Diuretic Drugs and the Treatment of Edema: From Clinic to Bench and Back Again

Despite wide variations in dietary NaCl intake, homeostatic mechanisms ensure that renal NaCl excretion matches intake at steady state. This does not imply, however, that extracellular fluid volume is maintained within narrow limits. In contrast with blood pressure, which appears to be tightly controlled, extracellular fluid volume varies significantly, even in normal individuals, when dietary NaCl intake changes. Cardiac, liver, or renal disease can perturb the relationship between NaCl intake and extracellular fluid volume and lead to symptomatic edema. All major classes of diuretic drugs in use today were developed between 1950 and 1970. These drugs were developed empirically, without knowledge of specific ion transport pathways, but experimental work during the past 15 years has shown that each major class of diuretic inhibits a specific ion transport protein in the kidney. These transport proteins have been characterized physiologically and the mechanisms by which each diuretic drug inhibits ion transport have been defined. Antibodies directed against these transport proteins have localized ion transport pathways to specific cell types along the nephron. Most recently, isoforms of each class of diuretic-sensitive Na transport pathway have been cloned. Ongoing experimental work is aimed at exploring relationships between families of transporters, determining the structural prerequisites for ion transport, and studying molecular mechanisms of transport regulation. Treatment of edema with diuretics is often straightforward, but can lead to adaptive changes in nephron structure and function. These adaptations can limit the effectiveness of diuretic drugs; maneuvers aimed at blocking these processes can be effective approaches to patients who are resistant to diuretic drugs.