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

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. Introduction 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 [1]. The glomerular capillary wall (responsible for ultrafiltration) is a trilaminate structure consisting of the basement membrane covered on the inner surface by fenestrated endothelium and wrapped around the outer surface by the podocytes. Under electron microscopy, disruption of this glomerular filter seen in many acquired and inherited nephropathies is associated with a diffuse effacement of the podocyte foot processes [2]. This effacement suggests a key role for the podocytes in the pathogenesis of idiopathic nephrotic syndrome, either as a target of a glomerular permeability factor or as the site of alteration of a structural component of the foot processes [2]. In fact, the major idiopathic glomerulopathies associated with proteinuria are the podocytopathies (minimal change disease and focal segmental glomerulosclerosis), as well as membranous nephropathy. The former are commoner in children than the latter. The podocytopathies are characterized by changes in the podocytes, which may be at the structural or molecular levels [3]. The changes at the molecular levels have recently assumed prominence as a new paradigm on the pathogenesis of idiopathic nephrotic syndrome in children. In addition, emerging data suggest that steroid-sensitive nephrotic syndrome, as well as a subset of steroid-resistant nephrotic syndrome (particularly those recurring after transplantation) have an immunological basis [3]. For instance, it appears that T cells in these patients promote the production of a circulating factor, which alters the permeability of the glomerular filtration barrier. Many vascular permeability factors have been postulated, and these include vascular endothelial growth factor, heparanase, hemopexin and soluble urokinase receptor (suPAR) [4,5]. In addition, podocytes have been found to express receptors for type 2 cytokines (interleukin-4 and interleukin-13) elaborated by T cells, which if activated may also disrupt glomerular permeability leading to proteinuria [6]. In a nut-shell, idiopathic nephrotic syndrome has been defined as a T-cell disorder associated with a functional renal impairment in which the molecular mechanisms leading from the stimulation of the immune system to the clinical expression of the renal disease can be analyzed according to five biological events: a Th 2 activation of T cells by interleukin-13; a yet unresolved glomerular permeability factor of immune origin; a molecular disorientation of slit diaphragms or glomerular basement membrane responsible for proteinuria; a podocyte cytoskeleton rearrangement responsible for foot process effacement; and renal avidity for sodium and edema formation resulting from a primary stimulation of tubular sodium, K+-ATPase and an increase of endothelial permeability [7]. This review will discuss the recent hypothesized molecular mechanisms involved in the pathogenesis of idiopathic nephrotic syndrome (the podocytopathies), and the therapeutic implications. Podocytopathies: The molecular basis The podocyte contributes in maintaining the structural integrity of the glomerular filtration barrier as its injury and loss results in Correspondence to: SN Uwaezuoke, Department of Pediatrics, UNTH, ItukuOzalla, Enugu, Nigeria, Tel: +2348033248108; E-mail: [email protected]