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：
10668298
负责人：
BRYAN R KESTENBAUM
金额：
$ 65.64万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668298
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 Continuous Glucose Monitor 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 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 Factors Sampling Sclerosis Severities Sodium Stress Structure Testing Thick Time Translating Tubular formation Urine Work absorption biomarker development cohort disorder subtype glomerular basement membrane glomerular filtration glomerular function high risk human disease improved inhibitor interstitial kidney biopsy lysosomal proteins modifiable risk new therapeutic target novel podocyte precision medicine premature prevent progression risk 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.

抽象的慢性肾脏病是 1 型糖尿病 (T1D) 的常见且严重的并发症。历史上，糖尿病根据典型的病理特征，被视为原发性肾小球肾病。然而，糖尿病还通过增加肾小管上皮细胞及其微环境的损伤来促进肾小管上皮细胞及其微环境的损伤。葡萄糖重吸收的作用以及直接刺激促炎和促纤维化途径。钠葡萄糖协同转运蛋白 2 抑制剂可阻止葡萄糖进入近端肾小管细胞，是最有效的抑制剂。有望减缓 2 型糖尿病肾病进展的新疗法。糖尿病肾小管损伤的令人信服的机制尚未完全转化为人类疾病，阻碍新的监测和治疗策略。该提案的目标是推进了解人体肾小管功能的演变、决定因素和临床后果患有 I 型糖尿病 (T1D)。我们将为两个地标添加管状功能和损伤的新颖测量 T1D 跨越肾脏疾病病程的临床试验。通过这些测量，我们将首先时间表征 T1D 中肾小管功能随时间变化的自然历史，识别潜在的危险因素肾小管功能丧失，并测试肾小管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下降。这构建 T1D 肾小管功能的详细自然史将为以下研究奠定必要的基础：未来制定新的干预措施以改善预防、监测和治疗。