Ischemic nephropathy due to bilateral renovascular disease (RVD) is increasingly recognized as cause of end-stage renal failure in the elderly, but a reliable non-invasive method of detection is nor available. Angiotensin converting enzyme inhibition (ACEi) may impair renal function in such patients, but a prospective study of its diagnostic validity has not been undertaken. We studied the effects of controlled exposure to ACEi on plasma creatinine in 108 patients at risk for severe bilateral atherosclerotic RVD, and compared the findings with subsequent angiography. ACEi was given for two weeks, or, to avoid acute renal failure, for four days if plasma creatinine had increased by 20% or more. If after two weeks of ACEi plasma creatinine had not increased by > or = 20%, while blood pressure was still elevated, plasma creatinine was remeasured after blood pressure control by addition of diuretics. The severity of RVD was scored by the stenosis grade of the best perfused kidney. Fifty-two patients had severe bilateral RVD, defined as > or = 50% stenosis to both kidneys (N = 23) or a solitary functioning kidney (N = 29). Of the others, 21 had less severe bilateral RVD, 20 unilateral RVD, and 15 no apparent RVD. Basal plasma creatinine was higher in severe bilateral RVD (median 170 mumol/liter, range 85 to 654 mumol/liter) than in the others (122 mumol/liter, 62 to 675 mumol/liter; P < 0.01), but not discriminative due to a large variability. The increase during ACEi was correlated with the degree of RVD (r = 0.53, P < 0.001). In 69 patients ACEi caused at least a 20% increase in plasma creatinine, in 26 cases by four days, in 31 after two weeks, and in 12 only after blood pressure control by diuretics. Among these were all 52 patients with severe bilateral RVD, 15 of the 41 patients with lesser forms of RVD, and two with normal renal arteries. Thus, in this selected population the criterion of > or = 20% rise in plasma creatinine upon ACEi was 100% sensitive to detect severe bilateral RVD, while its specificity was 70%. No case of acute renal failure was encountered, and plasma creatinine always recovered after stopping ACEi. In conclusion, controlled exposure to ACEi in these patients is safe, and ACEi-induced increase in plasma creatinine is a very sensitive detector of severe bilateral RVD in a high risk population.