Integrated Cardio-Renal Risk Prediction Models in Type 1 Diabetes

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）生物标志物发现和验证，本申请涉及的特定挑战主题为：03-DK-101发现NIDDK关注疾病的疾病风险、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型糖尿病患者继续提前15年死亡，发病率过高，医疗费用比一般人群高出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，并导致这些患者80%的死亡。糖尿病肾病和冠状动脉疾病交织在一起，表明共同的途径，但目前的风险预测是不够的。研究依据：近25%的T1 D患者发展为终末期肾病。传统的理论认为，导致糖尿病肾病的一系列事件从微量白蛋白尿开始，发展为明显的蛋白尿，最终发展为终末期肾病。ACE/ARB治疗的一级预防通常在发现持续性微量白蛋白尿时开始，然而，最近的前瞻性研究使用血清胱抑素C评估肾功能的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无微量白蛋白尿时开始开始，或尽管微量白蛋白尿缓解仍持续。到40多岁时，超过70%的1型糖尿病男性和50%的1型糖尿病女性会发生冠状动脉钙化（CAC）-一种显著的动脉粥样硬化斑块负荷的标志物。心血管疾病在肾脏疾病患者中尤其普遍，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1型糖尿病并发症的平行发生，而不是相继发生，它们共享许多重要的预测因子。需要准确预测个体的总体心肾风险，以指导治疗选择。因此，人们认识到需要更好的风险划分，无论是从发现额外的生物标志物还是应用上级方法来区分疾病状态。我们的方法：我们建议使用652名1型糖尿病成人患者的生物样本库，这些患者已通过1型糖尿病冠状动脉钙化研究进行了彻底的基因分型，并前瞻性随访了糖尿病肾病和冠状动脉疾病的发生情况（CACTI，R 01 HL 61753，1999- 2009）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充分表征的CACTI队列中研究生物标志物，以1）早期进行性肾功能下降，2）冠状动脉钙的存在和进展，以及3）合并肾脏和心血管疾病负担的发展。肾脏疾病和冠状动脉疾病（CAD）是1型糖尿病成人死亡的主要原因，但传统的肾脏疾病筛查试验（尿白蛋白和血清肌酐）是不够的，传统的CAD风险因素（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型糖尿病中存在全身炎症增加，并且已经表明炎症介质如尿酸、维生素D和骨代谢标志物在肾脏和心血管疾病中起作用。因此，发现和验证1型糖尿病成人心肾疾病的新生物标志物具有关键的公共卫生重要性。 公共卫生相关性：肾脏疾病和冠状动脉疾病（CAD）是1型糖尿病成人死亡的主要原因，但传统的肾脏疾病筛查试验（尿白蛋白和血清肌酐）是不够的，传统的CAD风险因素（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型糖尿病中存在全身炎症增加，并且已经表明炎症介质如尿酸、维生素D和骨代谢标志物在肾脏和心血管疾病中起作用。因此，发现和验证1型糖尿病成人心肾疾病的新生物标志物具有关键的公共卫生重要性。

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.