Diffusion Tensor Imaging MRI: A Novel Biomarker for Early Diabetic Nephropathy
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States. Its prevalence is increasing worldwide and will likely increase further as the epidemic of type 2 diabetes mellitus (T2DM) worsens. Although specific risk factors for progression to DN have been identified for T2DM patients as a whole, these factors do not reliably predict progression in individual patients. Currently available clinical indicators of kidney disease (e.g., elevated serum creatinine and microalbuminuria) lack the sensitivity and/or specificity to identify early-stage DN.Thus, more robust non-invasive screening tools are needed to detect early-stage DN prior to development of significant irreversible renal injury, when potential therapeutics/interventions may be most effective. Diffusion tensor imaging (DTI) is a quantitative diffusion Magnetic Resonance Imaging (MRI) technique that measures both the magnitude and directionality of water movement (fractional anisotropy, FA) to assess pathophysiologic changes. Preliminary data suggest that decreased medullary FA may be a biomarker for early DN, but additional studies are needed.The overall goals of the proposed pilot studies are to utilize DTI-MRI and a related imaging modality, IVIM, to obtain data necessary to design and implement a longitudinal study of medullary FA as a biomarker for early DN and to determine whether decreased medullary FA is due to changes in tubular microstructure or medullary perfusion. The hypotheses is that T2DM patients with apparently intact renal function will have a lower mean medullary FA and greater variance of medullary FA compared matched controls, suggesting the presence of a subset at risk for progression to DN and that low medullary FA results from changes in renal microstructure. Specific aims are: (1) To assess renal medullary FA in T2DM subjects without clinical evidence of renal disease vs. healthy controls; and (2)To define the mechanism underlying medullary FA changes in DN. Twenty-four (12M/12F) T2DM subjects, 40-60 years of age with eGFR (>80ml/min/1.73m2), no albuminuria and 5-10 years duration of T2DM will undergo DTI-MRI and IVIM scanning and results compared to 16 (8M/8F) age, race, gender and BMI-matched controls.

Novel MRI Imaging Biomarkers for Diabetic Complications
Type II diabetes mellitus (DM) affects millions of people worldwide and causes a myriad of complications that affect multiple organs in the body, including kidneys, heart, vasculature, gastrointestinal system, skin and eyes. These complications contribute to significant morbidity and mortality in diabetic patients; however, not all patients with DM these complications. Thus, it is of utmost importance to detect complications at the early stages of disease before irreversible damage has occurred, so that specific interventions can be targeted to high risk populations. Unfortunately, many of the clinical indicators of "end-organ" involvement are not evident until substantial damage has occurred. This challenge highlights the importance of developing non-invasive, clinically applicable biomarkers of early disease. Newer, quantitative magnetic resonance imaging (MRI) techniques, such as Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) and Magnetization Transfer MRI (MT-MRI), have the potential to detect early disease but have not been rigorously studied in human or animal models of DM. The proposed studies will apply these quantitative techniques to the study of two diabetic complications: diabetic nephropathy (DN) and non-alcoholic fatty liver disease (NAFLD). The overall hypothesis is that MRI imaging techniques can be used as quantitative biomarkers to monitor progression of diabetic and kidney and liver disease in the early stages of disease. The proposed studies will use the db/db mouse, a well-characterized DM model that develops features of DN and fatty liver disease. The specific aim of the proposal to develop MRI imaging techniques to assess the development of nephropathy and fatty liver disease in the db/db mouse. Db/db animals will be imaged serially at different ages using the quantitative MRI imaging techniques, MT-MRI (to assess kidney collagen and hypertrophy) and IDEAL (to assess liver fat deposition). MRI results will be correlated with histologic/biochemical and clinical assessments, in order to determine the applicability of these techniques to detecting early kidney and liver disease and monitoring disease progression.

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