Structural basis for reduced glomerular filtration capacity in nephrotic humans

Previous studies have established that in a variety of human glomerulopathies the reduced glomerular filtration rate (GFR) is due to a marked lowering of the ultrafiltration coefficient (K(f)). To identify the factors which lower K(f), we measured the filtering surface area per glomerulus, filtration slit frequency, basement membrane thickness, and GFR and its determinants in patients with minimal change and membranous nephropathies and in age-matched healthy controls. Overall values of K(f) for the two kidneys were calculated from GFR, renal plasma flow rate, systemic colloid osmotic pressure, and three assumed values for the transcapillary pressure difference. 'Experimental' values of the glomerular hydraulic permeability (k(exp)) were then calculated from K(f), glomerular filtering surface area, and estimates of the total number of nephrons of the two kidneys. Independent estimates of the glomerular hydraulic permeability (k(model)) were obtained using a recent mathematical model that is based on analyses of viscous flow through the various structural components of the glomerular capillary wall. Individual values of basement membrane thickness and filtration slit frequency were used as inputs in this model. The results indicate that the reductions of K(f) in both nephropathies can be attributed entirely to reduced glomerular hydraulic permeability. The mean values of k(exp) and k(model) were very similar in both disorders and much smaller in the nephrotic groups than in healthy controls. There was good agreement between k(exp) and k(model) for any given group of subjects. It was shown that, in both groups of nephrotics, filtration slit frequency was a more important determinant of the water flow resistance than was basement membrane thickness. The decrease in filtration slit frequency observed in both disorders caused the average path length for the filtrate to increase, thereby explaining the decreased hydraulic permeability.