Diuretic therapy in edematous diseases often yields an inadequate natriuretic response ("diuretic resistance"). To study the functional changes in patients with congestive heart failure, liver cirrhosis with ascites, and nephrotic syndrome, characterized by a reduced effective arterial blood volume (EABV), different diuretic strategies were studied. It was shown that monotherapy with hydrochlorothiazide or furosemide was followed by an inadequate natriuretic response. Correlation of diuretic response with pretreatment fractional sodium excretion of the patient revealed a clear-cut interdependency: Those patients were resistant whose FENa+ was greatly below normal (<0.2%). In addition, it was found that the coadministration of the carboanhydrase inhibitor acetazolamide to diuretic therapy was very effective. We therefore conclude that an increase in proximal-tubular Na+ reabsorption is the major ("pharmacodynamic") determinant for diuretic resistance in edematous diseases with functional "underfilling" of the vascular tree. This alteration of the kidney can easily be overcome by coadministration of a carboanhydrase inhibitor (e.g., acetazolamide).