When foots come first: early signs of podocyte injury in Fabry nephropathy without proteinuria.

murine and rat models of vascular endothelial growth factor depletion leading to endotheliosis, alpha-3 chain of collagen IV knock-out mouse, that represents a murine model of autosomal recessive Alport syndrome, Masugi nephritis model in rats, rare patients with a familial form of nephrotic syndrome in whom podocytes are fully preserved, even in the occurrence of heavy proteinuria, women with preeclampsia, that is histologically characterized by glomerular endotheliosis [7] . The damage to any of the three components of the GFB, that is, endothelial cells, GBM, and podocytes, can eventually lead to the development of proteinuria without necessarily determining the loss or effacement of podocyte foot processes. In addition, studies performed on human biopsies with a variety of diseases showed that FPE is rather dependent on the nature of the underlying disease than on the amount of urinary protein loss. No clear correlation between the degree of podocyte FPE and the entity of proteinuria can be established [1, 4, 8–10] , finally suggesting that FPE occurs in many, but not all, proteinuric diseases and that it is not necessary for the development of proteinuria. Thus, what kind of pathophysiological line links FPE and proteinuria seems to be anything but simple. Things become even more complicated if one considers that previous studies in animal models have shown that podocyte effacement can be seen in the absence of proteinuria. As an example, rats with puromycin aminoPodocytes are highly specialized epithelial cells that cover the glomerular basement membrane (GBM) with their foot processes, leading to permeselectivity, typical of the glomerular filtration barrier (GFB). As assessed by electron microscopy (EM), proteinuria is associated with striking changes in podocyte architecture and shape, that comprise loss or effacement of the podocyte foot processes and that can represent the solitary hallmark of disease or can be associated to the other abnormalities characteristic of the underlying disease, such as immune deposits or inflammation [1] . Alterations of podocyte architecture and loss of interdigitating foot processes (namely, foot process effacement, FPE) were first described by means of EM in 1950s as the morphological signs accompanying proteinuric diseases, such as minimal change nephrotic syndrome and glomerulonephritis [2] . Subsequently, most proteinuric renal diseases such as diabetic nephropathy and focal segmental glomerulosclerosis have been described as associated with ultrastructural abnormalities compatible with FPE. Furthermore, studies on congenital and familial forms of nephrotic syndrome caused by mutations in genes specifically expressed by podocytes support the hypothesis that podocyte FPE is the primary event that leads to proteinuria [1, 3–6] . However, from the late 1970s, both human and experimental models of proteinuric diseases in which podocyte FPE is not present have been reported, as for example Published online: January 15, 2015