Gentamicin sulfate was administered by intraperitoneal injection to male Sprague-Dawley rats in a dose of 100 to 120 mg/kg/day for 4 to 5 days to induce severe nephrotoxicity. In comparison to controls, insulin clearance was markedly decreased (2.87 ± 0.31 vs. 8.65 ± 0.31 ml/min/kg, P < 0.001) as was urinary osmolality (462 ± 36 vs. 1196 ± 46, P < 0.001). Surface tubules appeared heterogeneous. Some were plugged by whitish debris, whereas others were markedly dilated (I.D. = 41.5 ± 2 μ). All other tubules were moderately dilated (I.D. = 28.8 vs 20 μ). The microinfusion of tubules with cellular debris with an isotonic 'equilibrium' solution resulted in a rise in intratubular pressure to as high as 60 to 80 mm Hg, compared with 13 to 15 mm Hg in normal rats. In better functioning nephrons, free-flow pressure (FFP) was increased significantly (16.0 ± 0.5 vs. 10.2 ± 0.1 mm Hg, P < 0.001). Paired measurements of single nephron glomerular filtration rate (SNGFR) in these nephrons, made while monitoring intratubular pressure (ITP), revealed a rise in SNGFR when ITP was lowered from the initially high level to 10 mm Hg. Comparable changes in SNGFR were induced in normal rats by varying ITP from 10 to 15 mm Hg. The data suggest that in severe gentamicin nephrotoxicity, many cortical nephrons may be contributing very little to excretory function, presumably because of intratubular obstruction. The less impaired nephrons have reduced SNGFR, due in part to increased free-flow pressure. We conclude that varying degrees of tubular obstruction contribute to the reduction in whole kidney GFR in severe gentamicin nephrotoxicity.
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