Genetic models: clues for understanding the pathogenesis of idiopathic nephrotic syndrome
Authors: Corinne Antignac
Journal: Journal of Clinical Investigation (2002)

Ultrafiltration of plasma during primary urine formation in the glomerulus is one of the central functions of the kidney. The structurally complex glomerular capillary wall responsible for ultrafiltration consists of a basement membrane covered on the inner surface by fenestrated endothelium and on the outer surface by highly specialized epithelial cells, the podocytes (so called because of their characteristic interdigitating foot processes). In many acquired and inherited nephropathies, disruption of the glomerular filter is associated with extensive leakage of plasma proteins and a diffuse effacement of the podocyte foot processes, as detected by electron microscopy. The clinical hallmark of such glomerular dysfunction is nephrotic syndrome (NS), which is characterized by heavy proteinuria, edemas, hypoalbuminemia, and hyperlipidemia.

Idiopathic NS represents a heterogeneous group of glomerular disorders occurring mainly in children. This group is generally divided into steroid-sensitive and steroid-resistant NS, depending on the patient’s response to steroid therapy. Most patients show a favorable outcome to this treatment, although they may be subject to more or less frequent relapses of the disease. However, 10–20% of patients fail to respond and may develop end-stage renal failure. In these cases, although only minimal histological changes of the glomeruli can be observed by light microscopy at early stages, focal segmental glomerulosclerosis (FSGS), associated in some cases with mesangial proliferation, develops during the course of the disease. In approximately a third of these cases, nephrotic syndrome recurs almost immediately, with profuse proteinuria developing within 24 hours of the onset of diuresis. The sclerotic lesions of FSGS also recur and can be detected in subsequent renal biopsies of the transplanted kidney. Late-onset recurrences, occurring more than 3 months after transplantation, are also observed. Overall, recurrences occur at a mean time of 14 days after transplantation in children (1).

The effacement of podocyte foot processes observed by electron microscopy suggested a key role for the podocyte in the pathogenesis of idiopathic NS, either as a target of a glomerular permeability factor or as the site of alteration of a structural component of the foot processes. Accumulating data suggest that steroid-sensitive NS, as well as a subset of steroid-resistant NS (particularly those recurring after transplantation) have an immunological basis. Specifically, it appears that T cells in these patients promote the production of a circulating factor that alters the glomerular permeability of the filtration barrier. The nature of this factor remains elusive, but the decrease of proteinuria by ex vivo immunoadsorption using Sepharose-bound protein A or anti-Ig preparations supports the hypothesis that Ig’s are directly or indirectly (e.g., via an Ig-binding protein) involved in the mechanism causing proteinuria (2). Alternatively, other cases of steroid-resistant NS might be due to a primary defect in the glomerular filtration barrier, and these cases would not be expected to recur after transplantation, as the donor kidney does not bear the defect (Figure ​(Figure11).



Figure 1

Mechanisms underlying idiopathic NS. In both its steroid-sensitive and its steroid-insensitive form, this condition can apparently arise through a T cell dysfunction that leads to the synthesis of a still-unidentified circulating factor that compromises ...



Although idiopathic NS is usually regarded as a sporadic disease, genetic factors now cannot be ignored, as inherited cases of both steroid-resistant and steroid-sensitive NS have been described (3). Furthermore, idiopathic NS seems more severe in African-Americans, but the recurrence rate after transplantation is lower in this population (4). As discussed below, genetic analysis in animal models and human families has already shed considerable light on the molecular interactions that are affected in these patients.