Abstract
Minimal change disease (MCD) is an important cause of nephrotic syndrome and is characterized by massive proteinuria and hypoalbuminemia, resulting in edema and hypercholesterolemia. The podocyte plays a key role in filtration and its disruption results in a dramatic loss of function leading to proteinuria. Immunologic disturbance has been suggested in the pathogenesis of MCD. Because of its clinical features, such as recurrent relapse/remission course, steroid response in most patients, and rare familial cases, a genetic defect has been thought to be less likely in MCD. Recent progress in whole-exome sequencing reveals pathogenic mutations in familial cases in steroid-sensitive nephrotic syndrome (SSNS) and sheds light on possible mechanisms and key molecules in podocytes in MCD. On the other hand, in the majority of cases, the existence of circulating permeability factors has been implicated along with T lymphocyte dysfunction. Observations of benefit with rituximab added B cell involvement to the disease. Animal models are unsatisfactory, and the humanized mouse may be a good model that well reflects MCD pathophysiology to investigate suggested “T cell dysfunction” directly related to podocytes in vivo. Several candidate circulating factors and their effects on podocytes have been proposed but are still not sufficient to explain whole mechanisms and clinical features in MCD. Another circulating factor disease is focal segmental glomerulosclerosis (FSGS), and it is not clear if this is a distinct entity, or on the same spectrum, implicating the same circulating factor(s). These patients are mostly steroid resistant and often have a rapid relapse after transplantation. In clinical practice, predicting relapse or disease activity and response to steroids is important and is an area where novel biomarkers can be developed based on our growing knowledge of podocyte signaling pathways. In this review, we discuss recent findings in genetics and podocyte biology in MCD.
Highlights
Minimal change disease (MCD) is characterized by massive proteinuria without histological evidence of immune-mediated damage in the glomeruli
It was recently reported that proteases present in nephrotic plasma obtained from patients with focal segmental glomerulosclerosis (FSGS) can activate protease-activated receptor 1 (PAR1), leading to the podocin-dependent phosphorylation of the actinassociated protein vasodilator-stimulated phosphoprotein (VASP) in human podocytes and increased cell migration, suggesting a novel role for proteases and PARs in the pathogenesis of FSGS41,42
CD80 CD80 (B7-1) is a T cell co-stimulatory molecule involved in antigen processing that is unexpectedly expressed on podocytes in certain experimental and clinical disease states
Summary
Minimal change disease (MCD) is characterized by massive proteinuria without histological evidence of immune-mediated damage in the glomeruli. Epigenetic involvement in the pathogenesis of minimal change nephrotic syndrome in T cells has been suggested in a report showing that nuclear factor related to kappaB binding protein (NFRKB) was highly expressed in the nuclear compartment in T lymphocytes of MCD patients during relapse and that NFRKB promotes hypomethylation of genomic DNA in HEK cells transfected with NFRKB expression plasmid[21]. It was recently reported that proteases present in nephrotic plasma obtained from patients with FSGS can activate PAR1, leading to the podocin-dependent phosphorylation of the actinassociated protein vasodilator-stimulated phosphoprotein (VASP) in human podocytes and increased cell migration, suggesting a novel role for proteases and PARs in the pathogenesis of FSGS41,42. The circulating factors might be secreted by peripheral blood cells such as T or B cells by mesangial or endothelial cells in a paracrine manner or by the podocyte itself in an autocrine manner
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