Samuels Ryan, Bayerri Carla Roca, Sayer John A, Price D Ashley, Payne Brendan A I
aWellcome Trust Centre for Mitochondrial Research bInstitute of Genetic Medicine, Newcastle University cDepartment of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
AIDS. 2017 Jun 1;31(9):1297-1301. doi: 10.1097/QAD.0000000000001466.
To determine whether tenofovir disoproxil fumarate (TDF)-associated renal tubular dysfunction is associated with evidence of mitochondrial injury in urine.
Single-centre cross-sectional observational study of HIV-positive outpatients.
Biochemistry was performed on paired serum and urine samples. Mitochondrial DNA (mtDNA) was studied by real-time PCR and long-range PCR on cellular fractions of urine.
In total, 48 study participants were enrolled of whom half were TDF treated. Mean age was 43 years. 58% had estimated glomerular filtration rate at least 90, with no differences between ART treatment groups. Urinary phosphate wasting was common and independently associated with TDF exposure (P = 0.02). No study participants had low molecular weight proteinuria. Cellular mtDNA content in urine was heavily influenced by the cellularity of the sample. The mtDNA 'common deletion' mutation was detectable significantly more commonly in the urine of TDF exposed study participants compared with unexposed (13/22 TDF study participants (59%), 4/21 TDF (19%), P = 0.01). Common deletion levels were not associated with age, estimated glomerular filtration rate, or urinary phosphate wasting. No mtDNA measures were associated with current or nadir CD4 lymphocyte counts, duration of disease or antiretroviral therapy, or historical exposure to nucleoside analogue reverse transcriptase inhibitors with systemic mitochondrial toxicity.
The presence of mtDNA mutations in the context of TDF exposure adds weight to the hypothesis that TDF-associated renal damage is at least in part mitochondrially mediated. The assessment of mtDNA markers in urine may be a feasible noninvasive investigation for TDF-treated patients.
确定富马酸替诺福韦二吡呋酯（TDF）相关的肾小管功能障碍是否与尿液中线粒体损伤的证据相关。
对HIV阳性门诊患者进行的单中心横断面观察性研究。
对配对的血清和尿液样本进行生化检测。通过实时PCR和长程PCR对尿液细胞成分中的线粒体DNA（mtDNA）进行研究。
共纳入48名研究参与者，其中一半接受TDF治疗。平均年龄为43岁。58%的参与者估计肾小球滤过率至少为90，抗逆转录病毒治疗组之间无差异。尿磷排泄常见，且与TDF暴露独立相关（P = 0.02）。没有研究参与者有低分子量蛋白尿。尿液中的细胞mtDNA含量受样本细胞数量的严重影响。与未暴露的研究参与者相比，暴露于TDF的研究参与者尿液中mtDNA“常见缺失”突变的检测率明显更高（22名接受TDF治疗的研究参与者中有13名（59%），21名未接受TDF治疗的参与者中有4名（19%），P = 0.01）。常见缺失水平与年龄、估计肾小球滤过率或尿磷排泄无关。没有mtDNA指标与当前或最低点CD4淋巴细胞计数、疾病持续时间或抗逆转录病毒治疗，或既往暴露于具有全身线粒体毒性的核苷类似物逆转录酶抑制剂相关。
在TDF暴露情况下mtDNA突变的存在进一步支持了TDF相关肾损伤至少部分由线粒体介导的假说。对接受TDF治疗的患者评估尿液中的mtDNA标志物可能是一种可行的非侵入性检查。
