In this review we summarized the evidence favoring the concept that the major plasma proteins are passively transported across vascular walls through water-filled pathways by means of convection and diffusion. With regard to solute transport, a majority of microvascular walls seems to show a bimodal size selectivity. This implies the presence of a high frequency of functional small pores, restricting proteins, and an extremely low number of non-size-selective pathways, permitting the passage of macromolecules from blood to tissue, here denoted large pores. We discussed the general behavior of such a heteroporous system. A major consequence of two-pore heteroporosity is that large-solute transport must mainly occur due to convection through large pores at low filtration rates, that is, at normal or even zero lymph flows. Indeed, convection must be the predominating transport mode for most solutes across large pores when the net filtration rate is zero. Under these (transient) conditions, the convective leak of macromolecules across large pores will be counterbalanced by absorption of essentially protein-free fluid through protein-restrictive pores. In a heteroporous membrane, proteins can thus be transported by solvent drag across vascular walls in the absence of a net convection. Normally the steady-state transcapillary fluid flow (lymph flow) is about equally partitioned among small and large pores, which makes lymph essentially a "half and half" mixture of protein-free ultrafiltrate and plasma. With increasing fluid flows, however, the plasma filtrate will be progressively diluted, eventually reaching a protein concentration largely in proportion to the fractional hydraulic conductance accounted for by the large pores (alpha L). Under these high lymph flow conditions, not only the large-pore transport but also the small-pore transport (of smaller macromolecules) will become convective. At low lymph flows, however, the small-pore transport of smaller macromolecules is usually mostly diffusive. An important implication of capillary heteroporosity is that single-pore formalism is inadequate for correctly evaluating the capillary sieving characteristics. With the use of homoporous transport formalism, the "lumped" macromolecular PS and sigma will therefore vary as a function of transcapillary fluid flow (Jv). However, it is approximately correct to use single-pore formalism for conditions when Jv is very high during steady state. Thus, if minimal sieving coefficients can be measured for macromolecules, then these values will accurately reflect (1 - sigma).(ABSTRACT TRUNCATED AT 400 WORDS)

Venturoli, Daniele, and Bengt Rippe. Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability. Am J Physiol Renal Physiol 288: F605-F613, 2005; doi:10.1152/ajprenal.00171.2004.-Polydisperse mixtures of dextran or Ficoll have been frequently used as molecular probes for studies of glomerular permselectivity because they are largely inert and not processed (reabsorbed) by the proximal tubules. However, dextrans are linear, flexible molecules, which apparently are hyperpermeable across the glomerular barrier. By contrast, the Ficoll molecule is almost spherical. Still, there is ample evidence that Ficoll fractional clearances (sieving coefficients) across the glomerular capillary wall (GCW) are markedly higher than those for neutral globular proteins of an equivalent in vitro Stokes-Einstein (SE) radius. Physical data, obtained by "crowding" experiments or measurements of intrinsic viscosity, suggest that the Ficoll molecule exhibits a rather open, deformable structure and thus deviates from an ideally hard sphere. This is also indicated from the relationship between (log) in vitro SE radius and (log) molecular weight (MW). Whereas globular proteins seem to behave in a way similar to hydrated hard spheres, polydisperse dextran and Ficoll exhibit in vitro SE radii that are much larger than those for compact spherical molecules of equivalent MW. For dextran, this can be partially explained by a high-molecular-size asymmetry. However, for Ficoll the explanation may be that the Ficoll molecule is more flexible (deformable) than are globular proteins. An increased compressibility of Ficoll and an increased deformability and size asymmetry for dextran may be the explanation for the fact that the permeability of the GCW is significantly higher when assessed using polysaccharides such as Ficoll or dextran compared with that obtained using globular proteins as molecular size probes. We suggest that molecular deformability, besides molecular size, shape, and charge, plays a crucial role in determining the glomerular permeability to molecules of different species. capillary permeability; polysaccharides; macromolecules; reflection coefficient; transport POLYDISPERSE MIXTURES OF DEXTRAN, and more recently Ficoll, are frequently used as molecular probes in studies of glomerular permselectivity. After being filtered through the glomerular capillary wall (GCW), polysaccharides, unlike proteins, are left unreabsorbed by the proximal tubules. This implies that their sieving coefficients (), i.e., their filtrate-to-plasma concentration ratios, can be determined directly from their urinary clearances relative to that of a glomerular filtration rate marker (e.g., inulin). Infusing polydisperse mixtures of dextran or Ficoll and using chromatographic techniques to fractionate plasma and urine samples make it possible to simultaneously determine the for a wide spectrum of different-sized molecular probes, provided that proper size calibrations ...

