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型糖尿病的进行性慢性肾病（CKD）与显著的发病率和死亡率相关。很少有方法可用于早期检测CKD的糖尿病。我们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行性CKD。我们认为有比蛋白尿更好的标志物来预测糖尿病患者的CKD。这些包括反映小管间质损伤、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种有希望的血清和尿液生物标志物，它们反映了糖尿病肾病中这些不同的损伤途径。ACCORD研究表明，在3.5年的时间里，强化血糖控制与标准血糖控制相比，降低了蛋白尿的发生率，但没有降低CKD和终末期肾脏疾病的发生率（2.1%对2.2%）。这些发现需要解释，只是强调了预测2型糖尿病发生和进展的CKD的必要性。最终目标是为糖尿病患者肾脏疾病找到更好的替代物或治疗靶点。因此，我们提出的具体目标如下：具体目标1：确定预测发生和进展性糖尿病肾病的新型生物标志物。假设1a：在基线样本上测量的肾小管间质性损伤和其他肾脏疾病进展途径的新生物标志物将预测ACCORD中糖尿病肾病的发生。假设1b：从基线到生物标志物的变化将预测糖尿病肾病（ESRD）的快速进展。假设1c：与单独的人口统计学、临床和实验室变量相比，结合小管间质肾损害的新型生物标志物的综合模型将更好地预测DKD的发生和进展。使用在Specific Aim #1下开发的前5个生物标志物小组，了解强化血糖控制降低微血管结局（蛋白尿和视网膜病变）的途径，但没有减少ACCORD试验中CKD或ESRD事件的最终事件。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，这可能表明治疗时间不够长，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. PUBLIC HEALTH RELEVANCE: Diabetic kidney disease is a growing public health problem with enormous impact on morbidity and mortality. The potential impact of this project is to better understand the pathophysiology of initiation of diabetic kidney disease; improve prediction of diabetic kidney disease onset and progression; and development of novel targets for therapies to reduce the burden of diabetic kidney disease. Finally, this study will help explain the reasons that intensive glycemic control did not improve definitive kidney outcomes in the ACCORD trial.