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

描述（由申请人提供）： 糖尿病肾病（DN）占所有慢性肾脏疾病（CKD）的46%，其发展缓慢，并且在DN临床上明显之前可能存在严重的结构损伤。85%的DN发生在2型糖尿病（T2 DM）中。DN风险在T2 DM美国印第安人中非常高。在白人T2 DM中，更复杂的肾损伤模式影响临床结局并混淆临床分类。该联盟[明尼苏达大学（明尼苏达大学）和意大利帕多瓦大学，以及NIDDK的凤凰城流行病学和临床研究分支]共同进行了世界上大部分T1 DM和T2 DM的研究肾活检。大型皮马印度T2 DM队列，纵向跟踪了几十年，已经存储了DN整个自然史的样本。一个主要的优势是我们能够在检测到功能异常之前研究早期DN结构变化的生物标志物。此外，由于微量白蛋白尿（MA）与进展为蛋白尿（P）的风险仅为35-45%相关，因此我们将寻找这种进展的预测因子。最后，在非活检Pima队列中，我们可以检查从MA到P再到ESRD的进展率的预测因素。我们的目标是：（1）从白蛋白排泄率和其他变量（例如，持续时间、血压、血脂水平等）对于T1 DM和T2 DM患者（pts），（2）确定尿蛋白质组学和/或代谢组学模式是否预测潜在的肾结构或结构变化或临床进展，（3）确定随着DN从早期DN进展到晚期CKD，尿蛋白质组学和/或代谢组学模式的变化。队列包括>500名NA T1 DM患者，具有基线和5年活检以及基线和间隔临床和肾功能测量。2型糖尿病活检人群包括>200名皮马和>130名意大利北方患者。此外，有>2000名Pima患者没有进行肾活检。我们将首先对选定患者子集的尿液样本使用非靶向蛋白质组学和代谢组学方法，以获得更有针对性的检测方法，用于这些队列的更广泛调查。研究将在明尼苏达大学的世界级质谱设施中进行。数据分析涉及重复测量（维克森林U）和生物信息学（达特茅斯）统计专业知识。虽然重点是生物标志物的发现，协商验证监管过程的能力是在U/MN可用。 糖尿病肾病（DN）是肾功能衰竭的主要原因。早期识别有风险的患者可以选择更积极的糖尿病干预和更好的一级预防研究设计。由于糖尿病肾病，如冠状动脉疾病，可能是远远先进的临床检测之前，我们将重点放在研究人群中，我们已经研究了使用肾脏活检，以发展尿液检测早期糖尿病肾病使用先进的分子检测方法。

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.