Late Interventions in SNX Rats Reveal a Disconnect between GFR and Proteinuria

Many animal studies investigate therapies in the prevention setting and report proteinuria as the primary efficacy outcome, while the late intervention setting is more representative of human therapy and glomerular filtration rate (GFR) is more important than proteinuria. In this study, we used the subtotal nephrectomy (SNX) model, one of the few models that exhibits progressive GFR decline along with proteinuria, hypertension, glomerulosclerosis and tubulointerstitial fibrosis. To allow for development of kidney disease, we intervened six weeks after surgery with therapies known to be effective in the prevention setting. Both ACE inhibition (enalapril) and SIRT1 activation (SRT3025) reduced proteinuria, but only ACE inhibition reduced structural damage and neither improved GFR contrary to their effects in the prevention setting. These results demonstrate the difference in therapeutic efficacy in prevention versus late intervention, and show that in the SNX model, GFR, proteinuria, and structural damage are not inextricably linked.M.Sc