Kidney Tubular Functions in Type 1 Diabetes

1 型糖尿病的肾小管功能

• 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
• 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

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.

摘要 慢性肾脏病是1型糖尿病（T1 D）的常见和严重并发症。历史上，糖尿病 基于经典病理学特征，被认为是原发性肾小球肾病。然而，在这方面， 糖尿病还通过增加肾小管上皮细胞及其微环境的 葡萄糖重吸收的工作和直接刺激促炎和促纤维化途径。钠 葡萄糖协同转运蛋白-2抑制剂阻断葡萄糖进入近端肾小管细胞，是最常见的 2型糖尿病肾病的治疗方法 糖尿病中肾小管损伤的强制性机制尚未完全转化为人类 疾病，阻碍了新的监测和治疗战略。该提案的目的是推动 了解人肾小管功能的演变、决定因素和临床后果 1型糖尿病（T1 D）我们将增加新的测量肾小管功能和损伤的两个标志 T1 D的临床试验跨越肾脏疾病的过程。通过这些测量，我们将首次 时间表征T1 D中肾小管功能随时间的自然史，识别T1 D中肾小管功能的潜在风险因素， 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和肾小球肾功能的下降。的 构建T1 D肾小管功能的详细自然史将为研究T1 D肾小管功能奠定必要的基础。 未来开发新的干预措施，以改善预防、监测和治疗。