Molecular Mechanisms of Proteinuria in Minimal Change Disease

Abstract

Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury.

Keywords: circulating factor; immune cell; minimal change disease; nephrotic syndrome; podocyte; proteinuria.

Figure 1

Representative schematic of the pathogenesis in MCD. MCD is associated with immune dysregulation. Notably, there is a strong association between human leukocyte antigen (HLA) and susceptibility to idiopathic nephrotic syndrome. So, it is possible that children with MCD have a genetic predisposition toward immune dysregulation that, in turn, contributes to release of factors that may play a role in the pathogenesis of the disease. Also, infections often trigger relapse in these patients and this may be the result of an exaggerated immune response in a susceptible patient. Several candidate mediators, released by systemic T or B cells or by glomerular cells, have been suggested to play a role in the development of proteinuria in MCD, but to date, there is a no definitive mediator of MCD. The podocyte exhibits morphological and molecular changes involving key proteins such as synaptopodin, FAK, and nephrin, but these changes are not specific for MCD and the upstream pathways leading to these changes remain unknown. The glomerular basement membrane (GBM) and the endothelial cell also show subtle changes. Thus, there is a loss of anionic charges in the GBM, but this does not appear to be a key driver of proteinuria. More recently, there is evidence of endothelial cell activation and oxidative stress, but whether this may play a role in the disease or it may represent a paraphenomenon is unclear. MCD, minimal change disease; IL, interleukin; VEGF, vascular endothelial growth factor; Angptl4, angiopoietin-like 4; ZHX1, zinc fingers and homeoboxes; FAK, focal adhesion kinase; JAK, Janus kinase.