Biomarkers of Early Renal Functional Decline in Type 2 Diabetes

描述（由申请人提供）：尽管在过去20年中治疗有所改善，但糖尿病肾病是终末期肾病的主要原因。确定一种可以预测哪些患者将失去肾功能的生物标志物将使这些患者得到更好的治疗。可用的标志物如尿白蛋白既不敏感也不特异。我们确定尿结合珠蛋白浓度作为候选生物标志物，可以预测尚未显示疾病体征的糖尿病患者肾功能下降的发展。我们建议将结合珠蛋白作为预测肾功能下降的生物标志物。本提案的具体目的是：1）确定尿结合珠蛋白和其他候选生物标志物预测早期肾功能的能力 肾功能正常且无大量白蛋白尿的2型糖尿病患者的发病率下降，2）评估连续收集的尿液中测量的触珠蛋白和其他候选生物标志物预测ERFD的能力，以及3）确定尿触珠蛋白和其他候选生物标志物的能力预测现有糖尿病肾病的进展。我们将使用前瞻性采集的尿液样本，作为2型糖尿病VA血糖控制和并发症试验（VADT）的一部分。VADT包括1，700名随机接受强化或常规治疗的受试者。随访至少5年。入组时糖尿病的平均病程为11.1年。我们将使用该人群的一个子集，包括987例患者。我们还将使用前瞻性收集的样本来评估生物标志物预测现有肾脏疾病进展的能力。我们建议使用多反应监测（基于稳定同位素标准的丰度质谱分析）来测量尿液结合珠蛋白浓度以及一组额外的候选生物标志物的浓度。我们将测量从VADT队列和前瞻性采集的样本中连续采集的样本的浓度。这些研究将确定尿触珠蛋白预测无（目的1和2）和有（目的3）现有肾脏疾病受试者肾功能下降未来发展的能力。

DESCRIPTION (provided by applicant): Diabetic nephropathy is the leading cause of end stage renal disease in spite of improvements in therapy over the last 20 years. The identification of a biomarker that can predict which patients will lose renal function would enable better treatment for these patients. Available markers such as urinary albumin are neither sensitive nor specific. We identified urinary haptoglobin concentration as a candidate biomarker which can predict development of renal functional decline among patients with diabetes who do not yet show signs of disease. We propose to characterize the role of haptoglobin as a biomarker for the prediction of renal functional decline. The specific aims of this proposal are: 1) Determine the ability of urinary haptoglobin and other candidate biomarkers to predict early renal functional decline in patients with type 2 diabetes who have normal renal function and do not have macroalbuminuria, 2) Assess the ability of haptoglobin and other candidate biomarkers measured in serial collections of urine to predict ERFD and 3) Determine the ability of urinary haptoglobin and other candidate biomarkers to predict progression of existing diabetic kidney disease. We will use urine samples that were collected prospectively as part of the VA Glycemic Control and Complications in Diabetes Mellitus Type 2 trial (VADT). The VADT includes 1,700 subjects randomized to either intensive or conventional therapy. Follow up was at least 5 years. Mean duration of diabetes at enrollment was 11.1 years. We will use a subset of this population that includes 987 patients. We will also use prospectively collected samples to assess the ability of biomarkers to predict progression of existing kidney disease. We propose to use multiple reaction monitoring (a mass spectrometric analysis of abundance based on a stable isotopic standard) to measure urine haptoglobin concentrations as well as the concentration of a panel of additional candidate biomarkers. We will measure concentrations in serially collected samples from the VADT cohort and from the prospectively collected samples. These studies will define the ability of urine haptoglobin to predict the future development of renal functional decline in subjects without (aims 1 and 2) and with (aim 3) existing renal disease.