Kidney Tubular Functions in Type 1 Diabetes

1 型糖尿病的肾小管功能

基本信息

批准号：
10264925
负责人：
BRYAN R KESTENBAUM
金额：
$ 64.52万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264925
关键词：
Acidosis Albumins Albuminuria Arginine Atrophic Basement membrane Biological Assay Biopsy Blood capillaries Cardiovascular Diseases Cathepsins Cells Cessation of life Characteristics Chronic Kidney Failure Citrulline Clinical Clinical Trials Complication Data Development Diabetes Mellitus Diabetic Nephropathy Diagnosis Disease Disease Progression Distal End stage renal failure Epidermal Growth Factor Epithelial Cells Erythropoiesis Evolution Excretory function Exposure to Fibrosis Future Glomerular Filtration Rate Glucose Glycosylated hemoglobin A Goals Gold Impairment Inflammatory Injury Injury to Kidney Insulin-Dependent Diabetes Mellitus Intervention Iohexol Kidney Kidney Diseases Kidney Failure Laboratories Lesion Measurement Measures Metabolic Metabolism Methods Minerals Monitor Natural History Non-Insulin-Dependent Diabetes Mellitus Parents Pathogenesis Pathologic Pathology Pathway interactions Pattern Persons Plasma Prevention Proteomics Renal function Renal tubule structure Renin-Angiotensin System Risk Risk Factors Sampling Sclerosis Severities Sodium Stress Structure Testing Thick Time Translating Tubular formation Urine Work base biomarker development cohort disorder subtype glomerular basement membrane glomerular filtration glomerular function glucose monitor high risk human disease improved inhibitor/antagonist interstitial kidney biopsy lysosomal proteins modifiable risk new therapeutic target novel podocyte precision medicine premature prevent rat KIM-1 protein renal damage research clinical testing solute symporter urinary

项目摘要

ABSTRACT Chronic kidney disease is a common and serious complication of type 1 diabetes (T1D). Historically, diabetes has been viewed as a primary glomerular kidney disorder based on classic pathological features. However, diabetes also promotes injury to kidney tubular epithelial cells and their microenvironment through increased work of glucose reabsorption and direct stimulation of pro-inflammatory and pro-fibrotic pathways. Sodium glucose co-transporter-2 inhibitors, which block glucose entry into proximal tubular cells, are the most promising new treatment for slowing the progression of kidney disease in type 2 diabetes. Compelling mechanisms of kidney tubular injury in diabetes have been incompletely translated into human disease, impeding new strategies for monitoring and treatment. The goal of this proposal is to advance understanding of the evolution, determinants, and clinical consequences of kidney tubular functions in persons with type I diabetes (T1D). We will add novel measurements of tubular functions and damage to two landmark clinical trials of T1D spanning the course of kidney disease. Through these measurements, we will for the first time characterize the natural history of tubular functions over time in T1D, identify potential risk factors for the loss of tubular functions, and test whether measures of tubular functions and damage are associated with metabolic complications, changes in key pathologic features, and a decline in glomerular kidney functions. The construction of a detailed natural history of kidney tubular functions in T1D will lay needed groundwork for the future development of new interventions to improve prevention, monitoring, and treatment.

抽象的慢性肾脏疾病是1型糖尿病（T1D）的常见且严重的并发症。从历史上看，糖尿病基于经典病理特征，被视为一种主要的肾小球肾脏疾病。然而，糖尿病还通过增加而促进肾小管上皮细胞及其微环境的损伤葡萄糖重吸收和直接刺激促炎和促纤维化途径的工作。钠葡萄糖共转运蛋白-2抑制剂阻断葡萄糖进入近端管状细胞，是最多的有望在2型糖尿病中减缓肾脏疾病进展的新治疗方法。糖尿病中肾小管损伤的引人入胜的机制未完全翻译成人类疾病，阻碍监测和治疗的新策略。该提议的目的是进步了解肾小管功能的进化，决定因素和临床后果使用I型糖尿病（T1D）。我们将添加对管状功能的新颖测量和两个地标的损坏 T1D的临床试验跨越了肾脏疾病。通过这些测量，我们将进行第一个时间是T1D中随时间随着时间的时间的自然历史的特征，确定了潜在的风险因素管状功能的丧失，并测试管状功能和损伤的测量是否与代谢并发症，关键病理特征的变化以及肾小球肾功能的下降。这 T1D中肾小管功能的详细自然历史的构建将为该肾小管功能奠定必需的基础。未来开发新的干预措施，以改善预防，监测和治疗。