Thirty-four patients (65.3+/-3.3 years of age, mean+/-SEM) with hyperkalemia (serum potassium >5.0 mEq/L) had measurement of their renin-aldosterone system. Nineteen patients (56%) had plasma renin activity (PRA) >1.5 ng/mL/h, which was not low, while 15 (44%) had PRA <1.5. Twelve of the 15 hyporeninemic hyperkalemic patients were studied to determine whether their renin-aldosterone system responded to 2 weeks of furosemide, 20 mg daily. Four were nonresponders: PRA averaged 0.3+/-0.1 ng/mL/h, and it did not increase with furosemide or respond to captopril before or after furosemide. Eight patients were responders: PRA averaged 0.6+/-0.2 ng/mL/h and increased with furosemide to 5.5+/-3.4 ng/mL/h. Captopril failed to increase PRA before furosemide, but PRA increased to 15.3+/-8.4 ng/mL/h after furosemide. Plasma aldosterone was low in both nonresponders and responders (3.5+/-1.2 ng/dL vs 5.8+/-2.5 ng/dL) and did not increase significantly with furosemide (4.3+/-1.7 ng/dL vs 8.7+/-2.5 ng/dL). Serum potassium did not fall and therefore did not limit the rise in aldosterone. Renin responders had greater body weight, were predominantly female (6/8 vs 2/4) and were more likely to have diabetes mellitus (7/8 vs 0/4). Plasma atrial natriuretic peptide (ANP) fell with furosemide in 8 of 8 responders and in 1 of the 2 nonresponders in whom it was measured. Neither group had suppressed plasma prorenin levels, indicating no suppression of renin gene expression. These results indicate that many hyperkalemic patients do not have suppressed PRA. Further, a majority of patients with suppressed PRA have high levels of ANP and can respond to diuretic therapy with a rise in PRA and a fall in ANP, suggesting physiologic suppression of the renin system by volume expansion. A minority of hyperkalemic patients with suppressed PRA had PRA that did not increase under these study conditions.