Ellison D H
Division of Nephrology, Yale School of Medicine, New Haven, CT 06510.
Ann Intern Med. 1991 May 15;114(10):886-94. doi: 10.7326/0003-4819-114-10-886.
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, imparied 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.
利尿药在合理使用时通常可改善水肿。然而，有些患者会对其产生耐药性。利尿药耐药可能源于饮食不当、依从性差、生物利用度受损、利尿药分泌至肾小管管腔的功能受损，或其他药物干扰利尿药活性。当排除了易于治疗的利尿药耐药原因后，耐药性往往反映了钠潴留刺激的强度。最近的实验研究表明了肾脏适应慢性利尿治疗的方式，并指出了这些适应性变化如何可能限制利尿效果。首先，利尿药作用部位下游的肾单位节段会增加氯化钠（NaCl）重吸收，因为输送的NaCl负荷增加。其次，利尿药引起的细胞外液量收缩会刺激肾小管保留NaCl，直到下一次给予利尿药。第三，肾小管自身可能会肥大，因为它们受到利尿药引起的NaCl输送增加的长期刺激。这些适应性变化都会增加NaCl重吸收速率，并削弱利尿治疗的效果。当存在利尿药耐药时，使用作用于不同肾单位节段的第二种利尿药通常有效。最近的实验结果表明，第二类药物可能通过阻断限制利尿效果的适应性过程与第一种药物协同作用。基于对利尿药适应和耐药机制的理解，可以设计治疗方案来阻断特定的适应性机制并改善利尿治疗。
