MRI-based techniques to measure renal morphology in diabetic human kidneys
The broad, long-term goal of this work is to measure kidney nephron endowment in diabetic humans, in vivo. Each nephron contains a glomerulus, which functions as a high-pressure filter of blood macromolecules. Deficits in nephrons and glomeruli are correlated with renal diseases such as diabetes, obesity, and hypertension. There is currently no noninvasive technique to count the total number of functioning renal glomeruli and nephrons in vivo, and to identify areas of nephritis at an early stage. Such a technique would enable studies of diabetic complications of the kidney in humans. We propose that contrast-enhanced MRI, using MRI-detectable nanoparticles targeted to the glomerular basement membrane, can be used to accurately count the total number of glomeruli in the whole, intact kidney. This proposal is focused on establishing this technique in healthy and diabetic human donor kidneys. We further propose to develop an automated image processing package to quantify diabetic renal morphology. Once completed, the proposed work will open the possibility of real-time, in vivo glomerular counts in studies of renal and systemic diseases in humans.

Multi-scale imaging tools to map pathology and gene expression in the human kidney
The goal of this pilot and feasibility study is to develop a multi-scale framework to evaluate the human kidney, to provide an improved understanding of diabetic kidney disease. Pathologies associated with kidney disease are highly heterogeneous, with wide variability in presentation within and between subjects. This heterogeneity limits the ability of histopathology derived from biopsies due to sampling bias, despite recent significant advances in histologic analysis. In diabetic patients, even kidney biopsies are not normally performed to detect progression to diabetic kidney disease (DKD), and noninvasive imaging biomarkers are early in development. Thus, there is a lack in knowledge about 1) Early microstructural biomarkers that could predict which diabetic patients progress to DKD or end stage kidney disease and 2) How pathology relates to structure, function, and gene expression across the entire kidney. Here we bridge the gap between anatomical structure, microstructural features, and gene expression to provide a multi-scale, three-dimensional map of the whole, intact human kidney. These preliminary studies will be performed in donor kidneys from a local organ procurement organization, not accepted for transplantation. We will investigate kidneys from both healthy and diabetic kidneys to establish preliminary data to guide future work. In Aim 1 we will combine three-dimensional, multi-parametric MRI with image-guided site directed biopsy to correlate imaging features with histopathology and measure the level of intra- and inter-kidney heterogeneity present in typical tissue. We will also investigate how these parameters relate to vascular, glomerular, and pyramidal morphology. In Aim 2 we will investigate how both single-cell and bulk RNA profiles vary within and between kidneys and how these are related to gross microstructural features. We will compare parameters measured in Aims 1-2 between kidneys from the healthy and diabetic donors. Together, this work will establish the image acquisition and processing framework to evaluate the human kidney across the scales from gross anatomy to gene expression. It will also provide preliminary data to support studies to understand heterogeneous pathology and its etiology during development of DKD.

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