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

描述(由申请人提供)：父母RO1《肾脏功能是否决定衰老成功》在肾脏滤过功能轻度、年龄相关下降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丧失与肾脏其他关键功能损害的关系知之甚少。支持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的下降和肾脏内分泌功能的异常，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和肾脏损伤标志物与不良临床结局的关系。在这次修订的竞争更新中，我们从早期对胱抑素C作为肾脏滤过新标记物的新方向的研究扩展到对1500名年龄和种族分布平衡的动脉粥样硬化多种族研究(MESA)参与者和3044名来自健康老龄化和身体成分(Health ABC)研究(老年人队列)的参与者的一套全面的新肾脏损伤标记物的评估。我们还在250名肾捐献者中用肾脏组织病理学对这套肾损伤标志物进行了校准。我们的具体目标是：1)评估年龄与MESA肾脏损伤标志物的横断面相关性，以及肾损伤标志物与克利夫兰临床肾捐献者组织病理学的关系；2)评估Health ABC肾脏损伤标志物与矿物质代谢和血红蛋白产生异常的横断面关联性；3)在Health ABC纵向分析中确定肾损伤标志物与GFR下降的相关性；以及4)在Health ABC纵向分析中确定肾脏损伤标志物与衰老临床结局的相关性。这项建议直接回应了计划公告(PA 09-165)“衰老中的肾功能和慢性肾脏病”，因为它评估了“老年人慢性肾脏病的病因和病理生理学，以及随着年龄的增长慢性肾脏病发展的流行病学和危险因素”。研究人员在母公司R01和其他合作项目上合作了5年多，在母公司R01期间发表或出版的30多篇手稿卓有成效，其中包括一支由老年病学家、肾病学家、统计学家、流行病学家和生物标记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。在这项建议中，我们评估了新的尿液生物标记物及其与衰老、肾功能下降和临床结果的关系。我们计划开发一种新的范例来定义肾脏的衰老过程；一种潜在的方法来早期发现肾脏的慢性损伤；并最终开发新的治疗目标来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.