Developmental Causes of Focal Segmental Glomerulosclerosis

Background: Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular damage that includes idiopathic conditions as well as genetic and non-genetic forms. Among these various etiologies, different phenotypes within the spectrumof congenital anomalies of the kidney and urinary tract (CAKUT) have been associated with FSGS. Summary: Until recently, the main pathomechanism of how congenital kidney and urinary tract defects lead to FSGS was attributed to a reduced number of nephrons, resulting inbiomechanical stress on the remaining glomeruli, detachment of podocytes, and subsequent inability to maintain normal glomerular architecture. The discovery of deleterious single-nucleotide variants in PAX2, a transcription factor crucial in normal kidney development and a known cause of papillorenal syndrome, in individuals with adult-onset FSGS without congenital kidney defects has shed new light on developmental defects that become evident during podocyte injury. Key Message: In this mini-review, we challenge the assumption that FSGS in CAKUT is caused by glomerular hyperfiltration alone and hypothesize a multifactorial pathogenesis that includes overlapping cellular mechanisms that are activated in both damaged podocytes as well as nephron progenitor cells.