Kidney Tubular Functions in Type 1 Diabetes

摘要 慢性肾脏病是1型糖尿病(T1D)常见而严重的并发症。从历史上看，糖尿病 根据经典的病理特征，已被视为一种原发性肾小球疾病。然而， 糖尿病还通过增加对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 阻止葡萄糖进入近端肾小管细胞的葡萄糖共转运蛋白-2抑制剂是最多的 有望找到延缓2型糖尿病肾病进展的新疗法。 糖尿病肾小管损伤的强制机制尚未完全移植到人类身上 疾病，阻碍了监测和治疗的新战略。这项提议的目标是推进 了解人类肾小管功能的演变、决定因素和临床后果 患有I型糖尿病(T1D)。我们将为两个里程碑添加新的肾小管功能和损伤测量 横跨肾脏疾病病程的T1D临床试验。通过这些测量，我们将第一次 时间表征T1D中肾小管功能随时间的自然历史，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，主要病理特征的改变，以及肾小球功能的下降。这个 构建T1D肾小管功能的详细自然历史将为 未来发展新的干预措施，以改善预防、监测和治疗。

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.