Incidence and Implications of Subclinical Kidney Injury with Tenofovir based PrEP

项目摘要 富马酸替诺福韦二异丙酯(TDF)的抗逆转录病毒暴露前预防(PrEP) 恩曲他滨(TDF/FTC)降低未感染艾滋病毒的高危人群感染艾滋病毒的风险 个人。然而，对TDF/FTC PrEP的一个主要批评是肾脏和 骨骼毒性。虽然显性肾毒性很少见，但亚临床肾损伤很常见。 在艾滋病毒感染者中接受含有TDF的抗逆转录病毒治疗。TDF也一直在 与骨骼新陈代谢改变有关，包括骨矿密度下降， 骨转换标志的增加和骨折风险的增加，但与 肾脏损伤尚不清楚。我们假设TDF/FTC PrEP导致亚临床 未感染HIV的成人的肾脏损伤以及亚临床近端肾小管损伤 促进临床相关的肾功能下降和骨矿物质的改变 新陈代谢。我们将使用以下数据和银行样本来研究这一假设 Partners PrEP研究，一项随机、安慰剂对照试验，证明了 TDF/FTC PrEP在4758名未感染HIV的异性HIV-1成员中的疗效 乌干达和肯尼亚的血清不一致夫妇。血清的前瞻性文献 所有合作伙伴PrEP研究参与者的肌酐和非侵入性测量 近端肾小管功能障碍和骨转换的生物标志物 参与者将允许我们确定TDF/FTC PrEP原因是否与临床相关 肾脏损伤和骨代谢改变。在嵌套病例对照研究中，我们将 确定亚临床近端肾小管损伤是否是肾功能下降的危险因素 肾小球滤过率或骨转换增加。我们还将利用独特的 有机会研究TDF对健康成人的累积肾损伤，以便 药物性肾损伤尿液生物标志物的鉴定及其在药物方面的潜在应用 发展和毒性监测。建议的研究结果是可以预料到的。 对实施抗逆转录病毒PrEP和 预防艾滋病毒的替代方法。药物新生物标记物的鉴定 预计诱发性肾脏损伤将加速未来治疗艾滋病毒和艾滋病的药物开发 其他慢性病。

Project Summary Antiretroviral pre-exposure prophylaxis (PrEP) with tenofovir disoproxyl fumarate (TDF)/ emtricitabine (TDF/FTC) reduces the risk of HIV acquisition in high-risk HIV-uninfected individuals. However, a major critique of TDF/FTC PrEP is the potential for kidney and bone toxicity. Although overt kidney toxicity is rare, subclinical kidney injury is common in HIV-infected individuals on TDF-containing antiretroviral therapy. TDF has also been associated with altered bone metabolism, including declines in bone mineral density, increased markers of bone turnover, and increased fracture risk, but the relationship with kidney injury is not known. We hypothesize that TDF/FTC PrEP causes subclinical kidney injury in HIV-uninfected adults, and that subclinical proximal tubular injury promotes clinically relevant declines in kidney function and alterations in bone mineral metabolism. We will investigate this hypothesis using data and banked specimens from the Partners PrEP Study, a randomized, placebo-controlled trial that demonstrated efficacy of TDF/FTC PrEP in 4758 HIV-uninfected members of heterosexual HIV-1 serodiscordant couples in Uganda and Kenya. The prospective documentation of serum creatinine in all Partners PrEP Study participants and the measurement of noninvasive biomarkers of proximal tubular dysfunction and bone turnover in a nested subgroup of participants will allow us to determine whether TDF/FTC PrEP causes clinically relevant kidney injury and alterations in bone metabolism. In nested case-control studies, we will determine whether subclinical proximal tubular injury is a risk factor for decline in glomerular filtration rate or increased bone turnover. We will also leverage the unique opportunity to study cumulative TDF-induced kidney injury in healthy adults in order to identify urine biomarkers of drug-induced kidney injury with potential applications in drug development and toxicity monitoring. The results of the proposed research are expected to have significant implications for the implementation of antiretroviral PrEP and alternative approaches to HIV prevention. The identification of new biomarkers of drug- induced kidney injury is expected to accelerate future drug development for HIV and other chronic diseases.