Novel serum and urinary biomarkers of diabetic kidney disease

描述（由申请人提供）：2型糖尿病是全球主要的公共卫生问题。2型糖尿病患者的进行性慢性肾脏病（CKD）与显著的发病率和死亡率相关。有几种方法可用于早期检测糖尿病患者的CKD。我们这项提议的主要目标是开发新的尿液生物标志物，以更好地预测糖尿病患者的进展性CKD。我们认为有比白蛋白尿更好的标记物来预测糖尿病患者的CKD。这些包括反映肾小管间质损伤、炎症和纤维化以及氧化应激的生物标志物。我们已经确定了11个有希望的血清和尿液生物标志物，反映了糖尿病肾病中这些不同的损伤途径。雅阁研究表明，在3. 5年的时间内，强化血糖控制与标准血糖控制相比，降低了两个血糖治疗组之间的白蛋白尿发生率，但未降低CKD或终末期肾病的发生率（2. 1% vs. 2. 2%）。这些发现需要解释，只是强调了预测2型糖尿病中发生和进行性CKD的必要性。最终目标是确定糖尿病肾病的更好替代物或治疗靶点。因此，我们的具体目标是：具体目标1：确定新的生物标志物预测事件和进展性糖尿病肾病。假设1a：在雅阁中，通过基线样本测量肾小管间质性肾损伤和其他肾脏疾病进展途径的新生物标志物将预测糖尿病肾病的发生。假设1b：生物标志物从基线到基线的变化将预测糖尿病肾病（ESRD）快速进展的患者假设1c：结合肾小管间质肾损伤新生物标志物的综合模型将比单独的人口统计学、临床和实验室变量更好地预测事件和进展性DKD。使用在具体目标#1下开发的前5个生物标志物的面板，了解强化血糖控制降低微血管结局的途径（蛋白尿和视网膜病变），但在雅阁试验中并没有减少CKD或ESRD事件的确定性事件。假设2a：强化血糖控制将对24个月时最能预测进展性糖尿病肾病的血清和尿液生物标志物产生有益影响，这可能表明治疗持续时间不足以证明两组之间CKD和ESRD的差异。

DESCRIPTION (provided by applicant): Type 2 diabetes is a major public health problem worldwide. Progressive chronic kidney disease (CKD) in type 2 diabetes is associated with significant morbidity and mortality. There are few approaches available for the early detection of CKD in diabetes. Our primary goal of this proposal is to develop novel urine biomarkers to better predict progressive CKD in diabetics. We propose that there are better markers to predict CKD in diabetics than albuminuria. These include biomarkers that reflect tubulointerstitial injury, inflammation and fibrosis, and oxidative stress. We have identified 11 promising serum and urinary biomarkers that reflect these different pathways of injury in diabetic kidney disease. The ACCORD study demonstrated that intensive glycemic control vs. standard glycemic control over a period of 3.5 years reduced the incidence of albuminuria but did not reduce the incidence of incident CKD nor end-stage renal disease (2.1% vs. 2.2%) between the two glycemia-treatment arms. These findings require explanations and only underscore the necessity to predict incident and progressive CKD in type 2 diabetes. The ultimate goal is to identify better surrogates or therapeutic targets for kidney disease in diabetics. Thus, our specific aims for this proposal are the following: Specific Aim 1: To identify novel biomarkers predictive of incident and progressive diabetic kidney disease. Hypothesis 1a: Novel biomarkers of tubulointerstitial kidney injury and other pathways of kidney disease progression measured on baseline samples will predict incident diabetic kidney disease in ACCORD. Hypothesis 1b: Changes in biomarkers from baseline to will predict those with fast progression of diabetic kidney disease (ESRD) Hypothesis 1c: A comprehensive model incorporating novel biomarkers of tubulointerstitial kidney damage will predict incident and progressive DKD better than demographic, clinical and laboratory variables alone Specific Aim 2: Using the panel of the top 5 biomarkers developed under Specific Aim #1, to understand the pathways by which intensive glycemic control reduced microvascular outcomes (albuminuria and retinopathy) but did not reduce the definitive events of incident CKD or ESRD in the ACCORD trial. Hypothesis 2a: Intensive glycemic control will have a beneficial effect on the serum and urine biomarkers that are most predictive of progressive diabetic kidney disease at 24 months, potentially indicating that the duration of therapy was not sufficiently long to witness differences in CKD and ESRD between the two groups.