Familial forms of nephrotic syndrome

Abstract

The recent discovery of genes involved in familial forms of nephrotic syndrome represents a break-through in nephrology. To date, 15 genes have been characterized and several new loci have been identified, with a potential for discovery of new genes. Overall, these genes account for a large fraction of familial forms of nephrotic syndrome, but they can also be recognized in 10-20% of sporadic cases. These advances increase diagnostic and therapeutic potentials, but also add higher complexity to the scenario, requiring clear definitions of clinical, histopathological and molecular signatures. In general, genetic forms of nephrotic syndrome are resistant to common therapeutic approaches (that include steroids and calcineurin inhibitors) but, in a few cases, drug response or spontaneous remission suggest a complex pathogenesis. Finally, syndromic variants can be recognized on the basis of the associated extra-renal manifestations. In this educational review, clinical, histological and molecular aspects of various forms of familial nephrotic syndrome have been reviewed in an attempt to define a rational diagnostic approach. The proposed model focuses on practical and economic issues, taking into consideration the impossibility of using genetic testing as starting diagnostic tool. The final objective of this review is to outline a diagnostic flow-chart for clinicians and geneticists and to generate a rational scheme for molecular testing.

Fig. 1

Diagnostic flow-chart in children with early onset nephrotic syndrome (<1 year) or in patients <14 years demonstrating steroid resistance. Steroid resistance was defined by lack of anti-proteinuric effect after 45 days with prednisone 2 mg/kg and three pulses with methyl-prednisolone 10 mg/kg. DMS Diffuse mesangial sclerosis, FSGS focal segmental glomerulosclerosis, NPHS1 nephrin gene, NPHS2 podocin gene, PLCE1 phospholipase C epsilon 1 gene, WT1 Wilm’s tumor 1 gene, COQ2 para-hydroxybenzoate-polyprenyl-transferase gene, PDSS2 decaprenyl diphosphate syntase gene, mtDNA mitochondrial DNA