Dynamics of the glomerular filtration barrier - Physiological and pathophysiological aspects

Abstract: The dynamic properties of the glomerular filtration barrier (GFB) are of fundamental importance for the understanding of the physiology and pathophysiology of microalbuminuria and proteinuric diseases. In the studies of this doctoral thesis the properties of the rat glomerular filtration barrier were investigated under resting conditions and following a number of challenges using highly sensitive gel filtration chromatography (HPSEC) detection of FITC-Ficoll in serum and urine. This permeability model is extremely sensitive, and by using HPSEC, it was possible to measure extremely low concentrations of Ficoll molecules in the urine. Under resting conditions the sieving coefficient (θ; filtrate-to-plasma concentration ratio) for Ficoll 70Å was approximately 0.00001, and θ for albumin was found to be low, 0.0003 (or less). During increases in glomerular permeability θ for albumin and θ for Ficoll 50-80Å increased in parallel, conceivably reflecting an increase in the number of large pores in the GFB. In study I, lipopolysaccharide (LPS) induced sepsis produced increases in θ for albumin and θ for Ficoll 50-80Å, at 120 min after LPS injection. In anaphylaxis there was a rapid permeability response already after 5 min which was reversed within 40 min. In study II, laparotomy, with or without muscle crush trauma, induced an increase in glomerular permeability after 5 min, which was to a large extent sustained after 60 min. Hyperglycemia (study III) induced an increase in θ for Ficoll 50-80Å after 20 min, but not at 5 min, and after 60 min glomerular permeability was back to normal. The permeability increase seen after hyperglycemia at 20 min was totally abolished by a Rho-kinase inhibitor, indicating that the cytoskeleton of endothelial cells and/or podocytes may be involved. In study IV, high or low doses of ANP induced an increase in glomerular permeability for Ficoll 50-80Å, reaching its maximum at 5 and 15 min. During ANP infusion (cf. congestive heart failure) there was a bimodal response, with a dip after 30 min, after which θ for Ficoll 50-80Å again tended to increase. In this thesis the novel concept of a rapidly dynamic glomerular filtration barrier is introduced. During different challenges, the size-selectivity of the GFB, rather than its charge-selectivity, was found to be subject to rapid and reversible alterations.