Incidence and Implications of Subclinical Kidney Injury with Tenofovir based PrEP

项目摘要 富马酸替诺福韦酯（TDF）抗逆转录病毒暴露前预防（PrEP）/ 恩曲他滨（TDF/FTC）降低了高危HIV未感染者获得HIV的风险 个体然而，对TDF/FTC PrEP的一个主要批评是肾脏和 骨毒性虽然明显的肾毒性是罕见的，亚临床肾损伤是常见的 在接受含TDF的抗逆转录病毒治疗的HIV感染者中。TDF还被 与骨代谢改变相关，包括骨矿物质密度下降， 骨转换标志物增加，骨折风险增加，但与 肾损伤尚不清楚。我们假设TDF/FTC PrEP导致亚临床 未感染HIV成人肾损伤和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改变 新陈代谢.我们将使用来自以下地区的数据和库存标本来研究这一假设： Partners PrEP研究是一项随机、安慰剂对照试验， TDF/FTC PrEP对4758名未感染艾滋病毒的异性恋HIV-1成员的疗效 在乌干达和肯尼亚的血清不一致的夫妇。血清的前瞻性文件 所有合作伙伴PrEP研究参与者的肌酐和无创测量 近端肾小管功能障碍和骨转换的生物标志物， 参与者将使我们能够确定TDF/FTC PrEP是否会导致临床相关 肾损伤和骨代谢改变。在巢式病例对照研究中，我们将 确定亚临床近端肾小管损伤是否是 肾小球滤过率或骨转换增加。我们还将利用独特的 有机会在健康成人中研究累积的TDP诱导的肾损伤， 药物性肾损伤尿液生物标志物鉴定及其在药物中的潜在应用 发展和毒性监测。预期拟议研究的结果 对实施抗逆转录病毒PrEP具有重大意义， 预防艾滋病毒的替代方法。新的药物生物标志物的鉴定- 诱导的肾损伤有望加速未来HIV药物的开发， 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.