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

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 permeation/diffusion 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 ≈50% of normal