Precision immune reset in autoimmune kidney diseases: balancing the depth and cost of B-cell-targeted therapy

Treating autoimmune kidney diseases remains challenging because pathogenic B-cell activity spans circulating, tissue-resident, memory, and antibody-secreting compartments. Moreover, renal recovery often lags behind immunologic control. B-cell-targeted therapies now extend beyond anti-CD20 antibodies and include BAFF/APRIL blockade, CD19- and CD38-directed antibodies, bispecific T-cell engagers, and chimeric antigen receptor-engineered cells. This review examines the mechanistic and clinical evidence for these therapies in lupus nephritis, antineutrophil cytoplasmic antibody-associated glomerulonephritis, anti-glomerular basement membrane disease, membranous nephropathy, and IgA nephropathy. We interpret this evidence using a precision immune-reset framework that considers the dominant pathogenic compartment, the depth and durability of depletion, and the course of immune reconstitution. Anti-CD20 and BAFF/APRIL-directed therapies currently have the strongest disease-specific clinical support. Broader targeting of the B-cell lineage or plasma cells may help address tissue-persistent B cells and plasma-cell escape in selected patients with refractory disease. However, more extensive depletion may increase the risks of hypogammaglobulinemia, infection, impaired vaccine responses, cytopenias, delayed immune reconstitution, and treatment-specific toxicities. Suppression of pathogenic immunity also does not ensure rapid structural recovery of the kidney. We therefore propose a disease-specific framework that considers baseline immune reserve, pathogenic mechanisms, biomarker profiles, intrarenal activity, and the reversibility of kidney injury. Assessing both the suppression of pathogenic immunity and the recovery of protective immune function may improve the prospect of durable renal benefit while limiting unnecessary immunologic injury.