Kidney Tubular Functions in Type 1 Diabetes

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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.