Bardoxolone - Part 3

Last year, we had a post about Bardoxolone for the treatment of diabetic nephropathy. After one year of treatment, eGFR increased significantly in patients treated with Bardoxolone relative to controls. At the time, significant concerns were raised about the fact that albuminuria also increased in patients receiving the drug and it was uncertain both what the mechanism of this was and whether there would be any deleterious consequences. 

This week, an article was published in JASN which goes some way towards explaining the reason for the proteinuria. Under normal circumstances, a significant quantity of albumin is filtered in the glomerulus. Almost all of this albumin is reabsorbed in the proximal tubule by the cubilin-megalin complex. Defects in cubilin and megalin have been associated with albuminuria in animals and humans. It turns out that Bardoxolone downregulates the expression of megalin in monkeys in the proximal tubule. Thus, the increase in albuminuria may be due to decreased effectiveness of the retrieval process. At one year, there were no significant differences in renal histology between the treated monkeys and controls. 

This is a fascinating finding. There has been a lot of work done in the last few years regarding the effect of albuminuria itself on renal fibrosis. Even in the absence of any vascular changes, overload albuminuria is associated with increased fibrosis in animal models. So, why is there no damage seen in these monkeys? One of the postulated mechanisms of albuminuria-induced fibrosis is that megalin itself acts as a transmembrane receptor and stimulates EGF production in the presence of excess tubular albumin. This ultimately leads to increased interstitial fibrosis. The loss of megalin in treated monkeys means that this pathway might be downregulated. It should be said that these were healthy monkeys and the effect in humans with more albuminuria at baseline could be different. That said, this study goes some way towards alleviating some of the concerns that were raised last year.