Urinary Biomarkers in Biopsy Defined Early Nephropathy in Types 1 and 2 Diabetes

活检中的尿液生物标志物定义了 1 型和 2 型糖尿病的早期肾病

基本信息

批准号：
8114113
负责人：
S. Michael Mauer
金额：
$ 42.12万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114113
关键词：
Affect Age Albumins American Indians Bioinformatics Biological Assay Biological Markers Biopsy Blood Pressure Caucasians Caucasoid Race Chronic Kidney Failure Clinical Clinical Research Complex Coronary Arteriosclerosis Data Analyses Detection Diabetes Mellitus Diabetic Nephropathy Diagnosis Early identification End stage renal failure Epidemiologic Studies Excretory function Family Glomerular Filtration Rate Individual Injury Insulin-Dependent Diabetes Mellitus Intervention Italy Kidney Kidney Diseases Kidney Failure Laboratories Lesion Lipids Mass Spectrum Analysis Measures Mediation Metabolic Methods Microalbuminuria Minnesota Molecular National Institute of Diabetes and Digestive and Kidney Diseases Natural History Non-Insulin-Dependent Diabetes Mellitus Outcome Outcome Measure Patient Selection Patients Pattern Pima Indian Plasma Population Population Research Primary Prevention Process Proteinuria Proteomics Recording of previous events Research Residual state Retinal Diseases Risk Sampling Serum Severities Smoking History Staging Structure Surveys Testing Time Universities Urine Validation cohort design diabetic diabetic patient follow-up forest functional outcomes indexing inflammatory marker metabolomics public health relevance sex small molecule type I diabetic urinary

项目摘要

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN), causing 46% of all chronic kidney disease (CKD), develops slowly and there may be severe structural damage before DN is clinically apparent. 85% of DN occurs in type 2 (T2DM) diabetes. DN risk is extraordinarily high among T2DM American Indians. In Caucasian T2DM, more complex patterns of renal injury affect clinical outcomes and confuse clinical categorizations. Together, this consortium [Universities of Minnesota (U of MN) and Padova, Italy, and the Phoenix Epidemiology and Clinical Research Branch of NIDDK] have performed most of the research kidney biopsies in T1DM and T2DM in the world. The large Pima Indian T2DM cohort, followed longitudinally for decades, has stored samples through the entire natural history of DN. A major advantage is our ability to study biomarkers of early DN structural changes prior to detectability of functional abnormalities. Also, since microalbuminuria (MA) is associated with only a 35-45% risk of progression to proteinuria (P), we will search for predictors of this progression. Finally, in the non-biopsy Pima cohort, we can examine predictors of progression rates from MA to P to ESRD. Our aims are to: (1) develop a DN risk index (DNRI) from albumin excretion rate and other variables (e.g., duration, glycemia, blood pressure, lipid levels, etc.) for Tl DM and T2DM patients (pts), (2) determine whether urine proteomic and/or metabolomic patterns predict the underlying renal structure or changes in structure or clinical progression, (3) determine the changes in urinary proteomic and/or metabolomic patterns as DN progresses from early DN to advanced CKD. Cohorts include>500 NA T1DM pts, with baseline and 5-yr biopsies and baseline and interval clinical and renal functional measures. T2DM biopsy populations include >200 Pima and >130 Northern Italian pts. In addition there are >2000 Pima pts without renal biopsies. We will initially use non-targeted proteomic and metabolomic methods on urine samples of selected pt subsets to derive more targeted assays for broader surveys of these cohorts. Studies will be done in world class mass spectroscopy facilities at the U of MN. Data analysis involves repeated measures (Wake Forest U) and Bioinformatics (Dartmouth) statistical expertise. Although focused on biomarker discovery, capabilities for negotiating validation regulatory processes are available at the U/MN. PUBLIC HEALTH RELEVANCE: Diabetic nephropathy (DN) is the leading cause of kidney failure. Early identification of patients at risk could allow for patient selection for more aggressive diabetes intervention and better design of primary prevention studies. Since DN, like coronary artery disease, may be far advanced before becoming clinically detectable, we will focus heavily on research populations we have studied using kidney biopsies in order to develop urinary tests for early DN using sophisticated molecular detection methods.

描述（由申请人提供）：糖尿病性肾病（DN）导致所有慢性肾脏疾病（CKD）的46％发育缓慢，并且在DN在临床上可能存在严重的结构损害。 85％的DN发生在2型（T2DM）糖尿病中。在T2DM美国印第安人中，DN风险非常高。在高加索T2DM中，肾脏损伤的更复杂模式会影响临床结果并混淆临床分类。这个联盟[明尼苏达州的大学（MN的U）和意大利的Padova，以及NIDDK的凤凰流行病学和临床研究分支]在世界上进行了T1DM和T2DM的大多数研究肾脏活检。数十年来，大型PIMA印度T2DM队列纵向延续了数十年，它在整个DN的自然历史中都存储了样品。一个主要优点是我们在功能异常检测性之前研究早期DN结构变化的生物标志物的能力。同样，由于微量白蛋白尿（MA）仅与35-45％的蛋白尿风险相关（P），因此我们将搜索该进展的预测指标。最后，在非生物检查PIMA队列中，我们可以检查从MA到P到ESRD的进展速率的预测指标。我们的目的是：（1）从白蛋白排泄率和其他变量（例如，持续时间，糖症，血压，脂质水平等）中开发出DN风险指数（DNRI），用于TL DM和T2DM患者（PTS）（PTS），（PTS），（2）确定尿液蛋白质蛋白质蛋白质的结构或临床的结构是否不足或临床上的变化，或者是临床上的变化或变化。随着DN从早期DN到晚期CKD的发展，确定尿蛋白质组学和/或代谢组模式的变化。队列包括> 500 Na T1DM PT，具有基线和5年活检以及基线以及间隔临床和肾功能测量。 T2DM活检人群包括> 200个PIMA和> 130北部意大利PT。此外，还有> 2000个没有肾脏活检的PIMA PT。我们最初将在选定的PT亚群的尿液样本上使用非靶向的蛋白质组学和代谢组方法来得出更多针对性的测定，以进行这些同类群体的更广泛的调查。研究将在MN U的世界一流质谱设施中进行。数据分析涉及重复测量（Wake Forest U）和生物信息学（达特茅斯）统计专业知识。尽管专注于生物标志物发现，但在U/MN上可以提供谈判验证调节过程的能力。公共卫生相关性：糖尿病性肾病（DN）是肾衰竭的主要原因。早期鉴定处于危险的患者可以使患者选择更具侵略性的糖尿病干预和更好的初级预防研究设计。由于DN（例如冠状动脉疾病）可能在临床检测到临床上可能已经进展得多，因此我们将重点关注我们使用肾脏活检研究的研究人群，以便使用复杂的分子检测方法为早期DN开发尿测试。