Nephrotic syndrome / focal segmental glomerulosclerosis (FSGS)

Nephrotic syndrome is associated with dysfunction of the glomerular filtration barrier of the kidneys, leading to excessive loss of plasma proteins. Clinically, it is characterised by pronounced proteinuria and hypoalbuminaemia. In addition, oedema and hyperlipidaemia are observed.

Primary nephrotic syndrome in childhood is idiopathic in approximately 80% of cases and is usually steroid-sensitive (SSNS). Less than 20% of paediatric cases are steroid-resistant (SRNS). Depending on the study and the number of genes analysed, a genetic cause can be detected in about 30–50% of SRNS cases and in up to 97% of patients with congenital nephrotic syndrome. Data on genetic causes in adults are limited.

Nephrotic syndrome results from dysfunction of the glomerular filtration system and can be classified into primary and secondary forms based on the different causes of the disease. Primary NS, the most common form, may be idiopathic or genetically determined, whereas secondary forms may result from other concomitant diseases. Steroid-resistant NS (SRNS) often shows a histopathological correlation with focal segmental glomerulosclerosis (FSGS) and displays age-dependent and sometimes pronounced genetic heterogeneity.

In recent years, changes in numerous genes associated with the development of hereditary NS have been identified. Many are genes that encode podocyte proteins. In congenital NS, approximately 85% of cases are caused by pathogenic variants in the genes NPHS1, NPHS2, LAMB2, and WT1. In adult patients, variants are more frequently identified in the genes INF2, TRPC6, ACTN4, PAX2, LMX1B, and CD2AP. For steroid-sensitive NS, no genetic causes have been described to date, with the rare exception of the genes EMP2, KANK1 and KANK2.

In adults, nephrotic syndrome often occurs as a secondary condition in the context of other underlying diseases, including immunological systemic diseases, metabolic disorders, chronic infections, or intoxication.

Nephrotic syndrome comprises both idiopathic and genetically determined forms. Genetic causes are particularly relevant in congenital nephrotic syndrome and steroid-resistant nephrotic syndrome. The genetic contribution varies depending on age at onset, clinical presentation, and the genes involved.

Identification of a genetic cause of nephrotic syndrome is based on the detection of pathogenic variants in genes associated with hereditary NS. The likelihood of identifying a genetic cause depends on disease subtype, age at onset and the number of genes analysed.

Primary nephrotic syndrome can be distinguished from secondary forms caused by other underlying diseases. In paediatric patients, SRNS is frequently associated with focal segmental glomerulosclerosis. In adults, secondary nephrotic syndrome may occur in the context of immunological systemic diseases, metabolic disorders, chronic infections, or intoxications.

• Hoefele et al. 2018, medgen 30:140
• Bullich et al. 2015, Eur J Hum Genet 23:1192
• Sadowski et al. 2015, J Am Soc Nephrol 26:1279
• Lovric et al. 2014, Clin J Am Soc Nephrol 9:1109
• Vivante et al. 2014, Pediatr Nephrol 29:695
• Büscher et al. 2010, Clin J Am Soc Nephrol 5:2075