Dimensions of Kidney Tubule Health and Atherosclerotic Cardiovascular Disease and Heart Failure in Middle-Aged and Older Adults

中老年人肾小管健康状况与动脉粥样硬化性心血管疾病和心力衰竭的关系

• 批准号: 10588310
• 负责人: Orlando M Gutierrez
• 金额: $ 77.38万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-25 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588310
• 关键词: Address; Age; Age Years; Albumins; Albuminuria; Aldosterone Antagonists; Ankle; Atherosclerosis; Biological Markers; Black Populations; Black race; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic Kidney Failure; Cicatrix; Clinical; Cohort Studies; Communities; Coronary Artery Risk Development in Young Adults Study; Creatinine; Cross-Sectional Studies; Development; Dietary intake; Dimensions; Disease; Disease Marker; Dyslipidemias; Elderly; Event; Fibrosis; Functional disorder; Future; General Population; Glomerular Filtration Rate; Goals; HIV Infections; Health; Heart failure; Hispanic Populations; Homeostasis; Incidence; Individual; Injury; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Left Ventricular Mass; Life; Measures; Monitor; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Pathology; Pathway interactions; Persons; Population; Prevention strategy; Primary Prevention; Prognostic Factor; Renal function; Renal tubule structure; Research; Risk; Risk Factors; Risk Reduction; Role; Smoking; Specimen; Standardization; Stroke; Structure; Transplant Recipients; Tubular formation; Urine; absorption; adverse outcome; atherosclerosis risk; biomarker panel; blood glucose regulation; cardiovascular disorder risk; clinical risk; clinically relevant; cohort; coronary artery calcification; ethnic difference; experience; glomerular function; high risk; high risk population; improved; indexing; inhibitor; insight; intimal medial thickening; kidney biopsy; longitudinal analysis; middle age; mortality; mortality risk; nephrogenesis; new therapeutic target; novel; physical inactivity; prognostic; racial difference; repaired; screening; treatment strategy

ABSTRACT Two clinical measures are currently used to stage chronic kidney disease (CKD), the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR). The elevated morbidity and mortality risk that is experienced by persons with CKD is overwhelmingly a result of progressive atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) rather than kidney failure. Unfortunately, eGFR and ACR inadequately depict the kidney’s complexity because they represent glomerular function and injury respectively; yet the kidney is predominantly comprised of tubules, and the kidney tubules are responsible for myriad homeostatic functions that likely have more direct influence on the cardiovascular system than does damage to the glomerulus. Moreover, pathology studies have convincingly demonstrated that tubule damage is more prognostic for loss of kidney function than glomerular scarring. Novel urine measures that quantify the health of the kidney tubules have recently allowed us to define four additional dimensions of kidney health that independently influence risk for progressive CKD: proximal tubule injury, proximal tubule function, tubule fibrosis and repair, and tubule synthetic function. Our team has selected eight distinct urine measures that capture each of these four dimensions and comprise the Kidney Tubule Health Panel (KTHP). In specific, high-risk populations, the KTHP dimensions are strongly associated with risk for ASCVD, HF and mortality; but no studies have evaluated the contributions of kidney tubule health to the development of ASCVD and HF in the general population. Our global hypothesis is that kidney tubule damage and dysfunction are related to the onset and progression of ASCVD and HF. Within two well-established, general population cohorts, CARDIA and MESA, this proposal will address the following research questions that are critical to understanding the development of each dimension of kidney tubule disease and their role in promoting ASCVD and HF: 1) Does kidney tubule disease develop earlier and progress faster with advancing age than ACR and eGFR? 2) Is kidney tubule disease more severe in Black and Hispanic persons compared with White persons? 3) Which atherosclerotic risk factors have the strongest associations with each dimension of kidney tubule disease? 4) How strongly associated is kidney tubule disease with several subclinical CVD measures? 5) How strongly associated are kidney tubule disease markers with ASCVD and HF, and do they improve prediction of these endpoints? If these Aims are successful, these easily measured, non-invasive indices of kidney tubule health may have value for population screening, to provide insights into race/ethnic differences in kidney and cardiovascular disease, and to identifying pathways for novel therapeutics that target kidney tubules, such as the SGLT2 inhibitors and the non-steroidal aldosterone antagonists, that reduce risk for both kidney and cardiovascular adverse outcomes.

抽象的 目前使用两项临床措施来进行慢性肾脏疾病（CKD），估计的肾小球 过滤率（EGFR）和尿液相册与促偶然比率（ACR）。发病率和死亡率升高的风险 由CKD的人经历的是进行性动脉粥样硬化心血管的绝大多数结果 疾病（ASCVD）和心力衰竭（HF），而不是肾衰竭。不幸的是，EGFR和ACR不足 描述肾脏的复杂性，因为它们分别代表肾小球功能和损伤。但是 肾脏主要完成了小管，肾小管造成了无数稳态的负责 对心血管系统可能具有更直接影响的功能，而不是对 肾小球。此外，病理学研究令人信服地证明了小管损伤更多 肾功能丧失的预后，而不是肾小球疤痕。 量化肾小管健康的新型尿液测量最近使我们定义了四个 肾脏健康的其他维度独立影响进行性CKD的风险：近端细胞 损伤，近端管函数，管纤维化和修复以及管道合成功能。我们的团队选择了 八个不同的尿液测量，可捕获这四个维度并完成肾小管 健康小组（KTHP）。在特定的高风险人群中，KTHP维度与风险密切相关 用于ASCVD，HF和死亡率；但是，没有研究评估肾小管健康对 一般人群中ASCVD和HF的发展。我们的全球假设是肾小管损伤 功能障碍与ASCVD和HF的发作和进展有关。 在两个公认的一般人群，Cardia和Mesa中，该提案将解决 遵循研究问题，这些问题对于理解肾脏每个维度的发展至关重要 小管疾病及其在促进ASCVD和HF中的作用：1） 随着年龄的增长，进步速度比ACR和EGFR更快？ 2）黑色的肾小管疾病更为严重 与白人相比，西班牙裔人？ 3）动脉粥样硬化危险因素具有强大 与肾管疾病的每个维度的关联？ 4）肾管有多大相关 具有几种亚临床CVD措施的疾病？ 5）肾小管疾病有多密切 带有ASCVD和HF的标记，它们是否改善了这些终点的预测？如果这些目标是 成功，这些易于测量的肾小管健康的无创指数可能对人群具有价值 筛查，提供有关肾脏和心血管疾病种族/种族差异的见解，以及 识别针对肾小管的新型疗法的途径，例如SGLT2抑制剂和 非甾体醛固酮拮抗剂，降低了肾脏和心血管不良后果的风险。