Background: Serum creatinine is the most commonly used marker for estimation of glomerular filtration rate (GFR). To compensate for its drawbacks as a GFR marker, several prediction equations including several parameters are being used, with the Modification of Diet in Renal Disease (MDRD), Schwartz, and CounahanBarratt equations being the ones most widely accepted for estimation of relative GFR in mL ⅐ min ؊1 ⅐ (1.73 m 2 ) ؊1 . The present study analyzes whether these GFR prediction equations for adults and children might be replaced by simple prediction equations based on plasma concentrations of cystatin C. Methods: Data from 536 patients (0.3-93 years), consecutively referred for determination of GFR by an invasive gold standard procedure, were used for the analysis. Calculations of bias (median percentage of error), correlation (adjusted R 2 ), and percentage of estimates within 30% and 50% of measured GFR were used in the comparisons. Results: A cystatin C-based prediction equation using only concentration in mg/L and a prepubertal factor:

To model the changes in intraperitoneal dialysate volume (IPV) occurring over dwell time under various conditions in continuous ambulatory peritoneal dialysis (CAPD), we have, using a personal computer (PC), numerically integrated the phenomenological equations that describe the net ultrafiltration (UF) flow existing across the peritoneal membrane in every moment of a dwell. Computer modelling was performed according to a three-pore model of membrane selectivity as based on current concepts in capillary physiology. This model comprises small "paracellular" pores (radius approximately 47 A) and "large" pores (radius approximately 250 A), together accounting for approximately 98% of the total UF-coefficient (LpS), and also "transcellular" pores (pore radius approximately 4 to 5 A) accounting for 1.5% of LpS. Simulated curves made a good fit to IPV versus time data obtained experimentally in adult patients, using either 1.36 or 3.86% glucose dialysis solutions, under control conditions; when the peritoneal UF-coefficient was set to 0.082 ml/min/mm Hg, the glucose reflection coefficient was 0.043 and the peritoneal lymph flow was set to 0.3 ml/min. Also, theoretical predictions regarding the IPV versus time curves agreed well with the computer simulated results for perturbed values of effective peritoneal surface area, LpS, glucose permeability-surface area product (PS or "MTAC"), intraperitoneal dialysate volume and dialysate glucose concentration. Thus, increasing the peritoneal surface area caused the IPV versus time curves to peak earlier than during control, while the maximal volume ultrafiltered was not markedly affected. However, increasing the glucose PS caused both a reduction in the IPV versus time curve "peak time" and in the "peak height" of the curves. The latter pattern was also seen when the dialysate volume was reduced. It is suggested that computer modelling based on a three-pore model of membrane selectivity may be a useful tool for describing the IPV versus time relationships under various conditions in CAPD.

Employing the three-pore model of peritoneal transport and taking into account the polydispersed nature of ICO, it was possible to accurately computer simulate the UF profiles of ICO in accordance with reported data. The simulations suggest an advantage of using ICO in patients with type I UF failure, where UF with a high-MW osmotic agent will exceed that seen in patients not showing UF failure who are on glucose-based PD solutions.

We conclude that the new fluid with a higher pH and less GDPs is safe and easy to use and has no negative effects on either the frequency of peritonitis or peritoneal transport characteristics as compared with conventional ones. Our results indicate that the new solution causes less mesothelial and interstitial damage than conventional ones; that is, it may be considered more biocompatible than a number of conventional PD solutions currently in use.

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

Blood peritoneal clearances of various endogenous solutes in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) were evaluated according to recent developments of the two-pore theory of membrane permeability, using a non-linear transport formalism for the analysis. Based on results obtained from these calculations and taking lymphatic drainage into account, transport from peritoneal cavity to the blood was also simulated. With respect to solute transport the data were compatible with a functional blood-peritoneal barrier consisting of a two-pore membrane containing a large number of paracellular "small pores" of radius 40 to 55 A and a small number of "large pores" of radius 200 to 300 A. Solutes smaller than 25 A in radius were found to be permeating across the peritoneal membrane mainly by means of diffusion across the small pores, whereas solutes larger than 40 A were calculated to reach the peritoneal cavity exclusively by unidirectional convection across the large pores. In addition, water was simulated to be transported through transcellular "ultrapores" (radius less than 8 A) not accessible to hydrophilic solute permeation. Small solute absorption from the peritoneal cavity was found to occur by diffusion across small pores. Molecules larger than 25 to 30 A in radius (molecular weight above 25,000) were simulated to be absorbed from the peritoneal cavity exclusively via non-size-selective lymphatic drainage.