive cases. Immunologic remission precedes clinical remission by months. Reemergence of antibodies signifies impending relapse. Causes of rituximab resistance include reduced bioavailability, anti-rituximab antibodies, and chronic scarring despite immunologic remission. The latter precludes further immunosuppression. Reduced bioavailability may respond to redosing or use of the more potent B-cell depleters, obinutuzumab or ofatumumab, neither of which cross react with anti-rituximab antibodies. The roles of chimeric-autoantibody-effector-cell therapy, APRIL/BAFF inhibition, anti-plasma-cell therapy, or complement inhibition remain to be determined. Transplantation is optimal therapy for ESKD. Recurrence is common. In PLA2R-positive cases, antibody reemergence or titers failing to decrease post-transplantation indicates protocol biopsy. Recurrence is not likely to remit and should prompt consideration of rituximab.