Department of Pharmaceutical Science, Hirosaki University Graduate School of Medicine, Aomori, Japan.
Department of Pharmacy, Hirosaki Central Hospital, Aomori, Japan.
J Clin Pharm Ther. 2022 Sep;47(9):1409-1417. doi: 10.1111/jcpt.13679. Epub 2022 May 11.
Trimethoprim (TMP) inhibits the Na /K -ATPase present in the basement membrane of distal tubular epithelial cells. However, hyponatremia and hyperkalemia may develop in patients taking TMP-sulfamethoxazole (SMX). In addition, because TMP inhibits drug transporters, such as organic cation transporter 2 and multidrug and toxin extrusion protein 2-K in proximal tubules, reversible increases in the concentration of serum creatinine (SCr), the substrate of these transporters, may occur. Here, we investigated variability in SCr, serum sodium (Na ), and serum potassium (K ) concentrations after initiation of TMP-SMX treatment and evaluated the risk of hyponatremia and hyperkalemia in patients with increased SCr concentrations without changes in the glomerular filtration rate (GFR).
In this retrospective study, all patients aged 20 years or older who received oral TMP-SMX during hospitalization were enrolled. The patients with estimated creatinine (Cr) clearance (eCCr) lower than 30 mL/min were excluded, as were patients taking drugs that were likely to induce renal dysfunction, drugs other than glucocorticoids that were likely to induce electrolyte imbalances, or drugs other than TMP that inhibit tubular Cr secretion. Additionally, those with SCr concentrations elevated more than 30% from baseline or serum blood urea nitrogen concentration levels above 20 mg/dL during follow-up were also excluded.
In total, 111 patients were enrolled in the study. The common independent variable affecting the change rate in SCr, Na , and K concentrations (ΔSCr, ΔNa , and ΔK ) from baseline to the highest value during the follow-up period (14 days after initiation of TMP-SMX treatment) was the daily dose of TMP. There were significant correlations between ΔSCr and ΔNa or ΔK (ρ = -0.199, p = 0.036 and ρ = 0.244, p = 0.010, respectively). Kaplan-Meier curves for hyponatremia and hyperkalemia with greater than or equal to grade 1 severity showed different profiles when the TMP dose varied (≤ 160 vs. > 160 mg/day; p = 0.005 and 0.008). The cumulative incidences of both adverse effects were 64.7% (median: 7 days) and 29.4% in patients taking more than 160 mg/day TMP and 35.2% and 6.7% in patients taking 160 mg/day TMP or less. Thus, TMP may affect the kinetics of Cr, Na , and K in the proximal and distal tubules in a dose-dependent without changing the GFR.
This study is the first report to demonstrate the degree of changes in SCr, Na , and K concentrations after initiation of TMP-SMX treatment. If SCr is elevated after initiation of TMP-SMX treatment, clinicians should be aware of decreased Na and increased K concentrations. TMP may increase the risks of hyponatremia and hyperkalemia in a dose-dependent manner without altering GFR.
三甲氧苄氨嘧啶（TMP）抑制位于远端肾小管上皮细胞基底膜中的 Na+/K+-ATP 酶。然而，接受 TMP-磺胺甲噁唑（SMX）治疗的患者可能会出现低钠血症和高钾血症。此外，由于 TMP 抑制有机阳离子转运体 2 和多药和毒素外排蛋白 2-K 等药物转运体，这些转运体的底物血清肌酐（SCr）浓度可能会出现可逆性升高。在这里，我们研究了 TMP-SMX 治疗开始后 SCr、血清钠（Na）和血清钾（K）浓度的变化，并评估了在肾小球滤过率（GFR）无变化的情况下，因 SCr 浓度升高而发生的低钠血症和高钾血症的风险。
在这项回顾性研究中，纳入了所有在住院期间接受口服 TMP-SMX 治疗的年龄在 20 岁或以上的患者。排除了估计肌酐（Cr）清除率（eCCr）低于 30 mL/min 的患者，以及正在服用可能导致肾功能障碍的药物、除糖皮质激素以外可能导致电解质失衡的药物或除 TMP 以外可能抑制管状 Cr 分泌的药物的患者。此外，在随访期间，还排除了 SCr 浓度比基线升高超过 30%或血清血尿素氮浓度超过 20 mg/dL 的患者。
共纳入了 111 名患者。从基线到随访期间（TMP-SMX 治疗开始后 14 天）最高值的 SCr、Na 和 K 浓度（ΔSCr、ΔNa 和 ΔK）变化率的常见独立变量是 TMP 的日剂量。ΔSCr 与 ΔNa 或 ΔK 之间存在显著相关性（ρ=-0.199，p=0.036 和 ρ=0.244，p=0.010）。根据 TMP 剂量不同，低钠血症和高钾血症严重程度大于或等于 1 级的 Kaplan-Meier 曲线呈现不同的形态（≤160 与>160 mg/天；p=0.005 和 0.008）。在服用 160mg 以上 TMP 的患者中，两种不良事件的累积发生率分别为 64.7%（中位数：7 天）和 29.4%，而在服用 160mg 以下 TMP 的患者中，两种不良事件的累积发生率分别为 35.2%和 6.7%。因此，TMP 可能会以剂量依赖性方式影响近端和远端肾小管中 Cr、Na 和 K 的动力学，而不会改变 GFR。
本研究首次报道了 TMP-SMX 治疗开始后 SCr、Na 和 K 浓度的变化程度。如果 TMP-SMX 治疗开始后 SCr 升高，临床医生应注意 Na 降低和 K 升高。TMP 可能会以剂量依赖性方式增加低钠血症和高钾血症的风险，而不会改变 GFR。
