Vitamin D and Clinical Outcomes in Chronic Hemodialysis Patients

维生素 D 与慢性血液透析患者的临床结果

• 批准号: 7650503
• 负责人: Michel Benjamin Chonchol
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650503
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; Accounting; Address; Atherosclerosis; Attenuated; Autoimmune Diseases; Biological Assay; Bone Diseases; C-reactive protein; Calcium; Cardiac; Cardiac Death; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Pathways; Clinical Trials; Communicable Diseases; Data; Databases; Death Rate; Diabetes Mellitus; Diagnostic; Dialysis patients; Dialysis procedure; Dose; Enzymes; Epidemic; Event; Figs - dietary; Functional disorder; Future; Goals; Heart Diseases; Heart failure; Hemodialysis; Hormonal; Hospitalization; Hypertension; Hypertrophy; Immune System Diseases; Infection; Inflammation; Inflammatory; Interleukin-6; Kidney; Kidney Diseases; Lead; Link; Measures; Mediating; Mixed Function Oxygenases; Myocardial; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Organ; Outcome; Parathyroid Hormones; Pathogenesis; Patients; Phosphorus; Physiological; Plasma; Population; Predictive Value; Prevalence; Randomized; Relative (related person); Renal Osteodystrophy; Renal Tissue; Research; Research Proposals; Risk Factors; Role; Sampling; Secondary Hyperparathyroidism; Secondary to; Serum; Structural Models; Supplementation; Testing; Therapeutic; Time; Tissues; Upper arm; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Vitamins; adjudicate; analog; antimicrobial peptide; autocrine; base; cardiovascular disorder risk; cell type; cohort; cytokine; design; epidemiologic data; follow-up; high risk; hormone metabolism; human PTH protein; improved; inflammatory marker; insight; interest; medical complication; mortality; paracrine; primary outcome; public health relevance; secondary outcome; sound; trend

DESCRIPTION (provided by applicant): Cardiovascular diseases (CVD) and infectious diseases are the leading and second causes of death respectively in chronic hemodialysis (HD) patients. Traditional Framingham factors do not appear to sufficiently account for the CVD risks in this population. We therefore propose to explore the role of vitamin D deficiency as a non-traditional CVD risk factor. 25-hydroxyvitamin D (25(OH)D) is converted to the active form, 1,25-dihydroxyvitamin D (1,25(OH)2 D), by the enzyme 1-1-hydroxylase in the kidney. The discoveries that many extra-renal tissues also possess the 1-1-hydroxylase enzyme and vitamin D receptors have provided new insights into the important physiologic autocrine/paracrine roles of vitamin D in various organs, that are dependent on the availability of 25(OH)D from the circulating plasma. Accordingly, epidemiologic data have related 25(OH)D deficiency to CVD and infectious diseases in the non-uremic population. Information in the HD population in this regard is scarce and will constitute the main goal of the present application. We propose to use the stored serum samples and data base from the completed NIDDK-sponsored HEMO Study to examine the relationship between serum vitamin D levels, inflammatory markers and clinical events in chronic HD patients. The objectives of this application are: (1) To measure levels of 25(OH)D, 1,25(OH)2D, Interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs- CRP) in predialysis serum samples collected at baseline and during annual follow-up from chronic HD patients randomized in the HEMO Study. A total of 1228, 1188, 823, 552, 381 and 231 samples collected respectively at the baseline and in follow-up years 1-5 will be assayed (Aim 1). (2) To examine the relationship of serum 25(OH)D levels with cardiac composite outcomes and infectious composite outcomes during follow-up, after statistical adjustment for 1,25(OH)2D and known risk factors for these events (Aim 2 and Aim 3). (3) To examine whether the relationships of cardiac events with lower baseline and follow-up serum 25(OH)D levels are attenuated with statistical adjustment for serum levels of IL-6 and hs-CRP. Positive results of this analysis would suggest that these inflammatory markers are in the causal pathways of the clinical cardiac consequences of 25(OH)D deficiency (Aim 4). Understanding the relationship between serum 25(OH)D levels with clinical outcomes will yield interesting scientific information and have important diagnosti an therapeutic implications for chronic HD patients. PUBLIC HEALTH RELEVANCE: chronic kidney disease is very common in the U.S. but has been generally under-recognized in the last few decades. Patients with advanced kidney disease, especially those requiring chronic hemodialysis, have very high death rates due to heart diseases and infections. The reasons for these high risks are unclear. This research proposal will focus on another epidemic in dialysis patients, namely, vitamin D deficiency, which may be a contributing cause to their heart diseases and infections. Although vitamin D deficiency has long been known to cause bone diseases, evidence is rapidly accumulating in the general U.S. population showing that chronic vitamin D deficiency also causes hypertension, diabetes, myocardial infarction, heart failure, infections and disorder of the immune system, all of which are also very common medical complications in dialysis patients. This application will examine if vitamin D deficiency can indeed be linked to heart diseases and infections in chronic dialysis patients. If the results are positive, it would help to explain why these patients are at such high risks for heart diseases and infections. In addition, it would provide a sound basis for a large clinical trial of vitamin D supplementation to improve the very poor clinical outcomes of dialysis patients.

