Vitamin D and Clinical Outcomes in Chronic Hemodialysis Patients

简介(申请人提供)：心血管疾病和传染病分别是慢性血液透析(HD)患者的首要和次要死因。传统的弗雷明翰因素似乎不能充分解释这一人群中的心血管疾病风险。因此，我们建议探讨维生素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)被肾脏中的1-1-羟基酶转化为活性形式1，25-二羟基维生素D(1，25(OH)2D)。许多肾外组织也具有1-1-羟基酶和维生素D受体的发现，为维生素D在各种器官中重要的生理性自分泌/旁分泌作用提供了新的见解，这种作用依赖于循环血浆中25(OH)D的可获得性。因此，流行病学数据表明，在非尿毒症人群中，25(OH)D缺乏与心血管疾病和传染病有关。住房署人口在这方面的信息很少，这将构成本申请的主要目标。我们建议使用NIDDK赞助的完整血液研究中存储的血清样本和数据库来检查慢性血液透析患者血清维生素D水平、炎症标志物和临床事件之间的关系。本应用的目的是：(1)检测血液研究中随机选取的慢性血液透析患者透析前血清样本中25(OH)D、1，25(OH)2D、IL-6和高敏C反应蛋白(hs-CRP)的水平。将对在基线和后续1-5年分别收集的1228、1188、823、552、381和231个样本进行检测(目标1)。(2)在对1，25(OH)2D和已知危险因素(目标2和目标3)进行统计调整后，研究随访期间血清25(OH)D水平与心脏综合预后和感染性综合预后的关系。(3)通过对血清IL-6和hs-CRP水平的统计调整，探讨心脏事件与较低的基线和随访血清25(OH)D水平的关系是否减弱。这项分析的积极结果将表明，这些炎症标志物参与了25(OH)D缺乏的临床心脏后果的原因途径(目标4)。了解血清25(OH)D水平与临床结局的关系将产生有趣的科学信息，并对慢性血液透析患者的诊断和治疗具有重要意义。与公共健康相关：慢性肾脏疾病在美国非常常见，但在过去几十年里普遍被低估了。患有晚期肾脏疾病的患者，特别是那些需要长期血液透析的患者，由于心脏病和感染而死亡的比率非常高。这些高风险的原因尚不清楚。这项研究建议将重点放在透析患者的另一种流行病上，即维生素D缺乏，这可能是导致他们心脏病和感染的原因之一。虽然人们很早就知道维生素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，所有这些都是透析患者非常常见的医疗并发症。这项应用将检查维生素D缺乏是否确实与慢性透析患者的心脏病和感染有关。如果结果是积极的，这将有助于解释为什么这些患者心脏病和感染的风险如此之高。此外，这将为维生素D补充剂的大规模临床试验提供可靠的基础，以改善透析患者非常糟糕的临床结果。

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.