The Relation of Soluble Klotho with Cardiovascular Disease, Chronic Kidney Disease Progression, and Blood Pressure in the Systolic Blood Pressure Intervention Trial

收缩压干预试验中可溶性 Klotho 与心血管疾病、慢性肾病进展和血压的关系

• 批准号: 10451512
• 负责人: David Alan Drew
• 金额: $ 29.89万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451512
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Albuminuria; Attenuated; Biological Assay; Biological Markers; Biology; Blood; Blood Pressure; Cardiac; Cardiovascular Diseases; Cause of Death; Cell Maintenance; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Communities; Data; Development; Disease; Disease Progression; Enrollment; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Exhibits; Fibroblast Growth Factor; Fibrosis; Foundations; Functional disorder; Future; Gene Expression; Genes; Glomerular Filtration Rate; Health; Heart; Heart Hypertrophy; Human; Hypertension; Immunoprecipitation; Impairment; Individual; Injury; Injury to Kidney; Integral Membrane Protein; Intervention; Intervention Trial; Kidney; Kidney Diseases; Knockout Mice; Measurement; Measures; Metabolism; Minerals; Modeling; Outcome; Oxidative Stress; Participant; Pathologic; Patients; Performance; Persons; Pilot Projects; Production; Protocols documentation; Randomized; Recovery; Renal function; Renal tubule structure; Reporting; Reproducibility; Research; Risk Factors; Rodent; Rodent Model; Role; Sampling; Serum; Source; Specific qualifier value; Specimen; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Translational Research; Tubular formation; Urine; Vascular calcification; arm; blood pressure control; blood pressure intervention; cardiovascular disorder risk; cardiovascular risk factor; clinical risk; cohort; coronary fibrosis; fibroblast growth factor 23; high risk; human study; mortality; novel; overexpression; pre-clinical; preclinical study; prevent; renal damage; repaired; risk stratification; trial comparing

ABSTRACT Soluble α-klotho (“Klotho”) has systemic effects in maintenance of cell health including reduction of oxidative stress and fibrosis in the heart and kidney. Kidney tubules are the primary source of circulating (soluble) klotho and therefore the development of chronic kidney disease (CKD) results in klotho deficiency. Klotho deficiency may also paradoxically contribute to CKD progression. Rodent models of klotho deficiency display vulnerability to kidney injury and progression of kidney disease, while administration of exogenous klotho attenuates kidney damage and disease progression. Klotho deficiency may also contribute to excess cardiovascular disease (CVD) risk in CKD as klotho knockout mice display vascular calcification and pathological cardiac remodeling with cardiac hypertrophy and fibrosis. Further, blood pressure (BP) may influence klotho levels as preclinical data show that multiple models of hypertension all result in klotho deficiency. Thus far, the majority of clinical studies examining soluble klotho have relied primarily on a single commercial source of ELISA. There are concerns about the performance and reproducibility of this assay as the clinical data have been inconsistent. Some studies have reported no relationship or higher levels of soluble klotho with reduced kidney function, while others have shown a parallel decline in klotho and kidney function. This discrepancy has hindered widespread measurement of klotho in large-scale human studies and has led to a paucity of quality data examining the role of klotho in human CKD. Similarly, there are no longitudinal data on changes in klotho over time in CKD. In a pilot project using samples from the Systolic Blood Pressure Intervention Trial (SPRINT) we compared the most widely used commercial ELISA with an immunoprecipitation-immunoblot (IP-IB) assay, and found that the IP-IB assay exhibited superior performance. Subsequently, we hope to address the current lack of high quality human studies examining soluble klotho as a risk factor for CVD and CKD progression. SPRINT is the ideal cohort to answer these questions as the trial enrolled 2646 participants with CKD and has detailed CVD and kidney outcomes. This cohort is also well-suited to examine the patient-specific and disease-specific clinical factors that may impact longitudinal changes in soluble klotho including: the intensive vs. standard blood pressure control intervention, measures of mineral metabolism including FGF-23, and measures of kidney tubular injury/health. We propose to measure baseline serum and urine klotho concentrations in 2646 SPRINT participants with CKD at baseline as well as in a pre-specified subset of 1000 persons at year 1 and year 4 to: 1) compare the IP-IB assay with the commercial klotho ELISA; 2) determine the association of klotho with CVD events, death, and CKD progression; and 3) identify the clinical factors that influence longitudinal changes in klotho including intensive vs. standard BP control, markers of mineral metabolism and/or kidney tubular health. Such data can collectively set the stage for future klotho interventional trials, inform clinical risk- stratification models and provide a foundation for translational research in klotho biology and therapeutics.

摘要 可溶性α-klotho（“Klotho”）在维持细胞健康方面具有全身性作用，包括减少细胞内的氧化应激。 心脏和肾脏的压力和纤维化。肾小管是循环（可溶性）klotho的主要来源 因此慢性肾病（CKD）的发展导致Klotho缺乏。Klotho缺乏症 也可能自相矛盾地促进CKD进展。klotho缺陷的啮齿动物模型显示脆弱性 肾损伤和肾脏疾病进展，而外源性klotho的施用减弱了肾脏损伤和肾脏疾病进展。 损伤和疾病进展。Klotho缺乏症也可能导致过多的心血管疾病 (CVD)klotho基因敲除小鼠显示血管钙化和病理性心脏重塑， 心脏肥大和纤维化此外，血压（BP）可能会影响klotho水平，如临床前 数据显示，多种高血压模式均导致klotho缺乏症。到目前为止，大多数临床 检测可溶性Klotho的研究主要依赖于ELISA的单一商业来源。有 由于临床数据不一致，因此对该测定的性能和重现性存在担忧。 一些研究报告称，可溶性klotho与肾功能下降没有关系或水平较高， 而其他人则表现出klotho和肾功能的平行下降。这种差异阻碍了 在大规模的人类研究中广泛测量klotho，导致缺乏高质量的数据 研究klotho在人类CKD中的作用。同样，也没有关于klotho变化的纵向数据， CKD时间在一个使用来自收缩压干预试验（SPRINT）样本的试点项目中， 将最广泛使用的商业ELISA与免疫沉淀-免疫印迹（IP-IB）测定进行比较， 发现IP-IB测定法表现出优越的上级性能。随后，我们希望解决目前缺乏 高质量的人类研究，检查可溶性klotho作为CVD和CKD进展的风险因素。SPRINT 是回答这些问题的理想队列，因为该试验招募了2646名CKD参与者，并详细介绍了 CVD和肾脏结局。该队列也非常适合检查患者特异性和疾病特异性 可能影响可溶性klotho纵向变化的临床因素包括：强化与标准 血压控制干预，包括FGF-23在内的矿物质代谢的测量，以及 肾小管损伤/健康。我们建议在2646名受试者中测量基线血清和尿液klotho浓度。 基线时患有CKD的SPRINT参与者以及第1年时预先指定的1000人亚组， 第4年：1）比较IP-IB测定与商业klotho ELISA; 2）确定klotho CVD事件、死亡和CKD进展;以及3）确定影响纵向 klotho的变化，包括强化与标准BP控制、矿物质代谢和/或肾脏标志物 管健康。这些数据可以共同为未来的klotho干预性试验奠定基础，告知临床风险- 分层模型，并为klotho生物学和治疗学的转化研究提供基础。