Vitamin D and Clinical Outcomes in Chronic Hemodialysis Patients

描述（由申请人提供）：心血管疾病（CVD）和感染性疾病分别是慢性血液透析（HD）患者的主要和第二大死亡原因。传统的心血管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CVD危险因素的作用。25-羟基维生素D（25（OH）D）通过肾脏中的酶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，这些作用依赖于循环血浆中25（OH）D的可用性。因此，流行病学数据表明，在非尿毒症人群中，25（OH）D缺乏与CVD和感染性疾病有关。HD人群在这方面的信息是稀缺的，将构成本申请的主要目标。我们建议使用已完成的NIDDK申办的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。本申请的目的是：（1）测量基线和年度随访期间从HEMO研究中随机分配的慢性HD患者中采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。将对基线和随访1-5年时分别采集的共计1228、1188、823、552、381和231份样本进行分析（目标1）。(2)在对1，25（OH）2D和这些事件的已知风险因素进行统计学校正后，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（目的2和目的3）。(3)通过对血清IL-6和hs-CRP水平进行统计学校正，检查心脏事件与基线和随访血清25（OH）D水平较低的关系是否减弱。该分析的阳性结果表明，这些炎症标志物是25（OH）D缺乏症临床心脏后果的因果途径（目的4）。了解血清25（OH）D水平与临床结局之间的关系将产生有趣的科学信息，并对慢性HD患者具有重要的诊断和治疗意义。公共卫生相关性：慢性肾脏疾病在美国非常常见，但在过去几十年中普遍认识不足。晚期肾病患者，特别是需要长期血液透析的患者，因心脏病和感染而死亡率非常高。这些高风险的原因尚不清楚。这项研究计划将集中在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原因。虽然维生素D缺乏长期以来一直被认为会导致骨骼疾病，但在美国普通人群中迅速积累的证据表明，慢性维生素D缺乏也会导致高血压，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中非常常见的医疗并发症。该应用程序将检查维生素D缺乏症是否确实与慢性透析患者的心脏病和感染有关。如果结果是阳性的，这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补充剂的大型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.