RTA 405 caused significant weight loss and elevation of transaminases in treated rats. Also, proteinuria increased threefold. When this rat model is treated with ACEi, there is normally a decrease in proteinuria and renal damage. When the rats were treated with RTA 405 and an ACEi simultaneously, there was some reduction in proteinuria but not to baseline. The proteinuria was accompanied by evidence of severe glomerular and tubular damage.
It is possible that these results are due to a metabolite of RTA 405 which may not be present in humans and as a result, the findings are not necessarily generalizable to humans. However, these adverse effects are similar to those initially reported in the NEJM. The mechanism for the increased renal injury is uncertain at this time.