RENAL MECHANISM OF TRIMETHOPRIM-INDUCED HYPERKALEMIA
RENAL MECHANISM OF TRIMETHOPRIM-INDUCED HYPERKALEMIA
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DOI：
10.7326/0003-4819-119-4-199308150-00008
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发表时间：
1993-08-15
影响因子：
39.2
通讯作者：
ELLISON, DH
中科院分区：
文献类型：
--
作者：
VELAZQUEZ, H;PERAZELLA, MA;ELLISON, DH
目的：1) 确定甲氧苄啶治疗期间高钾血症的发生率和严重程度。 2) 检验甲氧苄啶通过阻断哺乳动物远端肾单位的钠通道来抑制肾钾排泄的假设。患者：连续30名接受含甲氧苄啶药物治疗的患者。研究中包括的所有患者均患有获得性免疫缺陷综合症（艾滋病）。 实验动物：39 只雄性 Sprague-Dawley 大鼠，接受正常大鼠饲料和自来水（允许自由饮用）。 干预： 人类：高剂量（每天 20 毫克/千克）甲氧苄啶治疗。大鼠：静脉注射甲氧苄啶（9.6 mg/h，每公斤体重）或肾远小管（1 mmol/L）。 测量：人类：测量血清和尿液电解质水平、血清肌酐、肾素、醛固酮和皮质醇水平，并计算跨肾小管钾梯度。大鼠：测量甲氧苄啶输注对尿钠、氯、钾浓度和尿量的影响。测量从肾远端小管获得的液体样品中的钠、氯、钾和菊粉浓度。测量远端小管壁上的电压。 结果：人类：尽管肾上腺皮质功能和肾小球滤过率正常，甲氧苄啶仍使血清钾浓度增加 0.6 mmol/L（95% CI，0.29 至 0.95 mmol/L）。在甲氧苄啶治疗期间，30 名患者中有 15 名观察到血清钾水平高于 5 mmol/L。大鼠：静脉注射甲氧苄啶可抑制肾钾排泄 40%（CI，21% 至 60%），并使肾钠排泄增加 46%（CI，9% 至 83%）。肾小管液中的甲氧苄啶 (1 mmol/L) 可抑制远端肾小管钾分泌 59%（CI，26% 至 92%），并使管腔负跨上皮电压去极化 66%（CI，46% 至 85%）。结论：甲氧苄啶（一种有机阳离子）的作用与阿米洛利类似，可阻断哺乳动物远端肾单位的顶膜钠通道。结果，跨上皮电压降低并且钾分泌受到抑制。这些对肾小管的直接影响继发肾钾排泄减少，导致大量接受含甲氧苄啶药物治疗的患者出现高钾血症。
Objectives: 1) To determine the incidence and severity of hyperkalemia during trimethoprim therapy. 2) To test the hypothesis that trimethoprim inhibits renal potassium excretion by blocking sodium channels in the mammalian distal nephron.Patients: Thirty consecutive patients who were treated with trimethoprim-containing drugs. All patients included in the study had the acquired immunodeficiency syndrome (AIDS).Experimental animals: Thirty-nine male Sprague-Dawley rats receiving normal rat chow and tap water (allowed free access).Intervention: Humans: high dose (20 mg/kg per day) of trimethoprim therapy. Rats: trimethoprim (9.6 mg/h, per kg body weight) was infused intravenously or into the renal distal tubules (1 mmol/L).Measurements: Humans: Serum and urine electrolyte levels, serum creatinine, renin, aldosterone, and cortisol levels were measured, and the transtubular potassium gradient was calculated. Rats: The effects of trimethoprim infusion on urinary sodium, chloride, and potassium concentration and urine volume were measured. Sodium, chloride, potassium, and inulin concentrations were measured in fluid samples obtained from kidney distal tubules. The voltage across the wall of the distal tubule was measured.Results: Humans: Trimethoprim increased the serum potassium concentration by 0.6 mmol/L (95% CI, 0.29 to 0.95 mmol/L) despite normal adrenocortical function and glomerular filtration rate. Serum potassium levels greater than 5 mmol/L were observed during trimethoprim treatment in 15 of 30 patients. Rats: Intravenous trimethoprim inhibited renal potassium excretion by 40% (CI, 21% to 60%) and increased renal sodium excretion by 46% (CI, 9% to 83%). Trimethoprim (1 mmol/L) in tubule fluid inhibited distal tubule potassium secretion by 59% (CI, 26% to 92%) and depolarized the lumen-negative transepithelial voltage by 66% (CI, 46% to 85%).Conclusions: Trimethoprim (an organic cation) acts like amiloride and blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced and potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs.