Cell biology and genetics of minimal change disease

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.

Keywords: Minimal change disease; circulating factor; focal segmental glomerulosclerosis; permeability; podocyte; steroid-resistant nephrotic syndrome; steroid-sensitive nephrotic syndrome.

Figure 1.. Scheme of lymphocyte dysfunction and circulating factors in minimal change disease (MCD).

By immune trigger such as viral infection, vaccination, and exposure to allergen, antigen-presenting cells and memory B cells present antigen to T lymphocyte. These cells are stimulated to secrete circulating factors in MCD. Rituximab depletes B cells and induces remission; on the other hand, rituximab has an effect on cytoskeleton stability of podocytes and blocks albumin permeability. Th17 skew in MCD may cause steroid resistance and cyclosporine A selectively attenuates Th17. Abbreviations: APCs, antigen presenting cells; CysA, cyclosporine A; CF, circulating factor; IL17, interleukin 17; Th17, helper T subset 17; TNF-a, tumor necrosis factor alpha.