Diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na+ losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na+ reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.

中文翻译：

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利尿剂抵抗的病理生理学及其对慢性心力衰竭治疗的影响

利尿抵抗意味着尽管将袢利尿剂的剂量增加到上限（每天一次或两次 80 毫克呋塞米或更多），但仍无法充分增加液体和钠 (Na+) 输出以缓解容量超负荷、水肿或充血。肾小球滤过率降低或心力衰竭）。它是慢性心力衰竭患者反复住院的主要原因，可预测死亡，但很难明确诊断。药代动力学机制包括呋塞米的生物利用度低且变化多端，以及所有袢利尿剂的持续时间短，这为肾脏提供了时间来恢复剂量之间利尿剂引起的 Na+ 损失。利尿剂抵抗的病理生理机制包括每日食盐摄入量过高，超过急性利尿剂引起的失盐量、低钠血症或低钾血症、低氯性代谢性碱中毒以及肾神经的反射激活。肾单位机制包括肾小管耐受性，即使在肾小管暴露于单剂量利尿剂期间也可能出现肾小管耐受性，或近端小管中的重吸收增强，从而限制了向循环的输送，或下游远端小管中的重吸收适应性增加集合管抵消了亨利环中 Na+ 重吸收的持续阻碍。这些为新策略提供了理论依据，包括同时使用阻断这些肾单位段的利尿剂，甚至在患有严重利尿剂抵抗的心力衰竭患者中联合使用多种利尿剂和利尿剂连续阻断肾单位。