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Cellular contributions to glomerular size-selectivity

2006; Elsevier BV; Volume: 69; Issue: 8 Linguagem: Inglês

10.1038/sj.ki.5000322

1523-1755

William M. Deen,

Electrolyte and hormonal disorders

The glomerular capillary wall permits free passage of low-molecular-weight solutes, while severely restricting large proteins. Although both cell layers (endothelium and epithelium) almost certainly contribute to this size-selectivity, their relative importance has been difficult to assess. The finding by Rippe et al. of an inverse relationship between the sieving coefficient of Ficoll and glomerular filtration rate sheds light on this. The glomerular capillary wall permits free passage of low-molecular-weight solutes, while severely restricting large proteins. Although both cell layers (endothelium and epithelium) almost certainly contribute to this size-selectivity, their relative importance has been difficult to assess. The finding by Rippe et al. of an inverse relationship between the sieving coefficient of Ficoll and glomerular filtration rate sheds light on this. In this issue, Rippe et al.1.Rippe C. Asgeirsson D. Venturoli D. et al.Effects of glomerular filtration rate on Ficoll sieving coefficients (θ) in rats.Kidney Int. 2006; 69: 1326-1332Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar show that if glomerular filtration rate (GFR) in healthy rats is increased from low (hydropenic) to normal levels, then the sieving coefficient of Ficoll is decreased. The sieving coefficient (θ, the Bowman's space-to-plasma concentration ratio) is the principal measure of how effective the glomerular barrier is at retaining a given macromolecule within the circulation. Ficoll is a polysaccharide that approximates an ideal, neutral sphere and is therefore the preferred marker of barrier size-selectivity. Numerous studies over the years with experimental animals or humans have shown that θ decreases with increasing molecular size, but information on the dependence of θ on GFR has been limited. The present finding that θ decreases with increasing GFR for a wide range of Ficoll sizes in vivo is consistent with recent results for globular proteins2.Lund U. Rippe A. Venturoli D. et al.Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys.Am J Physiol. 2003; 284: F1226-F1234Crossref PubMed Scopus (115) Google Scholar and with earlier data for dextran.3.Chang R.L.S. Ueki I.F. Troy J.L. et al.Permselectivity of the glomerular capillary wall to macromolecules. II. Experimental studies in rats using neutral dextran.Biophys J. 1975; 15: 887-906Abstract Full Text PDF PubMed Scopus (197) Google Scholar As noted by Rippe et al.,1.Rippe C. Asgeirsson D. Venturoli D. et al.Effects of glomerular filtration rate on Ficoll sieving coefficients (θ) in rats.Kidney Int. 2006; 69: 1326-1332Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar the inverse dependence of θ on filtration velocity is a hallmark of a membrane operating under conditions in which diffusion influences sieving. At filtration rates low enough to allow diffusion to compete with bulk flow (convection) of the solute, θ is larger than it would be if diffusion were absent. If filtration rates are very low, then even a molecule that has difficulty getting through the barrier will have time to equilibrate between filtrate and retentate, and θ → 1. The intrinsic selectivity of the barrier is then masked. At the other extreme, if water filtration is so rapid as to make diffusion negligible, then θ will fall to a minimum value that is determined by the membrane structure and by the characteristics (for example, size and shape) of the test molecule. That minimum value is sometimes written as 1 - σ, where σ is the reflection coefficient, and is denoted also as W, the convective hindrance factor.4.Deen W.M. Hindered transport of large molecules in liquid-filled pores.AIChE J. 1987; 33: 1409-1425Crossref Scopus (997) Google Scholar Using the latter notation, the sieving behavior of a homogeneous membrane is summarized by saying that W ≤ θ ≤ 1, the lower values of θ corresponding to the highest water filtration rates. This assumes that concentration polarization at the upstream side of the membrane is negligible, as appears to be true for the glomerulus.5.Deen W.M. Robertson C.R. Brenner B.M. Concentration polarization in an ultrafiltering capillary.Biophys J. 1974; 14: 412-431Abstract Full Text PDF PubMed Scopus (25) Google Scholar The sieving behavior just described is embodied inθ=W(1−epe)+We−pe(1) in which Pe is the Peclet number, a measure of the importance of convection relative to diffusion.4.Deen W.M. Hindered transport of large molecules in liquid-filled pores.AIChE J. 1987; 33: 1409-1425Crossref Scopus (997) Google Scholar The diffusion limit (θ → 1) corresponds to Pe → 0; the convection limit (θ → W) occurs for large Pe. For a given solute–membrane combination, Pe is proportional to the filtration velocity (that is, GFR). For different solutes and/or membranes, Pe is proportional to the membrane thickness and varies inversely with the aqueous diffusivity of the solute. Thus, Pe tends to be larger for thicker membranes and/or larger solute molecules (which diffuse more slowly). Equation (1) is well known in the ultrafiltration and reverse osmosis literature, an equivalent expression having been reported by Spiegler and Kedem6.Spiegler K.S. Kedem O. Thermodynamics of hyperfiltration (reverse osmosis): criteria for efficient membranes.Desalination. 