NEPHROTIC SYNDROME (FOCAL SEGMENTAL GLOMERULOSCLEROSIS, NS) core panel

Scientific Background

Nephrotic syndrome (NS) is a disease associated with a glomerular filtration dysfunction in the kidneys, leading to excessive loss of plasma proteins. Clinically, NS is characterized by high proteinuria and hypoalbuminemia. Additionally, edema and hyperlipidemia are observed. Based on the different causes of disease, primary NS—most common form, idiopathic but also genetic—can be distinguished from secondary forms resulting from other concomitant diseases. Primary NS in childhood is idiopathic in about 80% of cases and is usually steroid-sensitive NS (SSNS). Less than 20% of cases are steroid-resistant NS (SRNS); these often have a histopathological correlation with focal segmental glomerulosclerosis (FSGS) and are age-dependent, sometimes there is very pronounced genetic heterogeneity. In adults, NS often occurs secondary to other underlying diseases such as immunological systemic diseases, metabolic diseases, chronic infections or intoxication.

In recent years, changes in numerous genes associated with the development of hereditary NS have been identified. Many are genes that encode podocyte proteins. Depending on the study and the number of genes examined, a genetic cause can be detected in about 30-50% of SRNS cases; in congenital NS, it is up to 97% of patients. Only limited studies on genetic causes in adults are available. In congenital NS, about 85% of cases show causative variants in the genes NPHS1, NPHS2, LAMB2 and WT1; in adult cases, variants in the genes INF2, TRPC6, ACTN4, PAX2, LMX1B and CD2AP are more frequent. No genetic causes have yet been described for SSNS, with the rare exception of the genes EMP2, KANK1 and KANK2.

If a genetic form of NS is detected, further immunosuppressive therapy is usually not indicated in pediatric patients; however, partial remission could be achieved in individual patients with cyclosporine A. Adults respond significantly worse to glucocorticoid therapy and partial remission is considered a success.

References

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