Epidemiology, Pathophysiology and Treatment of Diabetic Nephropathy

糖尿病肾病的流行病学、病理生理学和治疗

基本信息

批准号：
9553270
负责人：
ROBERT G NELSON
金额：
$ 66.55万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9553270
关键词：
Advanced Glycosylation End Products American Biochemical Pathway Biological Markers Biological Preservation Biopsy Bradykinin Calibration Caucasians Clinical Communities Conduct Clinical Trials Data Developing Countries Development Diabetes Mellitus Diabetic Nephropathy Discrimination Disease Management Disease Progression Down-Regulation End stage renal failure Epidemiology Equation Functional disorder Future Gene Expression Genetic Glomerular Filtration Rate Health Healthcare Systems Human Incidence Individual Insulin-Dependent Diabetes Mellitus Iothalamate Kidney Kidney Diseases Kidney Failure Kinins Lesion Link Lymphocyte MDM2 gene Measures Medicine Meta-Analysis Non-Insulin-Dependent Diabetes Mellitus Outcome Outcomes Research Paper Participant Patients Pattern Peptides Persons Pima Indian Plasma Population Predictive Value Prevalence Proteins Publishing Renal Plasma Flow Renal function Reporting Research Risk Risk Factors Role Structure Systems Biology Therapeutic Agents Tissues Work clinically relevant cohort community based participatory research diabetes management disorder risk hemodynamics high risk loss of function metabolomics mortality neutrophil outcome forecast prevent response trend urinary

项目摘要

This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic kidney disease, except for the genetics of diabetic kidney disease, is now reported under this single project. In the last year, we demonstrated that kidney failure risk equations developed in a Canadian population showed high discrimination when validated in 31 multinational cohorts that included 721,357 individuals. In non-North American cohorts, a calibration factor was necessary. This equation can be incorporated into health care systems to assist clinicians in managing their patients by providing an estimate of their level of risk for kidney disease progression. We published several papers with the CKD Prognosis Consortium in the past year, including one which examined the predictive value of current estimated GFR versus past estimated GFR for future risk of end-stage renal disease or mortality. We found that both past and current estimated GFR were useful predictors that contributed substantially to the risk of these major adverse health outcomes. These papers were meta-analyses of multiple cohorts worldwide, and each study included over 1 million participants. We reported findings from community-based participatory research in which patient perspectives on the germane research questions were incorporated into the studies. We described how this approach to organizing health outcomes research was beneficial in acquiring community buy-in to management of diabetic kidney disease. This work sets the stage for much larger diabetic kidney disease management efforts in remote high-risk communities. Our systems biology efforts continue to yield interesting findings. By integrating publicly available human protein-to-protein interaction networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy, we identified an important functional role for MDM2 in the development of diabetic kidney disease. Significant downregulation of MDM2 gene expression was found in both the glomerular and tubulointerstitial compartments of kidney biopsy tissue from two independent cohorts, including the Pima Indians. We ultimately linked MDM2 to a reduction in 2 key metabolite biomarkers. In biomarker work, we reported that several advanced glycation end-products in Pima Indians with type 2 diabetes and early diabetic kidney disease are associated with specific lesions of diabetic kidney disease and with the loss of renal function that occurs in the presence of those lesions. We also found that a routine WBC count and differential provide clinically relevant information about diabetic kidney disease risk in Pima Indians and Caucasians with type 2 diabetes. Lymphocytes and neutrophils, which together represent >90% of WBCs, had the strongest associations with structural lesions of diabetic kidney disease in the Pimas and with renal function loss in French Caucasians from the SURDIAGENE study. Lastly, we found that in a type 1 diabetes cohort, higher plasma bradykinin and related peptide concentrations measured before the clinical onset of diabetic kidney disease were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic kidney disease.

该项目部分代表了先前报道为项目编号Z01 DK69037，Z01 DK069097和Z01 DK069000的工作的工作。它还报告了先前报告的工作编号DK069036-23，DK069063-17和DK069100-06的工作的延续。除糖尿病肾病的遗传学外，与糖尿病肾脏疾病有关的所有工作现已在这个单一项目下报道。在去年，我们证明了加拿大人口中开发的肾衰竭风险方程式在31个跨国公司中得到验证，其中包括721,357个人。在非北美队列中，需要校准因子。可以将该方程式纳入医疗保健系统中，以帮助临床医生通过提供肾脏疾病进展的风险水平来帮助管理患者。在过去的一年中，我们发表了几篇有关CKD预后联盟的论文，其中包括一篇研究了当前估计的GFR的预测价值与过去估计的GFR的预测价值，以实现终末期肾脏疾病或死亡率的未来风险。我们发现，过去和当前估计的GFR都是有用的预测因子，这些预测因素极大地促进了这些主要不良健康结果的风险。这些论文是全球多个同类群体的荟萃分析，每项研究包括超过100万参与者。我们报告了基于社区的参与性研究的发现，其中患者对Demane Research问题的看法已纳入研究中。我们描述了这种组织健康结果研究的方法如何有益于获得社区的糖尿病肾脏疾病管理。这项工作为在偏远高危社区中更大的糖尿病肾脏疾病管理工作奠定了基础。我们的系统生物学工作继续产生有趣的发现。通过使用来自糖尿病肾病患者的代谢组数据将公开可用的人蛋白与蛋白质相互作用网络与全球代谢网络相结合，我们确定了MDM2在糖尿病肾脏疾病发展中的重要功能作用。在包括PIMA印第安人在内的两个独立队列的肾脏活检组织的肾小球和肾小管间质室中发现了MDM2基因表达的显着下调。我们最终将MDM2与2个关键代谢物生物标志物的减少联系起来。在生物标志物工作中，我们报道说，患有2型糖尿病和早期糖尿病肾脏疾病的PIMA印第安人的几种晚期糖基化终产物与糖尿病肾脏疾病的特定病变以及在存在这些病变的情况下发生的肾功能丧失有关。我们还发现，常规的WBC计数和差异提供了有关2型糖尿病的PIMA印第安人和高加索人的临床相关信息。淋巴细胞和嗜中性粒细胞共同占WBC> 90％的淋巴细胞，与Surdiagene研究中法国高加索人的糖尿病肾脏疾病结构性病变和肾功能丧失有关。最后，我们发现，在1型糖尿病队列中，较高的血浆bradyinin和相关的肽浓度在糖尿病肾脏疾病的临床发作之前测量的与肾小球结构的保留有关，这表明这些Kinin浓度的升高可能反映了对早期肾脏结构变化的适应性反应。