Genetic testing for podocyte genes in sporadic focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a clinicopathological entity that manifests with severe proteinuria and/or nephrotic syndrome. FSGS is considered to represent a pattern of glomerular scarring, rather than a specific disease entity. The histological hallmark of FSGS is characterized by sclerosis that involves some, but not all, glomeruli and the affected glomeruli typically show involvement of only a portion of the capillary tuft. The aetiology of FSGS is diverse and can be divided into primary and secondary causes. Identifying the exact cause of FSGS has important therapeutic and prognostic consequences. Secondary FSGS is usually associated with a maladaptive response of the glomerulus to hyperfiltration or nephron loss, and can occur in conditions like hypertension, obesity, viral infection or drug toxicity. Secondary FSGS can also result from nonspecific scarring in the context of other glomerulopathies, including diabetic nephropathy, IgA nephropathy and lupus nephritis. Primary FSGS can be either ‘genetic’ or ‘idiopathic’. Genetic primary FSGS can be associated with mutations in several podocyte-associated genes, while idiopathic primary FSGS might be caused by either as yet unknown mutations, or by a circulating permeability factor [1]. In the current issue of Nephrology Dialysis Transplantation, Laurin et al. have examined the utility of genetic testing in sporadic FSGS. For this, pathogenic mutations in five podocyte-related genes (i.e. NPHS2, ACTN4, INF2 and PLCE1) and APOL1 risk alleles were tested in 28 children and 37 adults with sporadic FSGS. The authors identified biallelic pathogenic NPHS2 mutations in two Caucasian children. In addition, one novel nonsynonymous variant in INF2 was detected in an African American patient with adult-onset FSGS that could be potentially pathogenic. Some clinical features might be helpful in differentiating primary and secondary FSGS. Patients with secondary FSGS commonly present with slowly increasing proteinuria in the non-nephrotic range, while patients with primary FSGS show acute onset of nephrotic range proteinuria, often associated with features of nephrotic syndrome. The role of genetic factors in the development of primary FSGS has become increasingly obvious. Podocyte disorders lead to a spectrum of clinical presentations like congenital nephrotic syndrome, minimal change disease and FSGS. The heterogeneity of these disorders is reflected by the variability in disease phenotypes. Age of presentation, severity of proteinuria, response to steroids, time to dialysis and recurrence after transplantation may vary depending on the mechanism of injury. This complexity supports the impression that primary FSGS is probably a common downstream manifestation of a number of different mechanisms leading to glomerular damage. As for histopathological characteristics of different forms of FSGS, the Columbia classification distinguishes five subtypes, i.e. tip lesion, cellular, perihilar, collapsing and not otherwise specified. These variants are defined by light microscopy features, some of which correlate with prognosis and response to therapy. Although the perihilar variant has more often been associated with secondary forms of FSGS [2, 3], the Columbia classification does not clearly differentiate between primary or secondary FSGS. Podocyte foot process effacement is an ultrastructural feature of all glomerular proteinuric diseases and does not discriminate between different variants of primary and secondary FSGS. However, morphometric determination of the foot process width by electron microscopy can help to distinguish primary from secondary FSGS. There is only little overlap between foot process width in primary and secondary FSGS, and a cut-off of 1500 nm accurately differentiated primary from secondary FSGS [4]. However, there is no evidence that the degree of foot process effacement might also help to distinguish genetic from non-genetic primary FSGS. The last decades have witnessed an increase of interest in the role of the podocyte in primary FSGS. Podocytes are