Molecular Mechanisms of Rituximab in the Treatment of Nephrotic Syndrome

Watch for more news about the podocyte antigen SMPDL-3b as a potential therapeutic target in the management of nephrotic syndrome in the coming year.

Podocyte injury and death are the sine qua non of nephrotic syndrome. Efforts to abate or reverse such injuries through modulation of immunologic and neurohormonal pathways have led to great advances in the management of nephrotic syndrome, but current therapies lack specificity. The good news is there’s a new study that sheds light on a possible therapeutic target.

In recent years, rituximab has been the focus of considerable interest as an alternative therapy in the treatment of nephrotic syndrome (1). Rituximab is a chimeric mouse-human anti-CD20 monoclonal antibody that exerts its targeted biological effects through binding to the B-cell surface ligand CD20 to induce antiproliferative and proapoptotic signaling (2). Though no clear mechanism of B-cell-mediated podocyte injury has been identified, the recent discovery of sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) as an “off-target” podocyte antigen recognized by rituximab has provided exciting new insights into the molecular mechanisms of rituximab(3,4).

Little is known about SMPDL-3b or its biological relevance in podocytes, but this 455–amino acid protein of the acid sphingomyelinase family is suspected to facilitate the regulation of ligand-induced ceramide signaling, actin cytoskeletal dynamics, and cell viability. In a study of 41 pediatric kidney transplant recipients at high risk for recurrence of focal segmental glomerular sclerosis (FSGS), Fornoni and colleagues examined the interplay of rituximab with SMPDL-3b(4). The results demonstrate SMPDL-3b as a highly expressed podocyte antigen that is functionally linked to the maintenance of the podocyte actin cytoskeleton, as well as podocyte viability.

With depletion of SMPDL-3b expression, there is disruption of the podocyte actin cytoskeleton leading to podocyte apoptosis and recurrence of FSGS. When added to cultured human podocytes, rituximab binds to SMPDL-3b and preserves its ability to maintain podocyte viability. Recurrence of FSGS was reduced when rituximab was given to these high risk transplant recipients.

We expect that further work will help unravel the complexity of the intracellular signaling pathways that influence podocyte function and viability.


[1] Gentzon Hall, MD, PhD, and Michelle P. Winn, MD, are affiliated with theDuke University Medical Center, Department of Medicine, Division of Nephrology, Center for Human Genetics, in Durham.


1.Kemper MJ, Gellermann J, Habbig S, Krmar R, Dittrich K, Jungraithmayr T, et al. Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant 2011, Nov 9 [epub ahead of print].

2.Takei T, Nitta K. Rituximab and minimal change nephrotic syndrome: a therapeutic option. Clin Exp Nephrol 2011;15:641–7.

3.Perosa F, Favoino E, Caragnano MA, Dammacco F. Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor. Blood 2006;107:1070–7.

4.Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med. 2011; 3:1–10.

January 2012 (Vol. 4, Number 1)