Vitamin D and Clinical Outcomes in Chronic Hemodialysis Patients

描述（由申请人提供）：心血管疾病（CVD）和传染病分别是慢性血液透析（HD）患者的第一和第二大死亡原因。传统的弗雷明汉因素似乎不能充分解释这一人群的心血管疾病风险。因此，我们建议探索维生素D缺乏作为非传统心血管疾病危险因素的作用。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) 2d）。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在各种器官中重要的生理自分泌/旁分泌作用提供了新的见解，这取决于循环血浆中25(OH)D的可用性。因此，流行病学数据表明，25(OH)D缺乏与非尿毒症人群的心血管疾病和传染病有关。在这方面，关于艾滋病人口的资料很少，这将构成本应用程序的主要目标。我们建议使用已完成的niddk赞助的HEMO研究中储存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。该应用程序的目的是：(1)测量在基线和每年随访中随机从慢性HD患者中收集的透析前血清样本中的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）水平。在基线和随访1-5年分别收集1228、1188、823、5552、381和231个样本进行分析（目的1）。(2)为了检查随访期间血清25(OH)D水平与心脏综合结局和感染性综合结局的关系。(3)通过对血清IL-6和hs-CRP水平进行统计调整，检验心脏事件与较低的基线和随访血清25(OH)D水平之间的关系是否减弱。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（Aim 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：慢性肾脏疾病在美国非常常见，但在过去的几十年里，人们普遍对其认识不足。晚期肾病患者，特别是那些需要慢性血液透析的患者，由于心脏病和感染，死亡率非常高。造成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的另一种流行病，即维生素D缺乏症，这可能是导致他们心脏病和感染的一个原因。尽管人们早就知道维生素D缺乏会导致骨骼疾病，但在美国普通人群中迅速积累的证据表明，慢性维生素D缺乏还会导致高血压、糖尿病、心肌梗死、心力衰竭、感染和免疫系统紊乱，所有这些也是透析患者非常常见的医学并发症。该应用程序将检查维生素D缺乏是否确实与慢性透析患者的心脏病和感染有关。如果结果是积极的，它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，它将为维生素D补充的大规模临床试验提供良好的基础，以改善透析患者非常差的临床结果。

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.