PHYSICO-CHEMICAL ASPECTS OF RENAL TRANSPORT PROCESSES

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The normal glomerular capillary wall is extremely permeable to water, and yet very effective at preventing the loss of plasma proteins into the glomerular ultrafiltrate. In the principal forms of kidney disease both of these aspects of glomerular function tend to be impaired: there is a reduced capacity for filtration of water, accompanied by less ability to selectively retain plasma proteins. Clearance studies in experimental animals and humans using various exogenous polymers have established that the selectivity of the glomerular barrier to macromolecules is based on both molecular size and molecular charge, but the biophysical basis for normal or impaired selectivity remains poorly understood. Specifically, the mathematical models currently available to interpret such data offer little insight into how structural changes in the glomerular-capillary wall might affect its performance as an ultrafiltration membrane. The overall objective of the proposed research is to develop new theoretical models which will relate the size- and charge-selective properties of the glomerular barrier to the physical characteristics of particular structures within the capillary wall. One specific aim is to synthesize and characterize a new anionic test macromolecule, Ficoll sulfate, for use as a probe of glomerular charge-selectivity. A second aim is to study convection and diffusion of macromolecules of varying size and charge in well-characterized synthetic gels, which will be used as experimental models for transport in the glomerular basement membrane. The physical relationships established in those studies will assist in the achievement of a third specific aim, which is to analyze filtration and diffusion data obtained with neutral Ficoll and Ficoll sulfate in isolated rat glomerular basement membrane. The synthetic gels and the basement membrane will both be modeled as media where transport is through fluid-filled interstices among a disordered array of fibers, and the restrictions to molecules of varying size and charge will be interpreted in terms of physical parameters such as fiber radius, fiber charge, and average interfiber spacing. As the final major aim, a theoretical model for macromolecule transport across the intact glomerular capillary wall will be developed, based on a repeating structural unit consisting of a single epithelial filtration slit and corresponding areas of basement membrane and fenestrated endothelium. This model will be used to elucidate the contributions of the various individual structures to glomerular permeability properties observed in health and disease.