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<p>Podocytopathies, including minimal change disease and focal segmental glomerulosclerosis, represent the leading causes of nephrotic syndrome in children and adolescents. Although traditionally considered T-cell–mediated disorders, growing evidence over the last decade has reshaped this paradigm, highlighting a central role for B-cells, plasma cells, and humoral immune mechanisms in podocyte injury. The identification of pathogenic autoantibodies, particularly anti-nephrin IgG, and the involvement of complement activation have provided a strong mechanistic rationale for B-cell–targeted therapies. Rituximab, an anti-CD20 monoclonal antibody, has become an established steroid-sparing agent in steroid-dependent and frequently relapsing nephrotic syndrome, significantly reducing relapse rates and cumulative steroid exposure in pediatric patients. However, its efficacy is limited in steroid-resistant disease and in settings characterized by persistent autoantibody production or post-transplant recurrence. These limitations have prompted the exploration of next-generation anti-CD20 agents, such as obinutuzumab, which achieve deeper and more sustained B-cell depletion, as well as therapies targeting long-lived plasma cells, including anti-CD38 monoclonal antibodies. Emerging clinical data suggest that combined B-cell and plasma cell targeting may induce durable remission in refractory podocytopathies and recurrent post-transplant focal segmental glomerulosclerosis, while maintaining an acceptable safety profile. In parallel, novel strategies targeting the BAFF/APRIL axis and cellular therapies such as CAR-T cells are under investigation. This review summarizes current evidence on B-cell–directed therapies in podocytopathies, mostly in pediatrics, discusses unmet clinical needs, and outlines future perspectives toward precision, mechanism-based immunotherapy.</p> Graphical abstract <p>A higher resolution version of the Graphical abstract is available as <InternalRef RefID="MOESM1">Supplementary information</InternalRef></p> <p></p>

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B-cell-targeting therapies in podocytopathies

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月18日

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  • Carolina Bigatti,
  • Paolo Cravedi,
  • Andrea Angeletti

摘要

Podocytopathies, including minimal change disease and focal segmental glomerulosclerosis, represent the leading causes of nephrotic syndrome in children and adolescents. Although traditionally considered T-cell–mediated disorders, growing evidence over the last decade has reshaped this paradigm, highlighting a central role for B-cells, plasma cells, and humoral immune mechanisms in podocyte injury. The identification of pathogenic autoantibodies, particularly anti-nephrin IgG, and the involvement of complement activation have provided a strong mechanistic rationale for B-cell–targeted therapies. Rituximab, an anti-CD20 monoclonal antibody, has become an established steroid-sparing agent in steroid-dependent and frequently relapsing nephrotic syndrome, significantly reducing relapse rates and cumulative steroid exposure in pediatric patients. However, its efficacy is limited in steroid-resistant disease and in settings characterized by persistent autoantibody production or post-transplant recurrence. These limitations have prompted the exploration of next-generation anti-CD20 agents, such as obinutuzumab, which achieve deeper and more sustained B-cell depletion, as well as therapies targeting long-lived plasma cells, including anti-CD38 monoclonal antibodies. Emerging clinical data suggest that combined B-cell and plasma cell targeting may induce durable remission in refractory podocytopathies and recurrent post-transplant focal segmental glomerulosclerosis, while maintaining an acceptable safety profile. In parallel, novel strategies targeting the BAFF/APRIL axis and cellular therapies such as CAR-T cells are under investigation. This review summarizes current evidence on B-cell–directed therapies in podocytopathies, mostly in pediatrics, discusses unmet clinical needs, and outlines future perspectives toward precision, mechanism-based immunotherapy.

Graphical abstract

A higher resolution version of the Graphical abstract is available as Supplementary information