Novel biomarkers of kidney injury in HIV-infected men

描述（由申请人提供）：尽管治疗取得了进展，但hiv感染者与未感染者相比仍有更高的肾功能障碍风险。目前的肾功能测量，如血清肌酐和试纸蛋白尿，是hiv感染者肾脏损伤的晚期和非特异性标志物，不能区分肾单位损伤的病因或部位。对于接受替诺福韦（一种对近端小管上皮细胞有直接毒性的抗逆转录病毒药物）治疗的hiv感染者，早期识别小管功能障碍尤为重要。我们提出了一种评估hiv感染者肾脏健康的新模式，使用一组尿液生物标志物来检测早期肾损伤，定位肾单位内的病理，并将药物毒性与肾损伤的其他病因区分开来。我们最近在多中心艾滋病队列研究（MACS）中测量了886名hiv感染者和350名未感染男性的尿中白细胞介素-18 （IL-18）、肾损伤分子-1 （KIM-1）、a1-微球蛋白（a1m）和蛋白尿水平。目前的项目将比较艾滋病毒感染者和未感染者之间每种生物标志物的水平；确定艾滋病毒感染参与者中与每种生物标志物相关的具体风险因素；根据生物标志物水平确定替诺福韦使用对肾脏健康的影响；并在4年内评估每个尿液生物标志物与肾功能下降的纵向关联。利用生物标志物水平识别艾滋病毒感染者的早期肾损伤，可以在发生不可逆肾损伤之前进行有针对性的干预。此外，这些研究目标将为未来的纵向调查奠定基础，研究生物标志物在检测药物毒性方面的效用，特别是在接受肾毒性治疗的艾滋病毒感染者中。

DESCRIPTION (provided by applicant): Despite advances in therapy, HIV-infected individuals remain at higher risk for kidney dysfunction than uninfected individuals. Current measures of kidney function, such as serum creatinine and dipstick proteinuria, are late and nonspecific markers of kidney damage in HIV-infected individuals, and do not differentiate the etiology or site of injury within the nephron. Early identification of tubular dysfunction is particularly important in HIV-infected persons receiving tenofovir, an antiretroviral medication with direct toxicity to proximal tubular epithelial cells. We propose a novel paradigm for the assessment of kidney health in HIV-infected individuals, using a panel of urinary biomarkers which can detect early kidney injury, localize pathology within the nephron, and differentiate drug toxicity from alternate etiologies of kidney damage. We recently measured urine levels of interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), a1-microglobulin (a1m), and albuminuria in 886 HIV-infected and 350 uninfected men enrolled in the Multicenter AIDS Cohort Study (MACS). The current project will compare levels of each biomarker between HIV-infected and uninfected men; identify the specific risk factors associated with each biomarker among the HIV-infected participants; determine the impact of tenofovir use on kidney health based on biomarker levels; and evaluate longitudinal associations of each urine biomarker with kidney function decline over 4 years. Identification of early kidney injury in HIV-infected persons, using biomarker levels, could enable targeted interventions prior to the development of irreversible kidney damage. Additionally, these research objectives will lay foundation for future longitudinal investigations examining the utilities of biomarkers for the detection of drug toxicity, particulary among HIV-infected persons receiving nephrotoxic therapies.