Accelerating the Depletion of Circulating Anti-Phospholipase A<sub>2</sub> Receptor Antibodies in Patients with Severe Membranous Nephropathy: Preliminary Findings with Double Filtration Plasmapheresis and Ofatumumab

Patients with membranous nephropathy (MN) and persistent nephrotic syndrome (NS) are at increased risk of ­progression to end-stage renal disease. The discovery of ­autoantibodies against the podocyte-expressed M-type phospholipase A₂ receptor (PLA₂R) provided a clear pathophysiological rationale for interventions targeting the B-cell lineage to prevent antibody production and subepithelial immune-complex deposition. The anti-CD20 monoclonal antibodies, rituximab and ofatumumab, are safe and achieve remission of NS in approximately two-thirds of patients with MN. In patients with PLA₂R-related MN, remission can be predicted by anti-PLA₂R antibody depletion, and faster depletion is associated with earlier reduction of proteinuria and improved nephroprotection. Selective apheresis methods, such as double-filtration plasmapheresis (DFPP), may accelerate the clearance of autoreactive antibodies and at the same time avoid the side effects of plasma-exchange. In this preliminary, explorative, proof-of-concept study, we observed that in patients with PLA₂R-related MN, NS and high antibody levels, ofatumumab-induced B-cell depletion followed by DFPP accelerated anti-PLA₂R depletion compared to anti-CD20 monotherapy. This therapeutic regimen was safe and well tolerated. These observations may provide the background for controlled trials aimed at formally testing whether the addition of DFPP to anti-CD20 therapy could offer a novel therapeutic option, especially for patients with more severe MN.