From clinical to immunologic remission in lupus nephritis: Toward MRD-grade B-cell depletion

Current B-cell depletion strategies in lupus nephritis (LN) may encounter a mechanistic "glass ceiling." While rituximab remains an important therapeutic option, its activity can be constrained by CD20 internalization, antigenic modulation, and greater reliance on complement-dependent mechanisms, which may be less efficient in complement-consuming inflammatory states. Type II anti-CD20 antibodies, particularly obinutuzumab, offer a biologically distinct approach by favoring stronger effector-cell recruitment and direct cell-death programs while reducing target internalization. In this perspective, we examine whether these properties may support deeper B-cell depletion in proliferative LN. Drawing conceptually from hematologic oncology, we propose that minimal residual disease (MRD) may serve as a useful analogue for thinking about depletion depth in nephrology; however, MRD-like peripheral depletion should not be interpreted as a validated renal endpoint or as direct proof of intrarenal immune quiescence. High-sensitivity flow cytometry may refine quantification of residual circulating B cells, whereas biomarkers such as uCD163 may provide complementary information on ongoing intrarenal inflammatory activity rather than tissue B-cell depletion per se. At present, surveillance-based retreatment and fixed peripheral thresholds remain investigational. Overall, obinutuzumab expands the mechanistic and clinical horizon of LN therapy, while underscoring the need for studies linking depletion depth, tissue biology, safety, and durability of response.