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影响，包括氧化降低 心脏和肾脏的压力和纤维化。肾小管是循环（可溶）klotho的主要来源 因此，慢性肾脏疾病（CKD）的发展导致klotho缺乏症。 也可能矛盾地有助于CKD进展。克洛托缺乏症的啮齿动物模型显示漏洞 肾脏损伤和肾脏疾病的进展 损害和疾病进展。克洛托缺乏症也可能导致过度心血管疾病 （CVD）CKD的风险是Klotho敲除小鼠显示血管钙化和病理心脏重塑 心脏肥大和纤维化。此外，血压（BP）可能会影响Klotho水平作为临床前 数据表明，多种高血压模型都会导致klotho缺乏症。那远，大多数临床 研究固体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可重复性的担忧。 一些研究报告没有与肾功能降低的固体klotho水平或更高水平的关系， 而其他人则表现出克洛托和肾功能的平行下降。这种差异阻碍了 在大规模人类研究中，克洛索的宽度测量，导致质量数据很少 研究克洛托在人CKD中的作用。同样，也没有关于克洛托的变化的纵向数据 在CKD中的时间。在使用收缩压干预试验（Sprint）的样品的试点项目中，我们 将最广泛使用的商业ELISA与免疫沉淀 - 免疫印迹（IP-IB）测定法和 发现IP-IB分析暴露了出色的性能。随后，我们希望解决当前的缺乏 高质量的人类研究将固体klotho作为CVD和CKD进展的危险因素。短跑 当审判招募了2646名CKD参与者并已详细的参与者时，是回答这些问题的理想人群 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 可能影响固体Klotho纵向变化的临床因素，包括：密集与标准 血压控制干预，包括FGF-23在内的矿物质代谢的测量以及测量 肾小管损伤/健康。我们建议在2646年测量基线血清和尿液klotho浓度 在基线时具有CKD的Sprint参与者以及1年级的1000人的预先指定的子集 4年至：1）将IP-IB分析与商业Klotho Elisa进行比较； 2）确定克洛索的关联 随着CVD事件，死亡和CKD的进展； 3）确定影响纵向的临床因素 Klotho的变化，包括密集与标准BP控制，矿物质代谢和/或肾脏的标记 管状健康。这样的数据可以集体为未来的Klotho介入试验奠定基础，为临床风险提供信息 分层模型，为Klotho生物学和治疗的转化研究提供了基础。

项目成果

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• 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.

• 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.