Abstract
At the onset of diabetes, the kidney grows large and the glomerular filtration rate becomes abnormally high. These structural and hemodynamics changes affect kidney function and may contribute to the development of chronic kidney disease. The goal of this study is to analyze how kidney function is altered in patients with diabetes and the renal effects of an anti-hyperglyceamic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish that goal, we have developed a computational model of kidney function in a patient with diabetes and conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Simulation results indicate that diabetes-induced hyperfiltration and tubular hypertrophy enhances Na+ transport, especially along the proximal tubules and thick ascending limbs. These simulations suggest that SGLT2 inhibition may attenuate glomerular hyperfiltration by limiting Na+-glucose transport, raising luminal [Cl−] at the macula densa, restoring the tubuloglomerular feedback signal, thereby reducing single-nephron glomerular filtration rate.
Highlights
The prevalence of diabetes is rising worldwide, currently estimated to be 9.3% (463 million people) and expected to reach 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045 [1]
Plasma glucose is further elevated to 20 mM, resulting in glucose filtered load of 3.75 mol·day−1 glucose, which exceeds the glucose transport capability of the proximal tubule
The main goal of this study is to extend a computational model of the human kidney, and to apply that model to study the effects of diabetes and sodium-glucose cotransporter 2 (SGLT2) inhibition on solute and water transport along the nephrons
Summary
The prevalence of diabetes is rising worldwide, currently estimated to be 9.3% (463 million people) and expected to reach 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045 [1]. Even though the pathways that link diabetes to chronic kidney disease remain incompletely understood, diabetes is known to induce pathophysiological changes in the kidneys. At the very onset of diabetes, the kidney grows large and the glomerular filtration rate (GFR) becomes supranormal [4]. These structural and hemodynamic changes affect kidney function and may eventually lead to chronic kidney disease. Throughout the animal kingdom kidneys are known primarily for their function as filters, removing metabolic wastes and toxins from the blood for excretion in the urine
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