Chronic kidney disease (CKD) affects 14% of the U.S. population. CKD often includes damage to the kidney's filtration unit, the glomerulus, and such damage usually includes changes to the glomerular mesangium. Mesangial cells are known to respond to their immediate environment, including chemical and physical signals. Our understanding of the mesangial microenviroment is currently incomplete. The goal of the proposed study is to build a theoretical model of fluid and species transport throughout the mesangium. Building on the tradition established for glomerular capillary filtration by Deen and colleagues, I propose to build a model of transmural filtration through the mesangium. I will model plasma flow and macromolecular transport in the mesangium, apply this model to the specific case of IgA nephropathy, build a model of the stresses and strains in the mesangium, and incorporate biological feedback by allowing mesangial cells to contract in response to stretch. I will describe flow through the mesangial matrix using Darcy's Law, and flow in an adjacent glomerular capillary as Stokes flow. I will use finite-element analysis to solve the model equations in a single capillary, idealized as a straight tube, with its associated mesangium, idealized as a thin slab. Mesangial cells will also be modeled as rectangualr bodies, occupying the central portion of the mesangium. The results of this work will not provide not only a physical basis for understanding mesangial transport and filtration, but also a way to quantify the relative contribution of different parameters to mesangial accumulation. It will reveal the role of aberrant IgA glycosylation, alterations to mesangial cell receptors, and filtration fraction in causing macromolecular accumulation. These results will quantify the effects of proposed disease mechansims, which could suggest new treatment options, improving public health.
A common observation in kidney disease is irritation of the mesangium, a support tissue within the kidney. My project will build a model to understand the cells'environment in the mesangium, which will help explain how IgA nephropathy, and other diseases, occur and progress.
|Hunt, Sarah E; Dorfman, Kevin D; Segal, Yoav et al. (2016) A computational model of flow and species transport in the mesangium. Am J Physiol Renal Physiol 310:F222-9|