Renal failure and ACE inhibition: how much is too much?

The dose-response relationship between pharmacological blockade of the renin-angiotensin system (RAS) and angiotensin II concentration in the circulation, on the one hand, and decrease of blood pressure, on the other hand, has been well established. In contrast it is currently unclear which dose of ACE inhibitors and/or angiotensin receptor blockers is optimal for nephroprotection. Clinical studies are rendered quite complex by an early decrease of glomerular filtration after RAS blockade and by side effects at higher doses such as renal sodium loss, hyperkalemia, anemia, etc. Animal experiments and recent clinical studies suggest that the doses of ACE inhibitors or angiotensin receptor blockers required for maximal reduction of proteinuria (as a surrogate marker) and for optimal nephroprotection (retardation of the loss of glomerular filtration) exceed those required for maximal lowering of blood pressure. Ongoing studies try to define the relative merits of high dose monotherapy (ACE inhibitors or angiotensin receptor blockers) versus a combination therapy of the two.