(157g) Mathematical Modeling of Podocytes in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the primary cause for end-stage renal failure, is among the severe complications of diabetes, and is a significant factor leading to morbidity and mortality in both type I and type II diabetic patients. Hyperglycemia is known to initiate and exacerbate the pathophysiology of DKD. In the early stages of DKD, hyperglycemia induces increases in the rate of blood filtration through capillary beds (glomeruli) within the filtration units (nephrons) of the kidney [1]. The increase in glomerular filtration rate (GFR) contributes to glomerular injury, eventual damage to the tubular sections of nephrons downstream of the glomeruli, and loss of renal function. Damage to the epithelial cells called podocytes surrounding the glomerular capillaries is a critical factor in glomerular injury but is not immediately detectable with non-invasive clinical measurements of urine albumin concentration until after proteinuria develops due to substantial leakage of proteins through damaged glomeruli [1 – 2]. However, it is important to slow the rate of progression before irreversible loss of podocytes and nephrons occurs. In this work, we use mathematical modeling to investigate factors that contribute to the onset of nephropathy in DKD and seek to predict nephropathy in advance of detection of proteinuria by describing and simulating the mechanism of podocyte damage and loss. While mathematical models have been proposed for various renal physiological and pathophysiological processes, a quantitative description of the dynamics of podocyte injury at the onset and during the progression of DKD is lacking in the published literature. We have formulated a mathematical description of the mechanism of podocyte injury in DKD by including the contributions from glucose metabolism in the kidney during hyperglycemia, nephron hemodynamics, podocyte cell-signaling, and the dynamics of biomechanical forces that actively and passively alleviate or exacerbate effects of damage. These processes interact across multiple length and time scales. The mathematical model consists of a system of ordinary and partial differential equations and algebraic equations that are solved numerically. The intensity and duration of elevated GFR during periodic hyperglycemia is varied in simulations to investigate the influence on the transition to irreversible podocyte loss. The simulation results from the mathematical model are compared to published experimental data to assess the model ability to accurately and quantitatively predict how podocyte loss depends on filtration rate and the onset of proteinuria after hyperglycemic events.

[1] Lopez-Novoa JM, Martinez-Salgado C, Rodriguez-Pena AB, Lopez-Hernandez FJ. Common Pathophysiological Mechanisms of Chronic Kidney Disease: Therapeutic Perspectives. Pharmacol Ther 2010;128:61-81.

[2] Garg P, Holzman LB. Podocytes: Gaining a Foothold. Exp Cell Res 2012;318:955-63.