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

摘要 目前使用两种临床测量来对慢性肾病（CKD）进行分期，即估计的肾小球滤过率。 滤过率（eGFR）和尿白蛋白与肌酐比值（ACR）。高发病率和死亡率风险， CKD患者经历的主要是进行性动脉粥样硬化性心血管疾病的结果， 疾病（ASCVD）和心力衰竭（HF）而不是肾衰竭。不幸的是，eGFR和ACR不足以 描述了肾脏的复杂性，因为它们分别代表肾小球功能和损伤;然而， 肾脏主要由肾小管组成，肾小管负责维持各种体内平衡， 这些功能可能对心血管系统产生更直接的影响，而不是对心血管系统的损害。 肾小球此外，病理学研究已经令人信服地证明，肾小管损伤更多地是由于 比肾小球瘢痕形成更能预测肾功能丧失。 量化肾小管健康的新型尿液测量方法最近使我们能够定义四种 独立影响进展性CKD风险的肾脏健康的其他方面：近端小管 损伤、近端小管功能、小管纤维化和修复以及小管合成功能。我们的团队选择了 八个不同的尿液测量，捕获这四个维度中的每一个，并组成肾小管 健康小组（KTHP）。在特定的高危人群中，KTHP维度与风险密切相关 对于ASCVD、HF和死亡率的影响;但没有研究评估肾小管健康对ASCVD、HF和死亡率的贡献。 一般人群中ASCVD和HF的发展。我们的总体假设是肾小管损伤 和功能障碍与ASCVD和HF的发生和进展有关。 在两个成熟的普通人群队列（CARDIA和梅萨）中，该提案将解决 以下研究问题对于了解肾脏各方面的发育至关重要， 肾小管疾病及其在促进ASCVD和HF中的作用：1）肾小管疾病是否发展得更早， 随着年龄的增长比ACR和eGFR进展更快？2)肾小管疾病在黑人中更严重吗 和西班牙裔人与白色人的比较？3)哪些动脉粥样硬化危险因素最强 与肾小管疾病各方面的关系？4)肾小管与肾脏的 疾病与几个亚临床CVD措施？5)肾小管疾病与糖尿病的关系 与ASCVD和HF相关的标志物，它们是否改善了这些终点的预测？如果这些目标是 成功的，这些容易测量的，非侵入性的肾小管健康指标可能对人群有价值 筛查，以深入了解肾脏和心血管疾病的种族/民族差异，并 鉴定靶向肾小管的新型治疗剂的途径，如SGLT 2抑制剂和 非甾体醛固酮拮抗剂，可降低肾脏和心血管不良结局的风险。

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.