描述（申请人提供）：心血管疾病（CVD）和传染病分别是慢性血液透析（HD）患者死亡的主要原因和第二位原因。传统的弗雷明汉因素似乎不足以解释该人群的 CVD 风险。因此，我们建议探索维生素 D 缺乏作为非传统 CVD 危险因素的作用。 25-羟基维生素 D (25(OH)D) 通过肾脏中的 1-1-羟化酶转化为活性形式 1,25-二羟基维生素 D (1,25(OH)2 D)。许多肾外组织也具有 1-1-羟化酶和维生素 D 受体的发现为维生素 D 在各种器官中的重要生理自分泌/旁分泌作用提供了新的见解，这些作用依赖于 25(OH) 的可用性)D 来自循环血浆。因此，流行病学数据表明，非尿毒症人群中 25(OH)D 缺乏与 CVD 和传染病有关。 HD人群中这方面的信息很少，这将构成本申请的主要目标。我们建议使用已完成的 NIDDK 赞助的 HEMO 研究中存储的血清样本和数据库来检查慢性 HD 患者血清维生素 D 水平、炎症标志物和临床事件之间的关系。本应用的目标是： (1) 测量 25(OH)D、1,25(OH)2D、白细胞介素 6 (IL-6) 和高敏 C 反应蛋白 (hs-CRP) 的水平在 HEMO 研究中随机收集的慢性 HD 患者的基线和年度随访期间收集的透析前血清样本中。将分析在基线和后续第 1-5 年分别收集的总共 1228、1188、823、552、381 和 231 个样本（目标 1）。 (2) 在对 1,25(OH)2D 和这些事件的已知危险因素进行统计调整后，检查随访期间血清 25(OH)D 水平与心脏复合结局和感染复合结局的关系（目标 2 和目标3）。 (3) 检查心脏事件与较低基线和随访血清 25(OH)D 水平的关系是否通过对 IL-6 和 hs-CRP 血清水平进行统计调整而减弱。该分析的阳性结果表明，这些炎症标志物是 25(OH)D 缺乏的临床心脏后果的因果途径（目标 4）。了解血清 25(OH)D 水平与临床结果之间的关系将产生有趣的科学信息，并对慢性 HD 患者的诊断和治疗具有重要意义。公共卫生相关性：慢性肾脏病在美国非常常见，但在过去几十年中普遍未被充分认识。患有晚期肾病的患者，尤其是那些需要长期血液透析的患者，由于心脏病和感染而导致的死亡率非常高。这些高风险的原因尚不清楚。这项研究计划将重点关注透析患者中​​的另一种流行病，即维生素 D 缺乏症，这可能是导致心脏病和感染的一个原因。尽管长期以来人们都知道维生素 D 缺乏会导致骨骼疾病，但在普通美国人中，证据正在迅速积累，表明慢性维生素 D 缺乏还会导致高血压、糖尿病、心肌梗塞、心力衰竭、感染和免疫系统紊乱，所有这些这也是透析患者中​​非常常见的医疗并发症。该应用将检查维生素 D 缺乏是否确实与慢性透析患者的心脏病和感染有关。如果结果呈阳性，将有助于解释为什么这些患者患心脏病和感染的风险如此之高。此外，它还可以为补充维生素 D 的大型临床试验提供坚实的基础，以改善透析患者非常糟糕的临床结果。