Altered glomerular permselectivity and progressive sclerosis following extreme ablation of renal mass

Glomerular permselectivity to macromolecules, glomerular morphology, and glomerular localization of tracer macromolecules in four groups of male Munich-Wistar rats were studied. Group 1 rats underwent a laparotomy and sham nephrectomy and were fed a standard diet. Group 2 rats underwent right nephrectomy and infarction of five sixths of the left kidney and were fed a standard diet. Both groups 1 and 2 were studied 7 days after the surgery. Group 3 rats received the ablative procedure and diet as group 2 animals except that they were studied 14 days after surgery. Group 4 rats underwent the same ablative procedure as groups 2 and 3 but were fed a low protein diet and were studied at 7 days. This low protein diet was recently shown by us to prevent the characteristic increases in glomerular pressures and flows that otherwise occur with renal ablation. Urinary protein excretion increased more than four-fold in groups 2 and 3 as compared to group 1. Low protein feeding was effective in preventing the proteinuria in group 4. Fractional clearances of the neutral derivative of horseradish peroxidase were not different among the groups. Likewise, the fractional clearances of neutral dextrans up to 38 Å in molecular radius did not differ statistically in groups 1, 2, and 3. However, the associated hemodynamic changes in these ablated animals predict reductions in the fractional clearances of neutral macromolecules; thus, the observed lack of change in these fractional clearances suggests the presence of an offsetting glomerular size-selective defect. In accord with this prediction, fractional clearances of dextrans larger than 38 Å in radius were increased in groups 2 and 3, relative to group 1. Studies with charged horseradish peroxidase and dextran sulfate also demonstrated a defect in the charge-selective function of the glomerular capillaries, leading to increased fractional clearances of anionic macromolecules in groups 2 and 3. As with proteinuria, group 4 was protected from this defect, as evidenced by a slightly elevated fractional clearance of anionic horseradish peroxidase which, however, was not significantly different than that of group 1. Marked structural changes in remnant glomeruli were present in groups 2 and 3. The more marked changes in the latter group included focal and segmental detachment of endothelial and epithelial cells from the basement membrane and a progressive increase in mesangial matrix and cellularity. Native ferritin molecules accumulated to a striking degree within the mesangium of groups 2 and 3 rats. Group 4 animals were protected from this accumulation as well as from the structural changes described in groups 2 and 3. These findings therefore indicate that proteinuria in rats subjected to severe reductions in renal mass is associated with defects in the size- and charge-selective properties of the glomerular capillaries. These changes in permselectivity are coincidental with structural alterations of the capillary wall and mesangial accumulation of fibrin and exogenously administered ferritins. Low protein feeding is remarkably effective in reducing these functional and anatomic defects. Thus, our findings suggest that specific defects in glomerular structure and permselectivity attend the glomerular hemodynamic alterations that occur in remnant nephrons and that these lesions are prevented largely when the hemodynamic changes are mitigated.