This topic has had limited clinical impact so far and should therefore be studied further. Predictors of rituximab sensitivity have been studied in detail in hematologic disorders and only partially analyzed in nephrotic patients. different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these GSK2126458 (Omipalisib) steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this GSK2126458 (Omipalisib) patient population. Keywords: nephrotic syndrome, proteinuria, anti-CD20 monoclonal antibodies, glomerular disease, antibodies, monoclonal, child, humans, immunosuppressive agents, T-lymphocytes, rituximab Idiopathic Nephrotic Syndrome Idiopathic nephrotic syndrome is characterized by episodes of severe proteinuria and hypoalbuminemia (serum albumin <2.5 g/dl), often associated with dyslipidemia and hypercoagulability. Although mechanisms are poorly defined, idiopathic nephrotic syndrome includes some pathologic variants with polymorphic podocyte injury as a unifying feature (1). Diffuse foot-process effacement of podocytes is pathognomic of the two most common glomerular lesions in idiopathic nephrotic syndrome: minimal-change nephropathy and FSGS (2). Response to drugs varies from rapid and permanent disease remission after a short course of oral steroids to forms that are refractory to multidrug combination schemes. The terms steroid-sensitive, steroid-dependent, and steroid-resistant are used to differentiate clinical phenotypes, although other drugs are often used in combination with steroids. In Western countries, idiopathic nephrotic syndrome affects 2C2.7 new children per 100,000 children per year, with a prevalence of 16 cases per 100,000 (3). A substantial proportion of these children have a genetic disorder; almost 20 new genes have been discovered, documenting the involvement of the podocyte structure and function in the mechanisms of the disease (4). Despite genetic evolutions, the pathogenesis of nephrotic syndrome is poorly defined; it has been considered a T cell disorder for years (5), but evolution in basic immunology now suggests a more articulated immune cell interaction (6). Prednisone is the cornerstone of therapy for idiopathic nephrotic syndrome, inducing remission within 4C6 weeks in approximately 90% of cases (7). However, GSK2126458 (Omipalisib) the risk of relapse can be as high as 85% at 5 years, requiring reiteration of prednisone courses, often with the additional use of calcineurin inhibitors. Given the toxicity of protracted use of these and other immunosuppressive drugs, in recent years the anti-CD20 monoclonal antibody rituximab has gained popularity in the treatment of several immune-mediated disorders, including idiopathic nephrotic syndrome (8). Anti-CD20 Antibodies: Specificity and Mechanism of Action Anti-CD20 monoclonal antibodies are a class of drugs recognizing a 35-kD integral protein (CD20) expressed on the surface of B lymphocytes at various stages of differentiation, starting from preCB cells to the mature lineage, at which phase it reaches the highest concentration (9). Rituximab was the first chimeric molecule developed to treat B cell non-Hodgkin lymphomas (10). Its use was then extended to autoimmune anemia, rheumatic diseases (11,12) and, more recently, antibody-mediated conditions affecting the kidney, including ANCA-associated vasculitis (13) and membranous GN (14). Upon binding, the complex rituximab-CD20 is translocated into the lipid raft of the cell membrane, where it crossreacts with sphigomyelin phosphodieterase acid-like 3b protein (SMPDL-3b) (9). At this stage, B cells undergo a process that ends with their disappearance and that is postulated to be based on three different pathways: one is apoptosis, and the other two involve external mechanisms based on antibody- and complement-dependent cell-mediated cytotoxicity. Activation of caspase-dependent and independent pathways and of the gene are the two main mechanisms for apoptosis. Complement-dependent cytotoxicity has been demonstrated and is supported by the observation that rituximab infusion in humans results in rapid and profound depletion of complement. Antibody-dependent cellular toxicity is an important mediator of rituximab activity; it is effected by cells bearing the Fcreceptor (natural killer [NK] cells, monocytes, macrophages) that recognize the CD20-rituximab complex and lyse cells mounting the complex. In addition to general interest, these mechanisms are important in considering the possibility of predicting the effect of rituximab (see later discussion of this topic). In addition to the classic view, convincing evidence suggests that other mechanisms linked to the binding of rituximab to SMPDL-3b are active in several settings (Figure 1) that seem more kidney specific. They are important for explaining the unexpected effect Rabbit Polyclonal to RAD17 of rituximab in idiopathic nephrotic syndrome, which is classically a nonimmune disease, at least in the usual understanding of the term. Open in a separate window Figure.