Randomized trial of vitamin D and omega-3 fatty acids for diabetic kidney disease

描述(申请人提供)：我们建议进行一项随机、安慰剂对照的临床试验，使用维生素D3(胆钙醇)和omega-3脂肪酸(二十碳五烯酸和二十二碳六烯酸)来预防糖尿病肾病(DKD)的发展和进展。糖尿病患者发生肾脏疾病的风险很高，而DKD既是发达国家终末期肾脏疾病的主要原因，也是心血管疾病风险的有效放大因素。根据动物实验模型和早期人类研究的结果，维生素D和omega-3脂肪酸是预防和治疗DKD的有前景的干预措施。由于这些干预措施相对安全、廉价且可广泛获得，它们可能提供机会在大量人群中大幅减轻DKD的负担。我们的目标是测试维生素D3和/或omega-3脂肪酸能否在4年的治疗中防止蛋白尿的进展和肾小球滤过率的丧失，这是DKD的两种互补表现。为了有效和高效地检验研究假设，我们建议对维生素D和Omega-3试验(VITAL)进行辅助研究，这是一项由NIH资助的随机临床试验。在VITAL中，20,000名参与者(男性60岁，女性65岁)将按2x2析因设计随机分配给维生素D3(胆钙化醇)1600IU每日与安慰剂比较，以及二十碳五烯酸500 mg加二十二碳六烯酸500 mg与安慰剂比较，并平均跟踪5年以评估对心血管疾病和癌症事件的影响。利用VITAL已建立的基础设施，我们建议确定和招募1,500名在基线水平患有糖尿病的重要参与者，并确定研究干预对这一组人的蛋白尿和肾小球滤过率的影响。按照家长VITAL试验的简单和具有成本效益的设计，生物检验品将在当地收集并通过邮寄送到VITAL中心实验室。在基线和第4年收集第一个晨间尿液，以测量尿白蛋白/肌酐比率。同时采集血液样本以测量肾小球滤过率(使用血清肌酐和胱抑素C)、25-羟基维生素D、二十碳五烯酸和二十二碳六烯酸、C反应蛋白和血红蛋白A1c。拟议的研究旨在确定维生素D3和/或omega-3脂肪酸在DKD的发生和发展中是否具有因果和临床相关的影响。 公共卫生相关性：糖尿病肾病(DKD)是导致大量发病率和死亡率的原因之一。尽管广泛使用强化血糖控制和肾素-血管紧张素-醛固酮系统抑制剂，DKD的肾脏和心血管后果仍然很常见。这项研究将评估维生素D3和/或omega-3脂肪酸是否是安全和有效的干预措施，以减轻大量和不断增长的糖尿病人群中的DKD负担。

DESCRIPTION (provided by applicant): We propose a randomized, placebo-controlled clinical trial of vitamin D3 (cholecalciferol) and omega-3 fatty acids (eicosapentaenoic acid plus docosahexaenoic acid) to prevent the development and progression of diabetic kidney disease (DKD). Persons with diabetes are at high risk of developing kidney disease, and DKD is both the leading cause of end stage renal disease in the developed world and a potent amplifier of cardiovascular disease risk. Vitamin D and omega-3 fatty acids are promising interventions for DKD prevention and treatment, based on results of animal-experimental models and early human studies. Because these interventions are relatively safe, inexpensive, and widely available, they may offer opportunity to substantially reduce the burden of DKD in large populations. We aim to test whether vitamin D3 and/or omega-3 fatty acids prevent progression of albuminuria and loss of glomerular filtration rate, two complementary manifestations of DKD, over 4 years of treatment. To effectively and efficiently test study hypotheses, we propose an ancillary study to the Vitamin D and Omega-3 Trial (VITAL), an NIH-funded randomized clinical trial. In VITAL, 20,000 participants (men ages e 60 years, women ages e 65 years) will be randomly assigned in a 2x2 factorial design to vitamin D3 (cholecalciferol) 1600 IU daily versus placebo, and to eicosapentaenoic acid 500 mg plus docosahexaenoic acid 500 mg daily versus placebo, and followed for a mean of 5 years to assess effects on cardiovascular disease and cancer events. Leveraging the established infrastructure of VITAL, we propose to identify and recruit a sub-cohort of 1,500 VITAL participants with diabetes at baseline and to ascertain effects of study interventions on albuminuria and glomerular filtration rate in this group. Following the simple and cost-efficient design of the parent VITAL trial, biospecimens will be collected locally and delivered to the VITAL central laboratory by mail. First morning voids will be collected at baseline and year 4 for measurement of urine albumin-creatinine ratio. Blood samples will be collected simultaneously for measurement of glomerular filtration rate (using serum creatinine and cystatin C), 25- hydroxyvitamin D, eicosapentaenoic acid plus docosahexaenoic acid, C-reactive protein, and hemoglobin A1c. The proposed studies are designed to determine whether vitamin D3 and/or omega-3 fatty acids have causal and clinically relevant effects on the development and progression of DKD. PUBLIC HEALTH RELEVANCE: Diabetic kidney disease (DKD) is a cause of substantial morbidity and mortality. Despite widespread use of intensive glycemic control and renin-angiotensin-aldosterone system inhibitors, renal and cardiovascular consequences of DKD remain common. This study will evaluate whether vitamin D3 and/or omega-3 fatty acids are safe and effective interventions to reduce the burden of DKD among the large and growing diabetic population.