Dose-dependent effects of the ACE inhibitor,ramipril,on kidney function and structure in the Alport COL4A3 −/− mouse

Abstract

Introduction

ACE inhibitor treatment of Alport syndrome, undertaken when individuals are still presymptomatic/oligosymptomatic delays dialysis but substantial residual risk remains so that additional treatments are desperately needed. In contrast to humans, standard-dose ACE inhibition with ramipril 10 mg/kg/day in Alport mice almost completely prevents GFR loss, precluding the ability to test new add-on therapies. Accordingly, we sought to find a dose that mirrored the ∼50% improvement in GFR seen in humans.

Material and methods

Escalating doses of ramipril at 0.1, 1, 3 and 10 mg/kg/day, were administered to COL4A3^−/− mice.

Results

After four weeks, ramipril induced a logarithmic, dose-dependent decline in cystatin C, the primary GFR-based outcome, with efficacy apparent at 0.1 mg/kg/day and a 50% improvement at 1–3 mg/kg/day. Proteinuria, the study's secondary outcome, showed a similar dose-response. In contrast, structural improvements such as podocyte density, glomerulosclerosis and tubulointerstitial fibrosis were not evident below 3 mg/kg/day.

Conclusion

By exploring the dose-response relationship of RAS blockade in an Alport model, the present study shows that ramipril 1 mg/kg/day may be sufficient for examining additive effects of other agents on kidney function while 3 mg/kg/day is required in order to assess the effects of add-on therapy on kidney structure as well.