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

Clin J Am Soc Nephrol. 2015 Apr 7;10(4):592-600. doi: 10.2215/CJN.06260614. Epub 2015 Jan 29.

Abstract

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 increasing manifestation 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.

Keywords: WT1; children; nephrin; podocin; podocytopathies.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age Distribution
  • Age of Onset
  • Biopsy
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Europe / epidemiology
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Glomerulonephritis, Membranoproliferative* / diagnosis
  • Glomerulonephritis, Membranoproliferative* / epidemiology
  • Glomerulonephritis, Membranoproliferative* / genetics
  • Glomerulonephritis, Membranoproliferative* / therapy
  • Glomerulosclerosis, Focal Segmental* / diagnosis
  • Glomerulosclerosis, Focal Segmental* / epidemiology
  • Glomerulosclerosis, Focal Segmental* / genetics
  • Glomerulosclerosis, Focal Segmental* / therapy
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Infant
  • Infant, Newborn
  • Kidney Transplantation
  • Latin America / epidemiology
  • Male
  • Middle East / epidemiology
  • Mutation
  • Nephrosis, Lipoid* / diagnosis
  • Nephrosis, Lipoid* / epidemiology
  • Nephrosis, Lipoid* / genetics
  • Nephrosis, Lipoid* / therapy
  • Nephrotic Syndrome / congenital*
  • Nephrotic Syndrome / diagnosis
  • Nephrotic Syndrome / epidemiology
  • Nephrotic Syndrome / genetics
  • Nephrotic Syndrome / therapy
  • Phenotype
  • Prospective Studies
  • Recurrence
  • Registries
  • Remission Induction
  • Retrospective Studies
  • Risk Factors
  • Treatment Outcome
  • Young Adult

Substances

  • Genetic Markers
  • Immunosuppressive Agents

Supplementary concepts

  • Nephrosis, congenital
  • Nephrotic syndrome, idiopathic, steroid-resistant