Angiotensin-converting enzyme (ACE) inhibitors exert a renoprotective effect in both diabetic and nondiabetic renal disease with variable efficacy. Proteinuric patients with nondiabetic renal disease, normotension, and restricted protein and sodium intake were treated with ACE inhibitors without diuretics. Fifty-nine patients were treated with either lisinopril (10 mg/d; 36 patients) or enalapril (5 mg/d; 23 patients) over a period of 37.7 +/- 20.7 months. Urinary protein excretion decreased to less than 50% of pretreatment values after 1 to 37 months (6.9 +/- 8.8 months) of therapy in 33 patients (56%); in 29 patients, it reached less than 0.5 g/d of protein. Urinary protein levels remained low in 19 of the 33 patients (57.5%) throughout the entire posttreatment period (30.8 +/- 17.7 months). However, in the remaining 14 patients, escape from the antiproteinuric effect was detected after 19.2 +/- 13.4 months, evidenced by a decrease in the rate of change in creatinine clearance from 0.052 +/- 0.114 mL/min/mon during the low-proteinuria period to -0.697 +/- 1.101 mL/min/mon after the lapse of antiproteinuric effect (P: < 0.001). Although ACE inhibitors reduce the severity of proteinuria in patients with nondiabetic renal disease, our results show that a proportion of patients escape the antiproteinuric effect and subsequently develop an exacerbation of renal dysfunction.