1966; 1: 311-326Crossref Scopus (873) Google Scholar some 40 years ago. Thus, the dependence of θ on GFR that Rippe et al.1.Rippe C. Asgeirsson D. Venturoli D. et al.Effects of glomerular filtration rate on Ficoll sieving coefficients (θ) in rats.Kidney Int. 2006; 69: 1326-1332Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar and others have found suggests that the intrinsic size-selectivity of the glomerulus is partially masked at normal rates of filtration. Can we infer more about the glomerular barrier? In particular, recognizing that the capillary wall is not a homogeneous membrane but consists rather of three layers (endothelium, glomerular basement membrane (GBM), and epithelium), does the dependence of θ on GFR tell us something about the contributions of the individual layers to the overall size-selectivity? Insight into the interactions among the layers of the glomerular capillary wall is gained by consideration of a composite barrier consisting of n ‘simple’ membranes in series. For layer i of the composite, where i = 1 is farthest upstream and i = n farthest downstream, the derivation that leads to equation (1) can be generalized to obtainθi=Wiθi+1θi+2…θn(1−e−pe)+Wie−pei(2) where Wi is the hindrance factor and Pei the Peclet number for that layer. By definition, θn+1 = 1, so that equation (2) reduces to equation (1) if i = n. The new feature is that, for i < n, the sieving coefficient for layer i depends not just on Wi and Pei, but on the product of the sieving coefficients of all downstream layers (first term in the denominator). Thus, the layers are interdependent, the downstream parts affecting the sieving performance of the upstream parts. The description of such a composite barrier is completed by noting that the overall sieving coefficient is the product of those of the individual layers, or θ = θ1θ2…θn. The application of this last relation to the glomerulus has been discussed previously.7.Deen W.M. Lazzara M.J. Myers B.D. Structural determinants of glomerular permeability.Am J Physiol. 2001; 281: F579-F596PubMed Google Scholar Included in that review are structural details of the cellular layers and GBM that are omitted here for simplicity. Based on diffusion and sieving data for Ficoll in isolated rat GBM, and using equation (2) to relate the sieving coefficient in the GBM to that of the epithelial filtration slits, it has been concluded that, for an uncharged macromolecule the size of serum albumin, θGBM ≈ 1.7.Deen W.M. Lazzara M.J. Myers B.D. Structural determinants of glomerular permeability.Am J Physiol. 2001; 281: F579-F596PubMed Google Scholar Essentially, the Ficoll transport properties measured in vitro, the GBM thickness, and the filtrate velocity corresponding to a normal single-nephron GFR (SNGFR) combine to suggest a value of PeGBM that is too small for that layer to exhibit significant selectivity. Accordingly, although the GBM provides the dominant resistance to water flow (and thereby limits the GFR), the efficient retention in the circulation of molecules such as albumin is due mainly to a combination of endothelial and epithelial selectivity.7.Deen W.M. Lazzara M.J. Myers B.D. Structural determinants of glomerular permeability.Am J Physiol. 2001; 281: F579-F596PubMed Google Scholar The relative contributions of the two cell layers to barrier function have been difficult to discern, as it has not been possible to study either in isolation. Returning now to the dependence of θ on GFR, and approximating the glomerular barrier for this purpose as a two-layer membrane (1 = endothelium, 2 = epithelium), one can examine which combinations of layer characteristics make sense, beginning with the respective Peclet numbers for a molecule similar in size to albumin. Neither Pe1 nor Pe2 can be estimated from available data, and either might be small, moderate (roughly unity), or large at normal levels of GFR, leading to nine possible combinations. Most of those can be eliminated, however. Evidence that proteinuria may result from either endothelial or slit diaphragm pathology8.Deen W.M. What determines glomerular capillary permeability?.J Clin Invest. 2004; 114: 1412-1414Crossref PubMed Scopus (118) Google Scholar suggests that neither Peclet number is very small; if either were, the sieving coefficient for that layer already would be near unity and would not be increased appreciably by dysfunction. Moreover, if Pe1 is large, it can be shown from equation (2) that θ = θ1θ2 = W1, independent of Pe2. Thus θ would be independent of GFR, contrary to observation. Only two possibilities remain: (1) Pe1 is moderate and Pe2 is large, and (2) Pe1 and Pe2 are both moderate. For case (1), it follows from equation (2) that θ2 = W2 andθ=W1W2W2+(W1−W2)e−pei(3) Inspection of equation (3) reveals that θ can decrease with increasing Pe1 (increasing GFR) in this scenario, but only if W1 < W2. Thus, case (1) is viable, provided that the endothelium is intrinsically more selective than the epithelium (that is, has a higher σ or lower W). For case (2), the very complicated expression that results makes it difficult to draw general conclusions. Some possibilities are illustrated in Figure 1, in which θ is shown as a function of Pe for Pe = Pe1 = Pe2. Three combinations of W1 and W2 are considered, with W1W2 = 0.01 in each. If the two layers are the same (W1 = W2), then θ decreases monotonically with increasing Pe (or GFR), as for a simple membrane of double thickness and as in Figure 5 of Rippe et al.1.Rippe C. Asgeirsson D. Venturoli D. et al.Effects of glomerular filtration rate on Ficoll sieving coefficients (θ) in rats.Kidney Int. 2006; 69: 1326-1332Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Likewise, θ decreases monotonically if the upstream layer is much more selective (W1 << W2). In either situation, the minimum for θ equals W1; that is, the composite is no more selective than the upstream layer. For a much more selective downstream layer (W1 >> W2), the behavior is more complicated, with θ first decreasing and then increasing. However, in that case θ1 > 0.99 for all Pe, which is seemingly at odds with the evidence that endothelial injury can lead to proteinuria. Thus, case (2) is viable also, but apparently only if W1 does not greatly exceed W2. Incidentally, the difference between the last two curves, which is magnified as Pe increases, shows an advantage in placing the most selective layer upstream. In summary, the finding that θ for various macromolecules decreases with increasing GFR offers clues about the dynamics of sieving in the multilayer glomerular capillary wall. It is generally consistent with the idea that both cell layers contribute to the observed size-selectivity of the barrier. Kristin Mattern checked the derivation of equation (2). Support was provided by the National Institutes of Health.