Glomerular permeability: a never-ending saga
2009; American Physical Society; Volume: 296; Issue: 6 Linguagem: Norueguês
10.1152/ajprenal.00152.2009
ISSN1931-857X
Autores Tópico(s)Chronic Kidney Disease and Diabetes
ResumoEDITORIAL FOCUSGlomerular permeability: a never-ending sagaL. Gabriel NavarL. Gabriel NavarPublished Online:01 Jun 2009https://doi.org/10.1152/ajprenal.00152.2009This is the final version - click for previous versionMoreFiguresReferencesRelatedInformationPDF (50 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat the paper by tanner et al. (27) revisits the critical question of how the intricate glomerular capillary membrane provides such a highly restrictive barrier to macromolecules while still allowing the movement of vast volumes of protein-free fluid (1, 7, 13, 14, 20). In recent years, this topic has emerged from dormancy because of exciting new technology and because several recent studies presenting provocative data have challenged well-established concepts regarding glomerular permselectivity (5, 6, 20, 24). In particular, it has been proposed that vast quantities of protein are normally filtered and that tubular reabsorption of intact proteins is primarily responsible for preventing loss of protein from the body (6, 24). The complex nature of the glomerular capillary wall with three distinct components has given rise to many questions regarding the specific roles of each of the major barriers, with arguments going from one extreme to the other (2, 6–9, 16, 20). Furthermore, the role of charge on the glomerular endothelium and basement membrane has been challenged anew (21, 26), even though it was once thought to be comfortably settled. In essence, almost every aspect of glomerular permselectivity is under new scrutiny, and we can only hope that the new studies will bring an enlightened understanding rather than further confusion.The utilization of fluorescently labeled probes of varying molecular size and charge coupled with applications of modern two-photon confocal microscopy has provided a new approach to answer these unresolved questions. Although numerous studies have examined the permeability properties of the glomerular membrane, the authors emphasize that the high resolution of the new technology coupled with the extraordinary width of the glomerular basement membrane (GBM) in kidneys from Necturus maculosus (salamander or commonly known as the "mud puppy") allows visualization and quantitation of the fluorescent molecules in the GBM as well as in Bowman's space. This allows for a more detailed consideration of the specific barrier functions of the individual components of the capillary wall. Volumes have been written about barrier functions of capillary systems throughout the body (17, 20, 28), but it is recognized that the glomerular capillaries are among the most complex and challenging to understand.Tanner and colleagues (27) make several important points. Certainly, one of the most important conclusions is that the overall glomerular permeability to large macromolecules, in particular albumin, is extremely low with a sieving coefficient in the range of 0.999. Furthermore, the PS coefficient is so low (0.001 ml/min) that solute flux due to diffusion also approaches 0. These quantitative considerations also highlight the difficulty in attempting to evaluate mechanisms of proteinuria. Theoretically, an increase in protein passage across the glomerular membrane of 100-fold could be accounted for by a change in σ from 0.999 to 0.90. Similarly, relatively small changes in σ caused by the anionic residues could easily lead to a perceptible difference in the glomerular sieving coefficient (10, 14, 28).However, what about the GBM? Does the accumulation of macromolecules in the GBM mean that it has a very low σ? I would contend that it does not. The accumulation of the solutes in the Necturus GBM only means that σ of the GBM is less than σ of the podocyte layer. However, the GBM could still have a σ of 0.9 or even higher, which would contribute greatly to the exclusion of macromolecular passage and yet, with time, there would still be a slow accumulation of the solutes in the GBM. The consideration of permeability properties of barriers in series is quite complex and requires detailed quantitative analysis. Qualitatively, however, it can be concluded that if the second barrier has a higher σ than the first barrier, then solutes will accumulate within the first barrier over time even if σ of the first barrier is still relatively high. Thus some entry of these large molecules would still occur over time, and the concentration would continue to approach the plasma concentration because of the greater restriction to passage by the podocyte layer. Interestingly, the authors indicate in the legend to Fig. 6 in their article (27) that dextran fluorescence in the GBM appeared to increase with time and was greater at 5 h. This finding suggests that the GBM does restrict entry of the macromolecules. In essence, unless the rate of accumulation of the macromolecules in the GBM is carefully assessed, it can only be concluded that σ is greater for the podocyte layer than for the GBM, but it is not justifiable to conclude that the GBM is a minor player in restricting passage of macromolecules. Perhaps the authors will consider a study evaluating the time-dependent changes in GBM macromolecular concentrations using fluorescent probes with different effective pore radii to obtain a better estimate of the actual restrictive properties of the GBM in the Necturus kidney. These data, coupled with a mathematical model evaluating the barrier functions of the three glomerular barriers in series, could provide an improved understanding of the relative roles of each component.I thank Debbie Olavarrieta for assistance in the preparation of this manuscript.AUTHOR NOTESAddress for reprint requests and other correspondence: L. G. Navar, Dept. of Physiology, SL39, Tulane Univ. Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112 (e-mail: navar@tulane.edu) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationREFERENCES1 Arendshorst WJ, Navar LG. Renal circulation and glomerular hemodynamics. In: Diseases of the Kidney and Urinary Tract, edited by Schrier RW. 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