The effect of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein excretion

The optimal doses of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) for maximal reduction in urinary protein excretion are not known. Moreover, beneficial effects from ARBs, such as tissue protection owing to a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), may be independent of blood pressure-lowering by ARBs. In this investigation, we evaluated whether increasing the dose of candesartan cilexetil, in subjects already on the maximally-recommended FDA doses of 32 mg, would induce a further reduction in 24-hour urinary protein excretion in patients with heavy proteinuria (urinary protein excretion >1.5 g/day; mean 4.4±2 g/day). Ten patients were started on 16 or 32 mg of candesartan cilexetil daily. After 1-2 months of therapy, the dose was titrated upwards to 96 mg. In all subjects, there were further reductions in 24-hour urinary protein excretion when the dose was increased beyond the recommended 32 mg maximal dose. Increasing the dose of candesartan cilexetil to 96 mg was safe, as most subjects showed no changes in serum potassium and, as expected, only a slight increase (0.5-0.7 mg/dl) in serum creatinine. These data warrant further investigation, since some subjects may require higher doses of candesartan to achieve optimal regression of proteinuria.