The autoimmune architecture of childhood idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome (INS), the most common glomerular disorder in children, has long been considered an immune-mediated disease based on the efficacy of glucocorticoids at inducing remission. Nevertheless, the immune processes leading to podocytopathy have largely remained elusive. The success of B cell-depletion with rituximab, descriptions of B cell dysregulation during active disease, and the most recent discovery of autoantibodies targeting the major podocyte antigen Nephrin denote an autoimmune humoral etiology for INS. Research into the immune factors involved in INS pathogenesis have uncovered common features with other autoimmune disorders that will aid in prognostication and in guiding the expansion of our glucocorticoid-sparing therapeutic arsenal. In this review, we discuss the emerging autoimmune architecture of INS, with a specific focus on pediatric steroid-sensitive disease, including the podocyte-reactive B cell response that gives rise to anti-podocyte antibodies (APAs), the predisposing genetic factors that shape the podocyte-reactive immune landscape, and the immune triggers driving active disease.