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

描述（由申请人提供）：该项目的总体目标是了解HIV感染后肾脏疾病与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，影响到多达三分之一的艾滋病毒感染者。在一般人群中，肾脏疾病与虚弱有关，是一种功能储备不足的状态，对压力源的反应能力下降。肾脏疾病与可能导致功能下降和合并症的全身性变化相关，进而导致重大的死亡风险；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。一个有希望的途径围绕两种新蛋白，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，在小鼠模型中与衰老和过早死亡有关。它在人类衰老中的作用尚未得到很好的描述。在肾脏中，klotho作为FGF-23的共同受体，FGF-23是一种随着肾脏疾病的进展而稳步上升的蛋白质，并且与心血管疾病、慢性肾脏疾病的发生率和一般人群的死亡有关。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毒研究（WIHS）中对艾滋病毒感染者和未感染的男性和女性进行一项研究，其具体目的如下：1)评估肾损伤和肾功能标志物是否与艾滋病毒感染者和未感染者体内可溶性klotho和FGF-23水平相关；2)确定可溶性klotho和FGF- 23与haart治疗的hiv感染者和未感染者身体功能的关系。使用特征明确且多样化的hiv感染者和内部未感染hiv的参考人群，拟议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感染功能下降之间关系的理解的巨大空白。

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. PUBLIC HEALTH RELEVANCE: As HIV-infected patients live longer, they are experiencing physical decline at earlier ages than HIV-infected individuals. Kidney disease, which commonly affects HIV-infected individuals, is associated with functional decline, but how kidney disease contributes to functional decline in HIV infection is unclear. The results of this proposal which addresses this key issue can be used to develop focused interventions to prevent or slow physical decline among HIV-infected individuals.