Why the kidney glomerulus does not clog: a gel permeation/diffusion hypothesis of renal function

Abstract

Current interpretations of kidney function in terms of a coarse filter followed by a fine filter have difficulty explaining why the glomerulus does not clog. I propose, as an alternative, a semiquantitative hypothesis that assumes that the size-selective property of the glomerulus is a consequence of the limited fraction of space in the glomerular basement membrane (a concentrated gel) into which macromolecules can permeate. The glomerular epithelial cell slits and slit diaphragms are assumed to impose substantial resistance to liquid flow across the glomerulus without acting as a molecular sieve. Calculations based on gel behavior show that proteins cross the glomerular basement membrane mainly by diffusion rather than by liquid flow, whereas water crosses entirely by flow. Thus, diffusion provides most of the protein, whereas flow provides the diluent. As a result, the single-nephron glomerular filtration rate (GFR) becomes a prime factor in (inversely) determining the concentration of proteins in early proximal tubular fluid. Because the reabsorption of proteins from the tubules is a saturable process, the gel permeationdiffusion hypothesis readily accounts for the albuminuria observed when single-nephron GFR is substantially reduced by severe pathological decreases in slit diaphragm length, such as occur in minimal-change nephrotic syndrome in humans, in animals treated with puromycin aminonucleoside, or in humans or animals with mutations in the gene coding for nephrin. My hypothesis predicts that albuminuria will ensue, even with a normal kidney, if the single-nephron GFR falls below approximately 50% of normal.

Figure 1

Gel permeation as a factor in renal glomerular function. (Upper) The distribution of albumin molecules (black dots; number and size are approximately to scale) in an imaginary 7-nm (the diameter of albumin) ultrathin section of a glomerulus as predicted by gel permeation with an illustrative f value (see text) of 0.02. CS, capillary space; FEC, fenestrated endothelial cell; PFP, podocyte foot process; SD, slit diaphragm; US, urinary space. (Lower) The relationship between the Stokes radii, R, of eight proteins and the ratios (GF:P) of their concentrations in glomerular fluid and plasma observed experimentally in the dog (12). The graph, in the form predicted by Ogston's equation (boxed), plots the logarithm to the base 10 of GF:P (equivalent to f) against π(R + r)²⋅r. The radius of the gel fibers, r, was set at 0.75 nm. The plotted straight line accounts for 92% of the observed variance of GF:P (R² = 0.92; P = 0.0002); 1, myoglobin; 2, lysozyme; 3, β-lactoglobulin; 4, ovomucoid; 5, ovalbumin; 6, Bence Jones protein; 7, hemoglobin; and 8, serum albumin.

Figure 2

Steady-state concentrations and transport of albumin across the glomerulus. (Left) Transport by liquid flow only. (Right) Transport by diffusion only. (Center) Transport by flow and diffusion. The vertical dimension represents concentrations, and the arrows indicate transport. Effects of diffusion are blue and effects of flow are red. CS, capillary space; US, urinary space.

Figure 3

The simplest representation of glomerular and tubular function that was informative in computer simulations with STELLA. Red and blue emphasize the transport of albumin (Alb) and water, respectively, and black emphasizes factors controlling the tubular reabsorption of albumin and its eventual fate.

Figure 4

Effects of slit-diaphragm length on serum albumin concentration and urinary albumin excretion in 14 patients with minimal-change nephrotic syndrome. The data points are from Bohman et al. (18). CR, patients in complete remission with normal serum albumin and no proteinuria; IR, patients in incomplete remission with low serum albumin but no proteinuria; HP, patients with low serum albumin and heavy proteinuria. The blue and red lines show the simulated serum albumin concentrations and the simulated albumin excretion, respectively. Serum albumin and slit-diaphragm lengths are relative to the means of the three patients in complete remission (+). The albumin excretion is relative to that predicted by the simulation when the slit-diaphragm length is 20% normal (X).