The long and winding road to the etiology of idiopathic nephrotic syndrome in children: Focusing on abnormalities in the gut microbiota.

Childhood nephrotic syndrome is idiopathic in 90% of cases. Despite its relatively high prevalence (30-35 per 100 000 individuals under 15 years old), the etiology of the disease remains elusive. It has become clear that oxidants are elevated, and antioxidants are decreased, at onset of idiopathic nephrotic syndrome (INS). It was suggested that overexpression of podocyte CD80 induced by abnormalities of Tregs was involved in the pathogenesis of INS. Subsequently, it became clear that quantitative or qualitative reduction of Tregs has a profound impact on the development of INS. To address why Tregs are decreased at onset of INS, it was hypothesized that a decrease in Tregs may be associated with dysbiosis. Given the critical role of butyrate-producing bacteria in the differentiation of Tregs, the gut microbiota was analyzed with a particular focus on the abundance of butyrate-producing bacteria, and it was found that pediatric patients with INS had low levels of butyrate in their stool and a low percentage of butyrate-producing bacteria. Interestingly, it was recently reported that gut dysbiosis increases oxidative stress in the intestinal tract. Taken together, we currently hypothesize that gut dysbiosis is associated with a predisposition to INS because of immunological abnormalities characterized by abnormal Tregs with increased oxidative stress.