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The Physiologic Basis of Diuretic Synergism: Its Role in Treating Diuretic Resistance

David H. Ellison, MD
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Grant Support: By Merit Review and Career Development Awards from the Department of Veterans Affairs.

Requests for Reprints: David H. Ellison, MD, Division of Nephrology (2074 LMP), Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510.

Current Author Address: Dr. Ellison: Division of Nephrology (2074 LMP), Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510.

Ann Intern Med. 1991;114(10):886-894. doi:10.7326/0003-4819-114-10-886
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Diuretic drugs usually improve edema when used judiciously. Some patients, however, become resistant to their effects. Diuretic resistance may result from dietary indiscretion, poor compliance, impaired bioavailability, impaired diuretic secretion into the lumen of the renal tubule, or because other drugs interfere with diuretic activity. When easily treatable causes of diuretic resistance have been excluded, resistance often reflects the intensity of the stimuli to sodium retention. Recent experimental work has indicated ways in which the kidney adapts to chronic diuretic treatment and has indicated how these adaptations may limit diuretic effectiveness. First, nephron segments downstream from the site of diuretic action increase sodium-chloride (NaCl) reabsorption because the delivered NaCl load increases. Second, diuretic-induced contraction of the extracellular fluid volume stimulates kidney tubules to retain NaCl until the next dose of diuretic is administered. Third, kidney tubules themselves may become hypertrophic because they are chronically stimulated by diuretic-induced increases in NaCl delivery. These adaptations all increase the rate of NaCl reabsorption and blunt the effectiveness of diuretic therapy. When diuretic resistance is present, using a second diuretic drug that acts in a different nephron segment is often effective. Recent experimental results suggest that a second class of drug may act synergistically with the first by blocking the adaptive processes that limit diuretic effectiveness. On the basis of an understanding of the mechanisms of diuretic adaptation and resistance, treatment regimens can be designed to block specific adaptive mechanisms and to improve diuretic therapy.





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