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)占慢性肾脏病(CKD)的46%，发展缓慢，在临床表现为糖尿病肾病前可能存在严重的结构损害。85%的糖尿病肾病发生在2型糖尿病中。糖尿病肾病的风险在T2 DM美国印第安人中非常高。在高加索人T2 DM中，更复杂的肾脏损害模式会影响临床结果，并混淆临床分类。这个联盟[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会]一起进行了世界上大多数T1 DM和T2 DM的研究性肾脏活检。纵向跟踪了数十年的大型皮马印第安人T2 DM队列，在整个糖尿病肾病的自然历史中存储了样本。一个主要的优势是我们有能力在检测到功能异常之前研究早期糖尿病肾病结构变化的生物标记物。此外，由于微量白蛋白尿(MA)与进展为蛋白尿(P)的风险只有35%-45%相关，我们将寻找这种进展的预测因素。最后，在非活体PIMA队列中，我们可以检验从MA到P再到ESRD进展率的预测因素。我们的目标是：(1)根据白蛋白排泄率和其他变量(如病程、血糖、血压、血脂水平等)建立糖尿病肾病风险指数(DNRI)。对于T1 DM和T2 DM患者(PTS)，(2)确定尿蛋白组学和/或代谢组学模式是否预测潜在的肾脏结构或结构变化或临床进展，(3)确定尿蛋白组学和/或代谢组学模式在糖尿病肾病从早期糖尿病进展到晚期CKD过程中的变化。队列包括500例NAT1 DM患者，包括基线和5年活组织检查以及基线和间隔临床和肾功能测量。T2 DM活组织检查人群包括200例PIMA和130例意大利北部病例。此外，还有2000例PIMA患者没有进行肾活检。我们将首先对选定的PT亚群的尿样使用非靶向蛋白质组学和代谢组学方法，以得出更有针对性的分析方法，以便对这些队列进行更广泛的调查。研究将在明尼苏达大学世界级的质谱学设施中进行。数据分析涉及重复测量(维克森林大学)和生物信息学(达特茅斯)的统计专业知识。虽然专注于生物标记物的发现，但U/MN提供了协商验证管理过程的能力。 公共卫生相关性：糖尿病肾病是导致肾衰竭的主要原因。及早识别有风险的患者可以选择患者进行更积极的糖尿病干预，并更好地设计初级预防研究。由于像冠状动脉疾病一样，糖尿病肾病在临床可检测到之前可能是非常严重的，我们将主要关注我们通过肾脏活检研究的研究人群，以便利用复杂的分子检测方法开发早期糖尿病肾病的尿液检测方法。

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.