Pathogenesis of idiopathic nephrotic syndrome in children: molecular mechanisms and therapeutic implications

Abstract

The conventional paradigm on the pathogenesis of nephrotic syndrome revolves around the concept of a glomerular disorder which is characterized by massive proteinuria with consequent hypoalbuminemia, generalized edema and hyperlipidemia. However, the changes at structural and molecular levels of the podocytes have recently assumed prominence as a new paradigm on the pathogenesis of pediatric idiopathic nephrotic syndrome. A number of complex molecular pathways with inter-related nexus result in a molecular disorientation of the slit diaphragm or the glomerular basement membrane leading to proteinuria, as well as in a rearrangement of the podocyte cytoskeleton which is responsible for foot process effacement. In acquired podocytopathies such as focal segmental glomerulosclerosis and minimal change disease, the molecular changes observed in proteins from the cytoskeleton, cell transmembrane, and the slit diaphragm induce foot process effacement and changes in negative charges which eventuates in massive proteinuria. Development of drugs able to affect these molecular pathways that regulate podocyte injury offers hope for targeted and effective treatments for nephrotic syndrome in future. Moreover, the causal association between multiple genetic mutations and the podocytopathies may translate into novel therapeutic approaches in their treatment. This review will discuss the recent hypothesized molecular mechanisms involved in the pathogenesis of idiopathic nephrotic syndrome (the podocytopathies), and the therapeutic implications.