Beyond the Glomerulus: Novel Clinical Markers of Kidney Health and Prognosis

超越肾小球：肾脏健康和预后的新临床标志物

• 批准号: 9103527
• 负责人: Orlando M Gutierrez
• 金额: $ 79.5万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103527
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Age; Albuminuria; Anion Gap; Asians; Atherosclerosis; Bicarbonates; Biological Markers; Biological Process; Chronic Kidney Failure; Classification; Clinical Markers; Clinical assessments; Collaborations; Data; Development; Diagnosis; Disease; Disease Outcome; Distal; Electrolytes; End stage renal failure; Endocrine; Fibrosis; Functional disorder; General Population; Guidelines; Health; High Prevalence; Hispanics; Homeostasis; Host Defense; Individual; Injury; Interleukin-18; Kidney; Kidney Diseases; LCN2 gene; Lead; Measurement; Measures; Mediating; Metabolic acidosis; Methods; Morbidity - disease rate; Nutrient; Outcome; Participant; Persons; Population; Prevention; Public Health; Reasons for Geographic And Racial Differences in Stroke; Recording of previous events; Renal function; Renal tubule structure; Research; Resistance; Resources; Risk; Risk Factors; Serum; Serum Markers; Specimen; Staging; Staging System; Stroke; Tubular formation; UMOD gene; Urine; Vertebral column; base; clinical Diagnosis; cohort; community living; disorder risk; economic cost; follow-up; geographic difference; glomerular filtration; improved; individual patient; interest; interstitial; mortality; nephrogenesis; novel; outcome forecast; potential biomarker; procollagen Type III-N-terminal peptide; prognostic; prognostic value; public health relevance; racial difference; response; two-dimensional; urinary

 DESCRIPTION (provided by applicant): Currently, clinical assessment of chronic kidney disease (CKD) depends upon estimates of glomerular filtration (eGFR) and glomerular injury (albuminuria). This two-dimensional assessment of glomerular health forms the backbone of recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines because each represents a different component of CKD and each provides prognostic information on adverse kidney and non-kidney outcomes independent of the other. As defined, CKD is an enormous public health problem, due to its high prevalence, its economic costs, and its adverse impact on morbidity and mortality. Beyond glomerular filtration and glomerular injury, the kidney has many other critical biological functions that are primarily mediated by the tubulointerstitium; these include proximal tubule reabsorption, electrolyte transport, acid/base homeostasis, and endocrine actions. Neither eGFR nor albuminuria captures tubulo- interstitial abnormalities. Our preliminary data strongly suggest that a comprehensive assessment of kidney health in adults will require the addition of measures of tubulo-interstitial injury and tubular function. The broa objective of this proposal will be to develop a Kidney Tubule Health Panel (KTHP) that will be comprised of established and novel measures of kidney tubule injury and dysfunction. For kidney tubule injury, we will evaluate and compare the prognostic value of urinary measures of proximal tubule injury, distal tubule injury, and interstitial fibrosis. For kidney tubule dysfuncton, we will evaluate the prognostic utility of endocrine resistance, metabolic acidosis, decreased proximal tubule reabsorption, and host defense. Outcomes of interest will include development of end-stage renal disease (ESRD), progressive loss of kidney function and development of hospitalized acute kidney injury (AKI) (Aims 1 and 2). In Aim 3 we will develop the KTHP utilizing novel statistical approaches to select a parsimonious set of biomarkers that will maximize the prediction of ESRD, progressive loss of kidney function, and AKI. We will address our hypotheses in the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) and the Multi-Ethnic Study of Atherosclerosis (MESA), as they offer a broad age range of participants, a large representation of whites, blacks, Asians, and Hispanics, detailed measures of kidney risk factors, available urine and serum specimens and the outcomes of ESRD, loss of kidney function and AKI over 10 years. By broadening the assessment of kidney health and disease beyond the glomerulus, we believe that our KTHP can ultimately lead to improved understanding, classification, prevention, and treatment of CKD. Our proposal includes a collaborative team of PIs, each with expertise in different components of the application, a long-standing history of collaboration, and extensive expertise in both cohorts.

 描述（由适用提供）：目前，慢性肾脏疾病（CKD）的临床评估取决于肾小球过滤（EGFR）和肾小球损伤（蛋白尿）的估计。肾小球健康的这一二维评估构成了最近肾脏疾病改善全球结果（KDIGO）指南的主链，因为每种指南都代表了CKD的不同组成部分，并且每个人都提供了有关不良肾脏和非kidney结果的预后信息。正如定义的那样，CKD是一个巨大的公共卫生问题，由于其高龄，经济成本以及对发病率和死亡率的不利影响。除了肾小球滤过和肾小球损伤之外，肾脏还具有许多其他关键生物学功能，这些功能是由tubeloninterstitium介导的。这些包括近端小管的吸收，电解质传输，酸/碱稳态和内分泌作用。 EGFR和蛋白尿都没有捕获拟南芥的异常。我们的初步数据强烈表明，对成年人肾脏健康的全面评估将需要添加尺子互化损伤和管状功能的测量。该提案的BROA目标将是开发一个肾小管健康面板（KTHP），该面板将完成肾小管损伤和功能障碍的既定且新颖的测量结果。对于肾管损伤，我们将评估和比较近端管损伤，远端管损伤和间质纤维化的尿量测量的预后价值。对于肾管功能障碍，我们将评估内分泌耐药性，代谢性酸中毒，近端管重吸收和宿主防御的预后效用。感兴趣的结果将包括发展终末期肾脏疾病（ESRD），肾脏功能的进行性丧失以及住院的急性肾脏损伤（AKI）（AIMS 1和2）。在AIM 3中，我们将利用新型统计方法来开发KTHP，以选择一套脱颖而出的生物标志物，这些标志物将最大程度地提高ESRD的预测，肾脏功能的进行性丧失和AKI。我们将在中风研究中的地理和种族差异的原因和种族差异的原因和动脉粥样硬化的多种族研究（MESA）中解决我们的假设，因为它们为参与者提供了广泛的参与者，大量的白人，黑人，黑人，亚洲人和西班牙裔，以及西班牙裔，黑人，亚洲人和西班牙裔。 肾脏危险因素，可用的尿液和血清标本以及ESRD的结果，肾功能丧失和AKI的详细度量。通过将肾脏健康和疾病的评估范围扩大到肾小球之外，我们认为我们的KTHP最终可以改善对CKD的理解，分类，预防和治疗。我们的建议包括一个由PIS组成的协作团队，每个团队都有该应用程序的专家组成部分，长期的协作历史以及在两个队列中的广泛专业知识。