Transglomerular sieving of uncharged dextrans of graded size has been used to characterize the human glomerular capillary wall (GCW) as a heterosporous membrane with two parameters. One is ro, the radius of cylindrical, restrictive pores that occupy most of the membrane. The second, omegao was strongly related to both the magnitude and composition of proteinuria in 5 common glomerular diseases of man. We now wish to quantify two additional membrane parameters: cm, the net charge density of the GCW, may also contribute to proteinuria, and will be calculated from transglomerular sieving of an anionic dextran sulfate probe of known molecular size and charge. Kappaf, the ultrafiltration coefficient of all filtering glomeruli in the two human kidneys, is the product of hydraulic permeability and total surface area. Its determination requires knowledge of the transmembrane hydraulic pressure difference (DeltaP), which we propose to estimate from a theoretical analysis of dextran sieving data. To optimize the estimation, we will compare lambdaP estimated from dextran sieving data in rats with chronic glomerular disease to values estimated by micropuncture in the same animals. Existing theoretical models will be modified so as to optimize agreement and then applied to humans to estimate kappaf. This physiologic approach will be combined with morphometric examination of glomeruli. The dimensions and relative number of sclerosed (non-filtering) and remnant (filtering) glomeruli will be estimated to determine available filtration surface area. Alterations of the filtration barrier will also be evaluated morphometrically. Each membrane parameter (q 12 mo) and morphometric quantity (q 36 mo.), along with GFR and fractional protein clearances (q 6 mo.) will be used to monitor the course and progression rate of lupus-and diabetes-related glomerulopathies in longitudinal fashion for 5-10 years. We hope to gain insights into the pathogenesis of end-stage renal failure in these common disorders, and to evaluate the extent to which remnant hyperfiltration can offset the GFR- lowering effect of progression sclerosis of an increasing fraction of glomeruli. We also hope to define sensitive measures of barrier dysfunction that will successfully predict advancing glomerulosclerosis before a progressive fall in 2-kidney GFR can be identified.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine B Study Section (GMB)
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Stanford University
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