Charge selectivity of the glomerular filtration barrier in healthy and nephrotic humans.

Abstract

We used dextran sulfate (DS) to evaluate barrier charge selectivity in 11 nonproteinuric subjects and in 11 patients with the nephrotic syndrome due to either membranous nephropathy or minimal change nephropathy. The 3H-DS preparation spanned a molecular radius interval of 10-24A and exhibited size-dependent protein binding in vitro. Urine and ultrafiltrates of plasma were separated by size into narrow fractions using gel permeation chromatography. The sieving coefficient (0) for ultrafilterable DS of 15A radius averaged 0.68±0.03 in nonproteinuric vs. 0.95±0.05 in nephrotic subjects (P < 0.001). Uncharged dextrans of broad size distribution were used to evaluate barrier size-selectivity in separate groups of nonproteinuric subjects (n = 19) and nephrotic patients with either minimal change (n = 20) or membranous nephropathy (n = 27). The value of 0 for an uncharged dextran of similarly small radius (-18A) was significantly larger than that observed for DS in nonproteinuric subjects, but was similar in nephrotic individuals. Further, impaired barrier size-selectivity, as assessed by the sieving profile for uncharged dextrans (18-60A radius), failed to account fully for the observed level of albuminuria in almost half of the patients with either minimal change (9/20) or membranous nephropathy (12/27). Together these findings suggest that the human glomerular capillary wall normally provides an electrostatic barrier to filtration of negatively charged macromolecules such as albumin, and that impairment of this electrostatic barrier contributes to the magnitude of albuminuria in the nephrotic syndrome. (J. Clin. Invest. 1993.

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

“…[30][31][32][33][34][35][36][37] However, in all of these studies albuminuria was not markedly increased, thus supporting recent evidence for other mechanisms having an active role in albumin retrieval occurring in PTCs. FcRn, the only albumin transcytotic receptor yet identified, is concentrated in the apical region of the PTCs as shown in Figure 4B.…”

Deficiency of Endothelial Nitric-Oxide Synthase Confers Susceptibility to Diabetic Nephropathy in Nephropathy-Resistant Inbred Mice

“…The glomerular barrier restricts the passage of anionic macromolecules relative to uncharged molecules of similar size and configuration. 46 Previous studies showed that the charge selectivity resides mainly at endothelial cells or podocytes rather than the GBM, 47,48 and a more recent study has shown that endothelial cell glycocalyx, a negatively charged surface layer of membrane-associated proteoglycans and glycosaminoglycans, is a critical determinant in glomerular charge selectivity. 31 Furthermore, Arcos et al 28 showed that chronic NO inhibition using an NO inhibitor impairs glomerular endothelial charge barrier and causes albuminuria and GBM thickening.…”

Differential Expression of Nephrin According to Glomerular Size in Early Diabetic Kidney Disease

“…2 The underlying pathologic change responsible for proteinuria in various glomerular diseases is the loss of size-selective and/or charge-selective properties of the glomerular filtration barrier. [3][4][5][6][7] The glomerular filtration barrier is composed of three layers: A fenestrated endothelial layer, a glomerular basement membrane (GBM), and podocyte foot processes connected by a slit diaphragm. Traditionally, the GBM has been considered a coarse filter that restricts large molecules, whereas the slit diaphragm was thought to function as a fine filter that contributes to ultimate size selec-tivity, permitting permeability only to molecules that are smaller than albumin.…”