INTRODUCTION: Aldosterone seems to have deleterious effects on the kidneys. Many animal studies and a few clinical trials have shown that suppression of aldosteroneby aldosterone receptor blockers ameliorates these effects. METHOD: In a double-blind crossover study, patients with diabetic nephropathy who were already receiving either angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) were given spironolactone or matching placebo with 1 month of washout in between. Blood pressure (BP), serum creatinine, serum potassium, and spot urine protein/creatinine were measured at the beginning and end of each study period. RESULTS: Mean systolic BP on spironolactone went down from 153.64 (+/-25.95) at the beginning to 141.60 (+/-16.54) at the end of study (P = 0.01). Diastolic BP during spironolactone therapy did not change significantly. The urine protein/creatinine increased from 1.24 (+/-1.13) to 1.57 (+/-2.13) on placebo (P = 0.35) and decreased from 1.80 (+/-1.78) to 0.79 (+/-0.99) during spironolactone therapy (P = 0.004). In other words proteinuria increased by 24% during the placebo treatment period but decreased by half (57%) during the active treatment. Serum potassium increased from 4.29 (+/-0.47) to 4.64 (+/-0.55) during spironolactone therapy (P = 0.002), no significant change with placebo. Whereas serum creatinine did not change on placebo, it increased from 1.35 (+/-0.54) to 1.56 (+/-0.62) on spironolactone (P = 0.006). Glomerular filtration rate decreased from 61.91 (+/-23.4) to 53.94 (+/-23.58) on spironolactone (P = 0.0001) but not on placebo. CONCLUSIONS: Addition of a modest dose of spironolactone to a regimen of ACEI or ARB in patients with diabetic proteinuria causes further reduction in proteinuria and also lowers the systolic BP. As with ACEI or ARB, spironolactone modestly reduces the glomerular filtration rate and raises serum potassium.