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: 10618989
• 负责人: David Alan Drew
• 金额: $ 27.79万
• 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/10618989
• 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; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Exhibits; 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; Western Blotting; arm; blood pressure control; blood pressure intervention; cardiovascular disorder risk; cardiovascular risk factor; clinical risk; cofactor; 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; trial enrollment

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.

抽象的 可溶性 α-klotho（“Klotho”）在维持细胞健康方面具有系统性作用，包括减少氧化 心脏和肾脏的压力和纤维化。肾小管是循环（可溶性）克洛索的主要来源 因此，慢性肾脏病 (CKD) 的发展会导致 klotho 缺乏。克洛索缺乏症 矛盾的是，也可能促进 CKD 进展。 klotho缺陷的啮齿动物模型显示出脆弱性 导致肾损伤和肾病进展，而外源性克洛索的施用会削弱肾功能 损害和疾病进展。 Klotho 缺乏症也可能导致心血管疾病 klotho 基因敲除小鼠显示血管钙化和病理性心脏重塑，导致 CKD 的 (CVD) 风险 伴有心脏肥大和纤维化。此外，血压 (BP) 可能会影响 klotho 水平，因为临床前 数据显示，多种高血压模型都会导致克洛索缺乏症。迄今为止，临床上大多数 检查可溶性 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，人们对该测定的性能和重现性表示担忧。 一些研究报告称，可溶性克洛索水平与肾功能下降没有关系或较高水平， 而其他人则显示克洛托和肾功能同时下降。这种差异阻碍了 klotho 在大规模人类研究中的广泛测量导致了高质量数据的缺乏 检查 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。在使用收缩压干预试验 (SPRINT) 样本的试点项目中，我们 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，并且 发现 IP-IB 测定表现出优越的性能。随后，我们希望解决目前的不足 高质量的人体研究检查可溶性 klotho 作为 CVD 和 CKD 进展的危险因素。短跑 是回答这些问题的理想队列，因为该试验招募了 2646 名患有 CKD 的参与者，并详细介绍了 CVD 和肾脏结果。该队列也非常适合检查患者特异性和疾病特异性 可能影响可溶性克洛托纵向变化的临床因素包括： 强化与标准 血压控制干预、矿物质代谢（包括 FGF-23）测量以及 肾小管损伤/健康。第2646章 被人欺负 基线时患有 CKD 的 SPRINT 参与者以及在第一年和预先指定的 1000 人子集中患有 CKD 的参与者 第 4 年：1) 将 IP-IB 测定与商业 klotho ELISA 进行比较； 2）确定klotho的关联 CVD 事件、死亡和 CKD 进展； 3）确定影响纵向的临床因素 klotho 的变化，包括强化血压控制与标准血压控制、矿物质代谢和/或肾脏标志物 肾小管健康。这些数据可以共同为未来的 klotho 介入试验奠定基础，为临床风险提供信息 分层模型并为 klotho 生物学和治疗学的转化研究提供基础。

项目成果

How I Treat Rhabdomyolysis-Induced AKI?

如何治疗横纹肌溶解引起的 AKI？

• DOI: 10.2215/cjn.0000000000000372
• 发表时间: 2024
• 期刊: Clinical journal of the American Society of Nephrology : CJASN
• 作者: Lu,Yan;Neyra,JavierA
• 通讯作者: Neyra,JavierA

Assessment of prescribed vs. achieved fluid balance during continuous renal replacement therapy and mortality outcome.

在连续的肾脏替代疗法和死亡率结果期间，评估处方与达到的流体平衡。

• DOI: 10.1371/journal.pone.0272913
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Neyra, Javier A.;Lambert, Joshua;Ortiz-Soriano, Victor;Cleland, Daniel;Colquitt, Jon;Adams, Paul;Bissell, Brittany D.;Chan, Lili;Nadkarni, Girish N.;Tolwani, Ashita;Goldstein, Stuart L.
• 通讯作者: Goldstein, Stuart L.