Effects of shear flow-induced openings on glomerular fluid filtration and sizeselectivity

Abstract

Kidneys are vital organs of which main function is to maintain constant blood volume and composition by removing excess fluid and metabolic waste from the circulation through urine formation. It is believed that the first step of renal urine formation is the filtration of fluid and solutes through the glomerular barrier with its unique nanostructure. Two-third of the glomerular capillary surface area consists of three cellular layers, a filtration slit connected to epithelial foot processes, an associated area of glomerular basement membrane (GBM) and several endothelial fenestrae, commonly referred to as the filtration surface, whereas one-third of the glomerular capillary surface is a four-layered barrier with the glomerular mesangium located between the endothelial cell layer and GBM. A comparison between the mathematical model employing hindered transport theory and the ficoll sieving coefficient obtained from in vivo urinanalysis has shown that the assumption of the fluid and solute fluxes flowing through the intact glomerular barrier, although capable of explaining filtration of small and medium-sized solutes, greatly underestimates the sieving coefficient of solutes with the radius larger than 5 nm. In addition, it also contradicts with the fact that, even in normal humans, a small amount of red blood cells is observed in urine. Electron micrographs have shown red blood cells “escaping” through the small openings at the junction where the three-layered filtration surface meets the four-layered barrier. In the present work, the effects of these openings on the glomerular fluid and solute filtration are investigated using low-Reynolds-number fluid dynamics and hindered transport theory. Although their effects on the overall glomerular hydraulic permeability and the filtration of small and medium-sized solutes are found to be small, the presence of the possibly shear-induced openings greatly increases the sieving coefficient of large solutes, rendering the calculated sieving coefficients that agree well with the ficoll sieving coefficients obtained from experiments performed in normal humans and patients with diabetic nephropathy for the entire range of solute size.