Emerging Immune Cell Biomarkers in Primary Membranous Nephropathy: Immune Cell Profiling During Anti-CD20 B Cell-Targeted Therapy

Primary membranous nephropathy (pMN) is an antibody-mediated podocytopathy, most commonly caused by autoantibodies against the M-type phospholipase A2 receptor (PLA2R1). Rituximab (RTX), an anti-CD20 monoclonal antibody, is a first-line treatment for moderate-to-high-risk pMN, inducing partial or complete remission in about 60% of patients within 24 months. However, treatment response varies considerably, and current biomarkers, including anti-PLA2R1 titers and peripheral B cell counts, have limited predictive value for non-response or relapse. Beyond B cell depletion, RTX exerts broader immunomodulatory effects by influencing T cell subsets, monocytes, and natural killer (NK) cells involved in antibody-dependent cellular cytotoxicity. This review examines the peripheral immune cell changes that accompany anti-CD20 therapy and their value as candidate biomarkers. Total CD19+ B cell depletion is the standard pharmacodynamic measure of drug effect but correlates only loosely with clinical outcome. A specific B cell reconstitution profile was associated with pending relapse. Class-switched memory B cells remain depleted during sustained remission, and their premature re-expansion has been associated with subsequent relapse. Regulatory T cells are reduced in active disease and rise within days of infusion in patients who later respond. The systemic inflammation response index, derived from the routine differential count, has been associated with both 6- and 12-month remission. These observations derive from small, mostly single-center cohorts using heterogeneous panels and different RTX regimens. On the available evidence, immune cell profiling cannot yet be recommended for routine disease monitoring, and larger prospective studies with standardized panels are required.