The Aging Kidney: Chronic Injury, Impaired Functions and Clinical Outcomes

描述（由申请人提供）：母体RO 1“肾功能是否决定衰老成功”在肾脏滤过功能轻度、年龄相关性降低的临床重要性方面取得了重大进展。然而，尽管有这些进展，人们对衰老过程如何导致肾小球滤过率（GFR）下降以及GFR损失与肾脏其他关键功能受损的关系知之甚少。 这一建议的概念模型是，几种类型的慢性肾损伤-肾小管损伤，肾小球渗漏，间质纤维化和血管损伤-促进GFR下降和肾脏内分泌功能异常，包括25维生素D羟化和促红细胞生成素的产生。由此导致的矿物质代谢和血红蛋白产生的异常分别部分解释了GFR和肾损伤标志物与不良临床结局的关系。在这次修订后的竞争性更新中，我们从早期的半胱氨酸蛋白酶抑制剂C作为新的肾滤过标志物的研究扩展到对来自多种族动脉粥样硬化研究（梅萨）的1500名参与者（年龄和种族分布均衡）和3044名来自健康老龄化和身体组成研究的参与者的一组全面的新肾损伤标志物的评估。（健康ABC）研究，一组老年人。我们还校准了这套肾损伤标记物与肾脏组织病理学250肾脏捐赠者。我们的具体目标是：1）评估梅萨中年龄与肾损伤标志物的横截面关联，以及克利夫兰诊所肾供体中肾损伤标志物与组织病理学的关联; 2）评估Health ABC中肾损伤标志物与矿物质代谢和血红蛋白产生异常的横截面关联; 3）在Health ABC的纵向分析中确定肾损伤标志物与GFR下降的关联;以及，4）在Health ABC的纵向分析中确定肾损伤标志物与衰老的临床结果的关联。该提案直接响应了项目公告（PA 09-165）“老年人肾功能和CKD”，因为它评估了“老年人CKD的病因学和病理生理学，以及随着年龄增长发生CKD的流行病学和风险因素”。研究人员在R 01和其他合作项目上共同工作了5年多，在R 01期间发表或出版了30多篇手稿，并且包括一个由老年病学家，肾病学家，统计学家，流行病学家和生物标志物专家组成的多学科团队。 公共卫生相关性：慢性肾脏疾病，特别是在老年人中流行，是一个日益严重的公共卫生问题，对发病率、死亡率和资源利用产生巨大影响。在这项提案中，我们评估了新的尿液生物标志物及其与衰老、肾功能下降和临床结局的关系。我们计划开发一种新的范式来定义肾脏的衰老过程;一种早期检测慢性肾脏损伤的潜在方法;并最终开发新的治疗靶点，以减轻老年人慢性肾脏疾病的负担。

DESCRIPTION (provided by applicant): The parent RO1 "Does Kidney Function Determine Aging Success" made significant advances regarding the clinical importance of mild, age-related decreases in the kidney's filtration function. Despite these advances, however, little is known about how the aging process causes glomerular filtration rate (GFR) decline and the relationships of GFR loss to impairments of other critical functions of the kidney. The conceptual model underlying this proposal is that several types of chronic kidney injury - tubular damage, glomerular leak, interstitial fibrosis, and vascular injury - promote decline in GFR and abnormalities in kidney endocrine function, including 25 vitamin D hydroxylation and erythropoietin production. The resulting abnormalities in mineral metabolism and hemoglobin production, respectively, partially explain the relationships of both GFR and the markers of kidney injury with adverse clinical outcomes. In this revised competitive renewal, we expand from our earlier studies of cystatin C as a novel marker of kidney filtration in a new direction to an evaluation of a comprehensive set of novel kidney injury markers in 1500 participants from the Multiethnic Study of Atherosclerosis (MESA) with a balanced age and race distribution, and 3044 participants from the Health Aging and Body Composition (Health ABC) Study, a cohort of older adults. We also calibrate this set of kidney injury markers with kidney histopathology among 250 kidney donors. Our specific aims are: 1) to evaluate the cross-sectional associations of age with markers of kidney injury in MESA, and the association of markers of kidney injury with histopathology in Cleveland Clinic kidney donors; 2) to evaluate the cross-sectional association of markers of kidney injury with abnormalities in mineral metabolism and hemoglobin production in Health ABC; 3) to determine the association of kidney injury markers with decline in GFR in longitudinal analyses in Health ABC; and, 4) to determine the associations of markers of kidney injury with clinical outcomes of aging in longitudinal analyses in Health ABC. This proposal is directly responsive to the Program Announcement (PA 09-165) "Renal Function and CKD in Aging" as it evaluates the "etiology and pathophysiology of CKD in the elderly, and the epidemiology and risk factors for the development of CKD with advancing age". The investigators have worked together for more than 5 years on the parent R01 and other collaborative projects, have been extremely productive with more than 30 manuscripts published or in press during the period of the parent R01, and include a multidisciplinary team of geriatricians, nephrologists, statisticians, epidemiologists and biomarker experts. PUBLIC HEALTH RELEVANCE: Chronic kidney disease, particularly prevalent in the elderly, is a growing public health problem with enormous impact on morbidity, mortality and resource utilization. In this proposal, we evaluate novel urinary biomarkers and their relationship to aging, decline in kidney function and clinical outcomes. We plan to develop a novel paradigm to define the kidney's aging process; a potential method for the early detection of chronic injury to the kidney; and ultimately novel targets for therapies to reduce the burden of chronic kidney disease in the elderly.