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The dimensions of individual capillary segments were determined from a glomerular model constructed on the basis of electron micrographs of subserial ultrathin sections of kidney tissue from a rat made chronically uremic by subtotal nephrectomy. Hemodynamic calculations used computer programs for node pressure analysis and for the determination of path lengths and transit times from afferent to efferent arteriole. The afferent arteriole divided into five primary capillary segments. Three of these carried 84% of the flow through 632 paths, which accounted for 54% of the capillary endothelial area. Their mean path length was 520.97 micron, mean of segment numbers per path 17.66, and mean transit time 0.50 sec. The remaining two capillary segments carried 16% of the flow and led to paths accounting for the remaining 46% of the capillary area. The number of paths from the afferent arteriole through these two segments was 21,244. Mean path length from the initial node through these two segments was 852.18 micron, mean of segment numbers per path 29.62, and mean transit time 20.76 sec. The most striking difference between the two sets of paths was in transit time. This asymmetry would tend to reduce the filtration surface and the Kf (hydraulic conductance x filtering surface area) by causing early filtration pressure equilibrium in much of the capillary network, and suggests an intrinsic glomerular aspect of chronic renal insufficiency.

Subtotal nephrectomy in the rat gives rise to progressive proteinuria, glomerular hypertrophy, and glomerulosclerosis. The proteinuria antedates significant ultrastructural lesions demonstrable by conventional techniques; its mechanism is obscure. In this article it is shown that proteinuria in this system is not accompanied by evident changes in the ultrastructural distribution of anionic sites in the glomerular basement membrane, as determined by organ perfusion with two cationic probe molecules. It is suggested that the proteinuria may reflect a change in the steric aspect of glomerular ultrafilration, in which the loss of renal mass imposes a significant rise in capillary pressure in a structure whose capillaries are peculiar in the high pressures they normally sustain and in their lack of mechanical support from the interstitium. It is suggested that a sustained rise in capillary pressure overcomes the rigidity of the glomerular basement membrane, so that its pore size increases and proteinuria results from basement membrane failure.

Changes of glomerular volume in rats were measured up to 21 weeks following subtotal nephrectomy, using morphometric methods. A linear increase of glomerular volume was observed between 2 and 21 weeks after subtotal nephrectomy. This progressive increase in glomerular volume may reflect compensatory hemodynamic changes leading to an increased single nephron glomerular filtration rate.

In the development of disease of the glomerular capillary bed there is a triple association between loss of nephrons, adaptive hyperfunction of residual glomeruli, and hypertrophy and sclerosis of these glomeruli. Sclerosis is closely associated with hypertrophy, and both are closely tied to loss of nephrons. This paper quantifies the response over a period of 12 weeks of superficial cortical (SC), midcortical (MC) and juxtamedullary (JM) glomeruli of the Munich Wistar rat to the ablation of approximately 5/6 of renal tissue. The mean areas of peripheral and mesangial glomerular basement membrane (GBM) were estimated by stereologic methods. While the overall estimated area of the GBM increased in response to ablation by a factor of 2.4, the peripheral GBM area increased only by a factor of 2.15, and by way of contrast, the mesangial GBM area by a factor of 3.25. The latter difference is interpreted as a measure of glomerulosclerosis. There are no marked differences between the changes in SC, MC, or JM glomeruli. These findings are consistent with the association of glomerular hypertrophy and glomerulosclerosis, and with recent suggestions that glomerular hypertrophy and sclerosis following subtotal renal ablation are driven by local or circulating growth factors.

Kidney from normal male albino rats, of body weight 170-200 g, was fixed by arterial perfusion with buffered tannic acid-glutaraldehyde, and postfixed with osmium tetroxide. Random and isotropic ultrathin sections from 23 different glomeruli from five rats were mounted on slot grids for staining and electron microscopy. Prints of whole glomeruli at a magnification of 3,909 were analyzed by stereological methods. The mean glomerular volume was (8.048 +/- 0.474) X 10(5) mum3 if the glomeruli are treated as spheres. The area of the basement membrane was 0.281 +/- 0.017 mm2 per glomerulus, of which 0.184 +/- 0.011 mm2 represents peripheral basement membrane. The aggregate epithelial slit length per glomerulus was 65.19 +/- 3.84 cm, of which 48.69 +/- 2.87 cm represents epithelial slits abutting on the peripheral basement membrane. Assuming that a slit diaphragm is 390 A wide, and that the pores of the slit diaphragm represent 26% of its area, the mean pore area is 3.96 cm2, of which 2.96 cm2 represents the area of peripheral pores. These findings are discussed in the context of the hydrodynamic theory of glomerular ultrafiltration. We conclude that the porous substructure of the glomerular slit diaphragm is significant in determining the hydraulic conductivity of the glomerulus and hence also solute flux during ultrafiltration.

Subtotal nephrectomy in the rat is followed by glomerular hypertrophy, glomerulosclerosis, and, ultimately, renal failure. To gain more insight into this sequence, we have made a morphometric study of the glomerular changes following subtotal nephrectomy in the rat during the period of functional compensation before glomerulosclerosis appears. We found a twofold increase in glomerular volume as compared with controls 2 weeks after operation (to approximately 2 X 10(6) cu mu) followed by a linear increase to approximately 5 X 10(6) cu mu at 21 weeks. The rate of increase in glomerular volume in controls did not significantly exceed that of body weight. The volume increase after subtotal nephrectomy is a true hypertrophy, since other morphometric parameters expressed per unit glomerular volume (surface and length densities) were approximately 80% of control values at 2 weeks and constant thereafter. Glomerular hypertrophy up to 21 weeks is accompanied by a stable BUN and a gradually increasing proteinuria. We conclude that glomerular hypertrophy in this system is a pathologic rather than a compensatory process and suggest that it may represent a counter-productive response to hemodynamic changes serving to increase the glomerular filtration rate.

Physiological studies of glomerular function in the rat have been much advanced by the accessibility of superficial glomeruli for micropuncture in a mutant strain, the Munich Wistar (MW) rat. An important parameter studied in this way is the glomerular ultrafiltration coefficient, or Kf. Kf is the product of hydraulic permeability and of the effective filtration surface area. Confounding factors are the variation in anatomical glomerular filtration surface in the rat with body weight (BW) and with the anatomical position of the glomerulus. To establish appropriate anatomical values for the interpretation of Kf in the MW rat, we have carried out a morphometric study by electron microscopy of two groups of relatively mature male MW rats, of approximately 200 g and approximately 300 g BW respectively. We find that superficial cortical (SC) and midcortical (MC) glomeruli of MW rats of approximately 200 g BW have relatively low glomerular volumes and anatomical filtration surface areas, but that MW rats of approximately 300 g BW have larger SC and MC glomeruli of similar size to juxtamedullary (JM) glomeruli, and anatomical filtration surface areas comparable to values usually assumed in physiological studies. We ascribe this contrast between SC glomeruli of MW rats of approximately 200 g and approximately 300 g BW respectively to the maturation of SC glomeruli.