Integrated Cardio-Renal Risk Prediction Models in Type 1 Diabetes

描述（由申请人提供）：该申请涉及广泛的挑战领域（03）生物标志物的发现和验证，该申请涉及的具体挑战主题是：03- dk -101发现NIDDK感兴趣的疾病的疾病风险、进展或治疗反应的生物标志物。挑战：尽管在治疗方面取得了巨大进展，但1型糖尿病患者仍然比一般人群早15年死亡，发病率过高，医疗费用高出10倍以上。冠状动脉疾病和糖尿病肾病的风险仍然大大增加，导致这些患者80%的死亡。糖尿病肾病和冠状动脉疾病相互交织，提示有共同的途径，但目前的风险预测是不充分的。研究理由：近25%的T1D患者发展为终末期肾脏疾病。传统的理论认为，导致糖尿病肾病的一系列事件从微量蛋白尿开始，发展到明显的蛋白尿和最终的终末期肾脏疾病。ACE/ARB治疗的初级预防通常在发现持续性微量白蛋白尿时开始。然而，最近的前瞻性研究利用血清胱抑素C对肾功能的一系列测量改变了这一模式，表明肾小球滤过率的下降可能在没有微量白蛋白尿时开始，或者在微量白蛋白尿缓解后继续下降。到40多岁时，超过70%的男性和50%的1型糖尿病患者会出现冠状动脉钙化（CAC）——这是一种显著的动脉粥样硬化斑块负担的标志。心血管疾病在肾病患者中尤为普遍，但大多数心脏事件发生在白蛋白排泄率正常的患者中。越来越多的证据表明，糖尿病肾病和CAC是平行的，而不是顺序的，1型糖尿病的并发症，共享一些重要的预测因素。需要准确预测个体的整体心肾风险来指导治疗选择。因此，人们认识到需要通过发现额外的生物标志物或应用更好的方法来区分疾病状态，从而更好地划分风险。我们的方法：我们建议使用652名成人1型糖尿病患者的生物库，这些患者已经通过1型糖尿病冠状动脉钙化研究（CACTI, R01 HL61753, 1999- 2009）进行了彻底的基因分型和糖尿病肾病和冠状动脉疾病的前瞻性随访，以开发和验证1型糖尿病心肾并发症的综合生物标志物预测模型。我们的研究目的是在具有良好特征的CACTI队列中调查1)早期进行性肾功能下降的生物标志物，2)冠状动脉钙的存在和进展，以及3)肾脏和心血管联合疾病负担的发展。肾脏疾病和冠状动脉疾病（CAD）是成人1型糖尿病患者死亡的主要原因，但传统的肾脏疾病筛查试验（尿白蛋白和血清肌酐）是不充分的，传统的CAD危险因素（血脂异常、高血压、吸烟、肥胖）不能完全解释与1型糖尿病相关的疾病负担增加。肾脏和心血管并发症交织在一起，表明有共同的途径。1型糖尿病患者全身性炎症增加，尿酸、维生素D和骨代谢标志物等炎症介质被认为在肾脏和心血管疾病中都起作用。因此，发现和验证成人1型糖尿病患者心肾疾病的新生物标志物具有重要的公共卫生意义。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation, and the specific Challenge Topic that this application addresses is: 03-DK-101 Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest to NIDDK. The Challenge: Despite tremendous progress in treatment, patients with type 1 diabetes continue to die 15 years earlier, experience excess morbidity and have medical costs over 10 times higher than the general population. The risk of coronary artery disease and diabetic nephropathy is still greatly increased and responsible for 80% of deaths in these patients. Diabetic nephropathy and coronary artery disease are intertwined, suggesting common pathways, and yet current risk prediction is inadequate. Study Rationale: Nearly 25% of T1D patients develop end-stage renal disease. The conventional theory is that the sequence of events leading to diabetic nephropathy begins from microalbuminuria, progressing to overt proteinuria and eventual end-stage renal disease. Primary prevention with ACE/ARB treatment usually begins when persistent microalbuminuria is found. However, recent prospective studies using serial measurements of kidney function estimated from serum cystatin C have changed this paradigm by demonstrating that decline in glomerular filtration may begin in the absence of microalbuminuria or continue despite remission of microalbuminuria. By their mid 40's, over 70% of men and 50% of women with type 1 diabetes develop coronary artery calcification (CAC) - a marker of significant atherosclerotic plaque burden. Cardiovascular disease is particularly prevalent among patients with renal disease, but most cardiac events occur in patients with normal albumin excretion rates. Evidence has accumulated that diabetic nephropathy and CAC are parallel, rather than sequential, complications of type 1 diabetes, sharing a number of important predictors. Accurate prediction of the individual's global cardio-renal risk is needed to guide treatment choices. As a result, there is a recognized need for better risk partitioning, either from the discovery of additional biomarkers or the application of superior methods for discrimination of disease states. Our Approach: We are proposing to use the biobank of 652 adults with type 1 diabetes who have been thoroughly genotyped and prospectively followed for development of diabetic nephropathy and coronary artery disease by the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, R01 HL61753, 1999- 2009) to develop and validate integrated biomarker prediction models for cardio-renal complications in type 1 diabetes. Our study aims are the investigation of biomarkers within the well-characterized CACTI cohort for 1) early progressive renal function decline, 2) the presence and progression of coronary artery calcium, and the 3) development of combined renal and cardiovascular disease burden. Renal disease and coronary artery disease (CAD) are the leading causes of death among adults with type 1 diabetes, but traditional screening tests (urinary albumin and serum creatinine) for renal disease are inadequate, and traditional CAD risk factors (dyslipidemia, hypertension, smoking, obesity) do not fully explain the increased burden of disease associated with type 1 diabetes. Renal and cardiovascular complications are intertwined, suggesting shared pathways. Increased systemic inflammation is present in type 1 diabetes and inflammatory mediators such as uric acid, vitamin D and bone metabolism markers have been suggested to play a role in both renal and cardiovascular diseases. As a result, it is of critical public health importance to discover and validate new biomarkers for cardio-renal disease among adults with type 1 diabetes. PUBLIC HEALTH RELEVANCE: Renal disease and coronary artery disease (CAD) are the leading causes of death among adults with type 1 diabetes, but traditional screening tests (urinary albumin and serum creatinine) for renal disease are inadequate, and traditional CAD risk factors (dyslipidemia, hypertension, smoking, obesity) do not fully explain the increased burden of disease associated with type 1 diabetes. Renal and cardiovascular complications are intertwined, suggesting shared pathways. Increased systemic inflammation is present in type 1 diabetes and inflammatory mediators such as uric acid, vitamin D and bone metabolism markers have been suggested to play a role in both renal and cardiovascular diseases. As a result, it is of critical public health importance to discover and validate new biomarkers for cardio-renal disease among adults with type 1 diabetes.