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.
Highlights
Minimal change disease (MCD) is the most common type of nephrotic syndrome in children, whereas it only accounts for 10–16% cases in adults [1, 2]
The term MCD refers to a histological pattern characterized by the normal or near-normal appearance of glomeruli on light microscopy and immunofluorescence with podocyte foot process effacement (FPE) on electron microscopy as the sole abnormality observed in kidney biopsy [3]
For children who respond to steroid therapy, namely steroidsensitive nephrotic syndrome (SSNS), MCD represents the most common underlying histological pattern followed by focal segmental glomerulosclerosis (FSGS), a more severe form of nephrotic syndrome involving glomerular scarring [4]
Summary
Minimal change disease (MCD) is the most common type of nephrotic syndrome in children, whereas it only accounts for 10–16% cases in adults [1, 2]. The LPS model is thought to directly activate the Toll-like receptor 4 (TLR-4) and downstream inflammatory pathways on podocytes resulting in mild and transient proteinuria, FPE, and changes in nephrin phosphorylation [20, 42, 43] Both models resemble some key features of MCD (sudden proteinuria, MCD-like injury on histology, and changes in podocyte proteins) [25,26,27], though apparently by different mechanisms. A weakness of this model is that proteinuria is mild and transient, but contrary to the LPS model, it is not associated with clinical sepsis [47] This model seems promising because it is well-tolerated by mice and results in glomerular changes that mimic MCD, but it remains to be determined whether variations from the original Poly: IC model of proteinuria may yield higher and/or sustained proteinuria like that observed in human MCD. This model could serve to investigate potential mechanisms of disease progression and recurrence after transplantation
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