Blockade of the renin-angiotensin system (RAS) by inhibition of angiotensin converting enzyme (ACE) reduces proteinuria and slows loss of renal function in patients with diabetic nephropathy. But the optimal manner in which ACE inhibitors should be used to limit renal injury has been remarkably little studied. In particular, further studies are needed to identify treatments which should be combined with ACE inhibition to maximize the benefit of RAS blockade. The proposed studies will assess the value of two such treatments. The first aim will be to determine whether angiotensin receptor blockade increases the antiproteinuric effect of ACE inhibition is patients with diabetic nephropathy. The putative beneficial effect of adding angiotensin receptor blockade to ACE inhibition has been widely advertised but not adequately tested. Studies conducted to date have shown only that adding an angiotensin receptor blocker (ARB) reduces proteinuria in patients maintained on relatively low doses of an ACE inhibitor. The proposed study will assess the effect of adding an ARB to higher doses of an ACE inhibitor. These studies will reveal whether ARB addition has any effect that cannot be obtained more simply and more cheaply by ACE inhibition alone. The second aim will be to determine whether diuretic use increases the antiproteinuric effect of ACE inhibition in patients with diabetic nephropathy. Previous studies have shown that addition of a diuretic lowers proteinuria in patients with non-diabetic renal disease who are maintained on ACE inhibitors. This finding suggests that ACE inhibition reduces proteinuria most effectively when ECF volume is low. The proposed studies will establish where addition of a diuretic to an ACE inhibitor has the same beneficial effect in patients with diabetic nephropathy. Ultimately, the ability of improved RAS blocking regimens to slow the progression of diabetic nephropathy can only be established by large, long term trials. But the number of such trials which can be performed is limited. Short term trials, such as those described in this proposal, are urgently required to help identify treatment regimens which merit further, longer term study.