Shared Mechanisms and Markers of Renal Injury and Neurocognitive Impairment in People with HIV

项目总结 艾滋病毒携带者(PWH)经历了与衰老相关的慢性疾病的异常沉重的负担，这些疾病 对功能状态和生活质量有重大影响。慢性肾病(CKD)与神经认知 损害(NCI)是这一人群中经常遇到的两种典型的衰老障碍和 可能由一个共同的潜在机制联系在一起。而血管和代谢因素，除了改变 线粒体代谢、慢性炎症和氧化应激与CKD和NCI有关， 在同一个体中驱动多种此类疾病发展的共同机制的可能性 没有得到充分的探索。铁代谢改变是衰老的一个基本标志，它与几个 衰老过程的重要方面-炎症，线粒体功能降低，以及氧化应激- 我们的团队已经确定了一个至关重要的铁结合蛋白(铁蛋白)亚单位的水平是一种独立的 慢性阻塞性肺疾病患者抑制性治疗中神经认知功能的预测因素。初步 数据表明，在相同的个体中，这种蛋白质也与慢性肾脏病有关。在大脑中新发现的这种蛋白质的受体是 也在肾脏中表达，并同时作为慢性肾损伤的标志(Kim-1)，可能在 CKD。因此，我们提出，与HIV相关的铁蛋白亚基比例的变化可能解释了几种衰老 PWH中的现象，由于其中一个亚基在抗氧化反应、免疫细胞功能、 和线粒体能量代谢。在324名来自艾滋病毒观察性队列的参与者中 结果数据和生物样本，我们将测量血清和尿铁蛋白亚单位水平的KIM-1。具体来说， 我们计划如下：目标1：评估铁蛋白亚单位水平与氧化敏感标记物之间的关系 应激和现有血浆代谢物水平在病毒学抑制的PWH中的作用；目的2：评估相关性 尿Kim-1和铁蛋白亚基水平之间的关系，并评价Kim-1作为NCI的非侵入性标志物；目的： 确定铁蛋白亚基与流行的和偶发的CKD、NCI和脆弱结局的相关性，这些结果是 在这个中老年PWH队列中确定，调整了重要的混杂因素。由此产生的结果 概念验证研究可以显著提高我们对PWH中突出衰老的理解，强调 干预的新标记物和目标。

PROJECT SUMMARY People with HIV (PWH) experience an unusually high burden of chronic, aging-related diseases, which have major impact on functional status and quality of life. Chronic kidney disease (CKD) and neurocognitive impairment (NCI) are two prototype disorders of aging that are frequently encountered in this population and may be linked by a common underlying mechanism. While vascular and metabolic factors, in addition to altered mitochondrial metabolism, chronic inflammation and oxidative stress, are implicated in CKD and NCI, the possibility of shared mechanisms that drive development of multiple such disorders in the same individual has not been sufficiently explored. Altered iron metabolism is a fundamental hallmark of aging that links several important aspects of the aging process - inflammation, reduced mitochondrial function, and oxidative stress - and our team has identified levels of a critically important iron-binding protein (ferritin) subunit as an independent predictor of neurocognitive function in a longitudinal study of NCI in PWH on suppressive therapy. Preliminary data link this protein also to CKD in the same individuals. The newly identified receptor in brain for this protein is also expressed in kidney and doubles as a marker of chronic kidney injury (Kim-1), possibly playing a role in CKD. We therefore propose that an HIV-related shift in the ratio of ferritin subunits may explain several aging phenomena in PWH, due to the critical role of one of the subunits in antioxidant responses, immune-cell function, and mitochondrial energy metabolism. In 324 participants from an observational HIV cohort with a wealth of outcome data and biospecimens, we will measure ferritin subunit levels in serum and urinary Kim-1. Specifically, we plan the following: AIM 1: Evaluate associations between ferritin subunit levels, sensitive markers of oxidative stress, and existing plasma metabolite levels in virologically suppressed PWH; AIM 2: Assess associations between urinary Kim-1 and ferritin subunit levels, and evaluate Kim-1 as a noninvasive marker of NCI; AIM 3: Determine associations of ferritin subunits with prevalent and incident CKD, NCI, and frailty outcomes, which are ascertained in this cohort of middle-aged and older PWH, adjusting for important confounders. Results from this proof-of-concept study could significantly improve our understanding of accentuated aging in PWH, highlighting new markers and targets for intervention.