Size-selectivity of the glomerular barrier to high molecular weight proteins: Upper size limitations of shunt pathways

Abstract

To evaluate the large pore radius of the glomerular capillary filter, plasma-to-urine fractional clearances of a number of endogenous proteins were assessed in normal and in nephrotic Wistar rats in which proximal tubular reabsorption had been inhibited using lysine. The proteins studied varied in radius from 16.2 A (Beta 2-microglobulin) to 90 A (alpha 2-macroglobulin). The nephrotic syndrome was induced by puromycin aminonucleoside (PAN). A marked restriction of the transport of large proteins across the glomerular capillary wall was found, indicating that there are no non-discriminatory 'shunt pathways' in the glomerular barrier. Rather, there seems to be large pores of radius 110 to 115 A accounting for the clearance of large proteins into the primary urine. This protein excretion pattern was almost the same for control and nephrotic rats, except that in the latter, the number of large pores was increased 170 times. The ratio between the number of large and small pores was calculated to be approximately equal to 7 x 10(-7) in normal rats and to 1.2 x 10(-4) in PAN nephrotic rats, assuming no classic shunt pathways. If classic shunt pathways had still existed, they would normally contribute to no more than approximately equal to 10(-5) of the total glomerular filtration rate. We postulate that very large macromolecules like IgM will not pass the glomerular filter at all under normal conditions, whereas the urine concentration of alpha2-macroglobulin will normally be extremely low.

Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys

“…The following parameters were estimated: the small-pore radius (rs), the unrestricted pore area over unit diffusion path length [A 0/⌬X; from which the hydraulic conductance (LpS) could be calculated], and the fractional LpS accounted for by the large pores (␣L). The large-pore radius (rL) was set at 110 Å based on results from a previous study from our laboratory (34). Based on that estimate, the large-pore volume flow (Jv, L) was determined from the sieving coefficient of native albumin.…”

“…4 in Ref. 34), assuming rL to be 110 Å and ⌬ (the transglomerular oncotic pressure gradient) to be 26 mmHg, setting LpS at 0.36 ml ⅐ min Ϫ1 ⅐ mmHg Ϫ1 (from corrected data), as calculated from the value of A0/⌬X obtained (23,34).…”

The value of IgG-uria in predicting renal failure in idiopathic glomerular diseases. A long-term follow-up study

“…Glomerular diseases are characterised by an increased glomerular filtration and urine excretion of plasma proteins of the size of albumin and larger, i.e. glomerular proteinuria [2][3][4]. Glomerular proteinuria is associated with the development of progressive tubulointerstitial fibrosis [5].…”

An Extended Minimal Physiologically Based Pharmacokinetic Model: Evaluation of Type II Diabetes Mellitus and Diabetic Nephropathy on Human IgG Pharmacokinetics in Rats

“…One of the main reasons for the limited elimination of proteins is the very efficient mechanism of reabsorption of proteins by proximal tubule epithelial cells. An estimate of the efficiency of this system can be gauged by studies that inhibited proximal tubular reabsorption with lysine; in the presence of lysine, up to 450-and 5-fold increases in renal clearance can be seen with low and high molecular weight proteins, respectively (43,44,46). In the case of DM/DN and CKD, increases in the urinary Fig.…”