Anti-inflammatory Therapy in Diabetic CKD

糖尿病 CKD 的抗炎治疗

基本信息

批准号：
8586105
负责人：
Dominic S Raj
金额：
$ 35.28万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8586105
关键词：
Accounting Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Attenuated Bacteria Bifidobacterium Cardiovascular Diseases Cardiovascular system Chronic Kidney Failure Cicatrix Clinical Clinical Trials Colon Cystatins Data Diabetes Mellitus Diabetic Nephropathy Dietary Fiber Dipeptidyl Peptidases End stage renal failure Endotoxemia Endotoxins Equilibrium Extracellular Matrix Fibrinogen Food Functional disorder Funding Opportunities Generations Glomerular Filtration Rate Growth Growth Factor Human Hyperglycemia Hypoglycemia Hypoglycemic Agents Image Imaging Techniques Inflammation Inflammatory Insulin Resistance Intake Interleukin-6 Intervention Intervention Studies Intestines Inulin Kidney Kidney Diseases Knowledge Left Ventricular Mass Link Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Metabolic Molecular Morbidity - disease rate Motion Myocardial Natural History Nephrons Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Outcome Study Participant Pathway interactions Patients Pharmaceutical Preparations Phase Pilot Projects Placebos Plasma Property Proteinuria Randomized Recovery Recruitment Activity Renal function Reporting Research Design Risk Risk Factors Safety Slice Study Subject Techniques Time Toxin Tumor Necrosis Factor-alpha Ventricular cardiovascular disorder risk cardiovascular risk factor catalyst chemokine cytokine diabetic follow-up glomerulosclerosis gut microbiota high risk improved inflammatory marker inhibitor/antagonist innovation interstitial microbial mortality non-diabetic novel prebiotics public health relevance treatment effect

项目摘要

DESCRIPTION (provided by applicant): Diabetes is the most common cause of end-stage renal disease (ESRD) in the US. In patients with type 2 diabetes mellitus (T2DM), persistent inflammation underpins the progression of chronic kidney disease (CKD) to ESRD and the associated cardiovascular disease. Linagliptin is an oral anti-hyperglycemic agent that has anti-inflammatory, anti-proteinuric, and cardio-renal protective properties. The human gut harbors 1014 bacteria, and gut microbial imbalance has been linked to inflammation, insulin resistance, and atheroscleroisis. Prebiotic oligofructose enriched inulin (p-inulin) has been shown to restore gut microbial balance, thereby reducing endotoxin generation and attenuating inflammation. In a two-by-two factorial clinical trial we will randomize 120 T2DM-CKD patients to receive linagliptin/p-inulin/placebo daily for 12 months. First, we will demonstrate the feasibility of recruitment, randomization, and retention of study participants to record endpoints in at least 90 percent of participants. Secondly, we will establish the efficacy of linagliptin and p-inulin in reducing systemic inflammation. We will study the change in plasma levels of endotoxin and selected markers of inflammation with treatment. Alterations in gut microbial flora will be determined using quantitative real time-PCR. Thirdly, we propose to evaluate the effect of treatment with linagliptin and p-inulin on selected exploratory clinical end- points. We will evaluate the rate of decline of kidney function using the slope of estimated glomerular filtration rate and plasma cystatin level. The change in proteinuria will also be quantitated. Progression/regression of atherosclerosis will be studied using state of art phase-sensitive dual inversion recovery magnetic resonance spectroscopy (MR) imaging. We will determine left ventricular mass and function using a highly innovative MR imaging technique. This novel pilot study will prove the concept, establish feasibility, and generate preliminary data to justify the launching of a full-clinical trial.

描述（由申请人提供）：在美国，糖尿病是终末期肾病 (ESRD) 的最常见原因。在 2 型糖尿病 (T2DM) 患者中，持续的炎症是慢性肾病 (CKD) 进展为 ESRD 和相关心血管疾病的基础。利格列汀是一种口服降血糖药，具有抗炎、抗蛋白尿和心肾保护作用。人类肠道内有 1014 种细菌，肠道微生物失衡与炎症、胰岛素抵抗和动脉粥样硬化有关。富含益生元低聚果糖的菊粉（β-菊粉）已被证明可以恢复肠道微生物平衡，从而减少内毒素的产生并减轻炎症。在一项 2×2 析因临床试验中，我们将随机抽取 120 名 T2DM-CKD 患者，每天接受利格列汀/β-菊糖/安慰剂治疗，持续 12 个月。首先，我们将证明招募、随机化和保留研究参与者以记录至少 90% 参与者的终点的可行性。其次，我们将确定利格列汀和β-菊糖在减少全身炎症方面的功效。我们将研究治疗后血浆内毒素水平和选定炎症标志物的变化。将使用定量实时 PCR 确定肠道微生物菌群的变化。第三，我们建议评估利格列汀和β-菊糖治疗对选定的探索性临床终点的效果。我们将使用估计的肾小球滤过率和血浆胱抑素水平的斜率来评估肾功能的下降率。蛋白尿的变化也将被定量。将使用最先进的相敏双反转恢复磁共振波谱（MR）成像来研究动脉粥样硬化的进展/消退。我们将使用高度创新的 MR 成像技术确定左心室质量和功能。这项新颖的试点研究将证明这一概念，建立可行性，并生成初步数据，以证明启动全临床试验的合理性。