Association of kidney disease, klotho and FGF23 with functional decline in HIV

描述（由申请人提供）：本项目的总体目标是了解肾脏疾病与HIV感染后身体功能下降之间的关系。肾脏疾病是艾滋病毒感染者中最常见的非传染性疾病之一，影响多达三分之一的艾滋病毒感染者。在一般人群中，肾脏疾病与虚弱、功能储备差和应对压力的能力下降有关。肾脏疾病与全身性变化相关，可能导致功能下降和共病，进而导致显著的死亡风险;然而，肾脏疾病可能影响身体功能的途径，特别是在HIV感染和抗逆转录病毒治疗的背景下，需要进一步研究。一个有前途的途径围绕两个新的蛋白质，klotho和成纤维细胞生长因子-23（FGF-23）。Klotho是一种新发现的激素，主要在肾脏中产生，并与小鼠模型中的衰老和过早死亡有关。它在人类衰老中的作用还没有得到很好的描述。在肾脏中，klotho作为FGF-23的共受体，FGF-23是一种随着肾脏疾病进展而稳步上升的蛋白质，与一般人群中的心血管疾病、慢性肾脏疾病和死亡有关。为了解决这些关键问题，我们建议在多中心艾滋病队列研究（MACS）和妇女机构间艾滋病研究（WIHS）中对HIV感染和未感染的男性和女性进行研究，其具体目的是：1）评估肾损伤和肾功能标志物是否与HIV感染和未感染个体中可溶性klotho和FGF-23水平相关;和2）确定HAART治疗的HIV感染和HIV未感染个体中可溶性klotho和FGF- 23与身体功能的关联。使用具有内部HIV未感染参考人群的HIV感染个体的良好表征和多样化队列，所提出的研究将提供新的数据，并填补我们对肾脏疾病、klotho、FGF-23和HIV感染中功能下降之间的关联的理解的巨大空白。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the association between kidney disease and declines in physical function in HIV infection. Kidney disease is one of the most common non-infectious diseases occurring among the HIV-infected population, affecting up to one-third of HIV-infected persons. In the general population, kidney disease has been associated with frailty, a state of poor functional reserve and diminished capacity to respond to stressors. Kidney disease is associated with systemic changes that may contribute to functional decline and co-morbid conditions which, in turn, lead to significant risk for mortality; however, the pathways by which kidney disease may impact physical function, especially in the context of HIV infection and antiretroviral treatment, need further study. One promising pathway centers around two novel proteins, klotho and fibroblast growth factor-23 (FGF-23). Klotho is a newly discovered hormone which is primarily produced in the kidneys and has been associated with aging and premature death in mouse models. Its role in human aging has not been well-delineated. In the kidneys, klotho serves as a co-receptor for FGF-23, a protein that rises steadily with kidney disease progression and has been associated with cardiovascular disease, incident chronic kidney disease, and death in the general population. To address these key issues, we propose to perform a study of HIV-infected and HIV-uninfected men and women nested within the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) with these specific aims: 1) to evaluate whether markers of kidney injury and kidney function are associated with soluble klotho and FGF-23 levels in HIV-infected and HIV-uninfected individuals; and 2) to determine the associations of soluble klotho and FGF- 23 with physical function in HAART-treated HIV-infected and HIV-uninfected individuals. Using well- characterized and diverse cohorts of HIV-infected individuals with internal HIV-uninfected reference populations, the proposed studies will provide novel data and fill a large gap in our understanding of the associations between kidney disease, klotho, FGF-23, and functional decline in HIV-infection.