Department of Internal Medicine, Section of Infectious Diseases.
Department of Internal Medicine, Section of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.
J Infect Dis. 2016 Feb 15;213(4):561-8. doi: 10.1093/infdis/jiv466. Epub 2015 Sep 23.
Exposure to tenofovir disoproxil fumarate (TDF) may cause renal toxicity. Inhibitors of TDF's apical multidrug-resistance-associated protein efflux-transporters (MRPs) in the renal proximal tubule could enhance this unwanted effect.
We performed a cohort study involving patients with human immunodeficiency virus type 1 (HIV) infection. All patients had a suppressed viral load and were receiving TDF as a part of combination antiretroviral therapy. Data on mean cumulative defined daily doses (DDDs) of MRP inhibitors (NSAIDs, PDE5-i, salicylates, dipyridamole) were collected. The effects of MRP inhibitors on the estimated glomerular filtration rate (eGFR) and proximal tubular function were evaluated by generalized linear models, with adjustment for renal- and HIV-specific factors.
A total of 721 HIV-infected patients were included (76.3% were male; median age, 45 years; median CD4(+) T-cell count, 600 cells/mm(3)). The median duration of TDF exposure was 54 months, and the total cumulative exposure duration was 3484 patient-years. Three hundred twenty-one patients had MRP inhibitor exposure, ranging from 0.02 to 120 mean DDDs/month. Exposure to MRP inhibitors was associated with an additional mean eGFR change of -1.4 mL/min (95% confidence interval [CI], -2.9 to .1 mL/min) over 12 months in patients with ≥1 year of continuous TDF exposure. Associations were observed between MRP inhibitor exposure and eGFR declines of >10 mL/min (odds ratio [OR], 1.38; 95% CI, .97 to 1.95), or >25% (OR, 2.14; 95% CI, 1.19 to 3.85) since initiation of TDF therapy. Overall, no clinically significant associations were found between MRP inhibitor exposure and abnormal protein, glucose, or phosphate handling in the proximal tubule or with the presence of ≥2 of these markers.
Concomitant incidental exposure to MRP inhibitors and TDF did not result in major additional TDF-related renal toxicity in HIV-infected patients.
替诺福韦二吡呋酯（TDF）的暴露可能会引起肾毒性。在肾近端小管中 TDF 的顶端多药耐药相关蛋白外排转运体（MRP）的抑制剂可能会增强这种不良作用。
我们进行了一项包含人类免疫缺陷病毒 1 型（HIV）感染患者的队列研究。所有患者的病毒载量均得到抑制，并且正在接受 TDF 作为联合抗逆转录病毒治疗的一部分。收集了 MRP 抑制剂（非甾体抗炎药、PDE5-i、水杨酸盐、双嘧达莫）的平均累积定义日剂量（DDD）的数据。通过广义线性模型评估 MRP 抑制剂对估算肾小球滤过率（eGFR）和近端肾小管功能的影响，调整了肾脏和 HIV 特异性因素。
共纳入 721 名 HIV 感染患者（76.3%为男性；中位年龄 45 岁；中位 CD4+T 细胞计数 600 个/立方毫米）。TDF 暴露的中位时间为 54 个月，总累积暴露时间为 3484 患者年。321 名患者有 MRP 抑制剂暴露，范围为 0.02 至 120 个平均 DDD/月。在连续 TDF 暴露时间≥1 年的患者中，MRP 抑制剂暴露与 12 个月内 eGFR 平均额外下降 1.4 mL/min（95%置信区间[CI]，-2.9 至.1 mL/min）相关。在 TDF 治疗开始后，MRP 抑制剂暴露与 eGFR 下降>10 mL/min（比值比[OR]，1.38；95%CI，.97 至 1.95）或>25%（OR，2.14；95%CI，1.19 至 3.85）之间存在关联。总体而言，在 HIV 感染患者中，MRP 抑制剂暴露与近端肾小管中异常蛋白、葡萄糖或磷酸盐处理之间，或与这些标志物中的≥2 个标志物同时存在之间，没有发现明显的临床相关关联。
在 HIV 感染患者中，意外同时暴露于 MRP 抑制剂和 TDF 并未导致 TDF 相关的主要额外肾毒性。
