Article Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

Background and objectives Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. Design, setting, participants, & measurements Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Results Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasingmanifestation age: from 66% in congenital nephrotic syndrome to 15%–16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%–45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. Conclusions The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease. Clin J Am Soc Nephrol 10: 592–600, 2015. doi: 10.2215/CJN.06260614 Introduction Approximately 12%–15% of children with idiopathic nephrotic syndrome do not respond to oral steroid therapy (1,2). Steroid-resistant nephrotic syndrome (SRNS) is a challenging clinical condition with highly variable outcomes, and 50% of children progress to ESRD within 15 years (3,4). Although in some patients, temporary or persistent remission is achieved by intensified immunosuppressive therapies (IITs), others exhibit a multidrug-resistant phenotype. Historically, diagnostic evaluation and prognostic classification relied largely on histopathologic assessment. In recent years, abnormalities in a growing number of genes essential for podocyte development, structure, and function have been identified in patients with congenital nephrotic syndrome (CNS) and SRNS (5). The ongoing discovery of genetic podocytopathies is about to redefine the physiopathologic understanding, diagnostic assessment, prognostic judgment, and therapeutic approaches in childhood-onset SRNS. However, the development of evidence-based management algorithms has been hampered by the low incidence of SRNS, which is estimated at 2–4 per million person-years (1). To overcome the limitations imposed by the rarity of the disorder, the PodoNet Consortium has created Due to the number of contributing authors, the affiliations are