For many years since renal biopsies entered the armamentarium of the nephrologist, the standard approach to assessment was light microscopy with gradual addition of selected special stains, immunofluorescence, and then electron microscopy. An explosion in understanding of the spectrum of etiologies underlying the limited repertoire of lesions in the kidney, coupled with in-depth mining of morphologic lesions and their implications for prognosis, has ensued over the last decades. An exciting direction for exploration of new information for pathogenesis of glomerular diseases was driven by the seminal observation that mutations in nephrin were causal in congenital nephrotic syndrome of Finnish type.¹ This observation was followed by the beautiful studies by Holzman et al.² These studies provided a detailed initial characterization in the mouse of the nephrin protein, coded by the Nphs1 gene. Holzman et al.² cloned and sequenced the full-length cDNA of the nephrin open-reading frame and developed an immunoaffinity-purified polyclonal antiserum against the cytoplasmic domain. They identified nephrin as a glycoprotein that was located in the kidney only in visceral glomerular epithelial cells at the junction between mature podocyte foot processes. Nephrin immunostaining positivity was detected even in the newborn mice during early stages of development when the earliest slit pores and slit diaphragms were developing. From these carefully done studies of morphology made possible by the development of novel tools, Holzman et al.² could show the localization of nephrin. They also suggested that nephrin was a putative cell adhesion molecule of the immunoglobulin superfamily. These early studies were foundational for subsequent additional work confirming that nephrin is a key component of the slit diaphragm.

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