Ultrastructural model for size selectivity in glomerular filtration

Abstract

A theoretical model was developed to relate the size selectivity of the glomerular barrier to the structural characteristics of the individual layers of the capillary wall. Thicknesses and other linear dimensions were evaluated, where possible, from previous electron microscopic studies. The glomerular basement membrane (GBM) was represented as a homogeneous material characterized by a Darcy permeability and by size-dependent hindrance coefficients for diffusion and convection, respectively; those coefficients were estimated from recent data obtained with isolated rat GBM. The filtration slit diaphragm was modeled as a single row of cylindrical fibers of equal radius but nonuniform spacing. The resistances of the remainder of the slit channel, and of the endothelial fenestrae, to macromolecule movement were calculated to be negligible. The slit diaphragm was found to be the most restrictive part of the barrier. Because of that, macromolecule concentrations in the GBM increased, rather than decreased, in the direction of flow. Thus the overall sieving coefficient (ratio of Bowman’s space concentration to that in plasma) was predicted to be larger for the intact capillary wall than for a hypothetical structure with no GBM. In other words, because the slit diaphragm and GBM do not act independently, the overall sieving coefficient is not simply the product of those for GBM alone and the slit diaphragm alone. Whereas the calculated sieving coefficients were sensitive to the structural features of the slit diaphragm and to the GBM hindrance coefficients, variations in GBM thickness or filtration slit frequency were predicted to have little effect. The ability of the ultrastructural model to represent fractional clearance data in vivo was at least equal to that of conventional pore models with the same number of adjustable parameters. The main strength of the present approach, however, is that it provides a framework for relating structural findings to the size selectivity of the glomerular barrier.

Imaging of the Porous Ultrastructure of the Glomerular Epithelial Filtration Slit

“…The mean pore radius of the best fitting log-normal distribution was u ϭ 11.4 nm, and the SD of the corresponding normal probability distribution was s ϭ 1.39 ( Figure 3B). In MWF rats, the majority of pores had an area ranging from 250 to 500 nm 2 , as in normal controls, with a mean pore area of 564 nm 2 . Of note, in MWF rats, a small fraction of the pore population was detected to have a large size (Ͼ2500 nm 2 ).…”

“…To estimate the relative importance of pore size on water filtration, we calculated the distribution of fractional pore area ( Figure 4A). Mean pore area was 494 nm 2 , with a higher frequency of pore area ranging from 250 to 500 nm 2 . The largest pores detected in normal rats has an area Ͻ2500 nm 2 .…”

“…1 It has been indicated that most of the restriction of macromolecule ultrafiltration is caused by the epithelial filtration slits, because plasma proteins can cross endothelial cells and glomerular basement membrane (GBM) more easily. 2 Changes in glomerular permselective function resulting in increased glomerular filtration of plasma proteins and incomplete tubular reabsorption are responsible for loss of proteins in the urine. These events have been linked to the progression of renal diseases.…”

“…Theoretical models of glomerular size selectivity have been conventionally used to derive intrinsic membrane selective properties from fractional clearance of test macromolecules in terms of density and size of hypothetical pores perforating the glomerular capillary wall. 2,4,5 Thus, according to the two-pore theory, in the normal rat, the radius of small pores is in the range of 4.5 to 5.0 nm and that of large pores is between 8.0 and 10.0 nm. 6 Similarly, according to the lognormal pore radii distribution model, the mean pore radius is in the range of 3.5 and 4.5 nm, and the largest pores of the distribution have radii up to 8.0 nm or larger.…”

Functional Human Podocytes Generated in Organoids from Amniotic Fluid Stem Cells

“…7 The diaphragm's 3D, porous ultrastructure is probably one of the best available morphologic correlates to the barrier's permeability property and sieving function, which enables the filtration of high water flow and small solutes and, at the same time, differential retention of macromolecules within blood. [29][30][31][32] Altogether, the high degree of maturation of the epithelial barrier in the implanted tissue offers unprecedented evidence of the efficiency of organoid-based approaches in terms of functional capacity.…”