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      Endotoxin-Induced Renal Failure

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          Endotoxin-induced hypotension and altered renal microcirculation could lead to tubular injury, particularly at the physiologically hypoxic outer medulla. We explored this hypothesis in isolated perfused kidneys and in vivo in rats subjected to endotoxemia. Rat kidneys were removed 15 min after endotoxin injection in vivo (from Escherichia coli 0127:B8, 1 mg/kg i.p.) and perfused with oxygenated medium supplemented with 20 amino acids and endotoxin. Glomerular filtration rate and filtration fraction markedly declined (0.4 ± 0.1 ml/min and 1.1 ± 0.1, respectively) as compared with control kidneys (0.7 ± 0.1 ml/min and 1.8 ± 0.1, n = 8–12 per group; p < 0.05). Hypoxic injury to medullary thick ascending limbs in the innermost outer medulla increased (47 ± 9% of tubules vs. 16 ± 8% in controls, p < 0.05). When rats were preconditioned with an additional endotoxin injection 16 h earlier (a manipulation that markedly reduces cortical and medullary blood flow), glomerular filtration rate and filtration fraction further declined to 0.1 ± 0.0 ml/min and 0.4 ± 0.1, respectively (p < 0.01), and tubular sodium reabsorption fell to 81 ± 12 vs 98 ± 0% in controls (p < 0.05). Tubular damage, however, did not increase (20 ± 7%), probably reflecting a decline in reabsorptive workload and oxygen requirement. In rats subjected to a single or two repeated daily doses of endotoxin (1 mg/kg i.p.) plasma creatinine comparably rose 41% on the average over 24 h, creatinine clearance fell by 27% (p < 0.0001), but tubular damage was absent. By contrast, in rats preconditioned with indomethacin and the nitric oxide synthase inhibitor N<sup>G</sup>-nitro- L-arginine methyl ester (10 mg/kg), the addition of endotoxin markedly augmented outer medullary hypoxic tubular damage both in S<sub>3</sub> segments (27 ± 10 vs 1 ± 1%) and in medullary thick ascending limbs (38 ± 11 vs. 10 ± 5%, n = 7–8; p < 0.05). It is concluded that under special conditions, such as altered medullary oxygen balance or defective nitric oxide or prostaglandin synthesis, endotoxin may predispose to hypoxic outer medullary tubular damage.

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          Hypoxia of the renal medulla--its implications for disease.

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            Endotoxin-Induced Renal Failure

            The pathogenesis of sepsis-induced renal failure is multifactorial and only partially understood. In these studies we evaluated intrarenal microcirculatory changes during endotoxemia and the potential role of nitric oxide (NO) and endothelin in these changes. In anesthetized rats endotoxin infusion [lipopolysaccharide (LPS), Escherichia coli serotype 0127:B8; 10 mg/kg/h] resulted in hypotension and a transient enhancement of renal blood flow, with cortical vasodilation and a loss of outer medullary vasodilatory response to hypotension. The initial cortical vasodilation was abolished by the NO synthase inhibitor NG-nitro- L -arginine methyl ester, but not by indomethacin. Direct NO measurements disclosed a gradual rise in cortical NO, despite the waning vasodilatory effect, suggesting antagonizing vasoconstrictive stimuli. In rats pretreated by LPS (1 mg/kg i.p. 1 day earlier) the renal blood flow was reduced to 55% of that of controls. Moreover, the vasodilatory response to LPS infusion was converted into profound cortical and medullary vasoconstriction. In these preconditioned rats the endothelin receptor antagonist bosentan evoked a vasodilatory response and attenuated the vasoconstrictive reaction to LPS infusion. The infusion of another LPS ( E. coli serotype 0111:B4) exerted predominant and protracted renal vasodilation without hypotension. In conclusion, different LPS exert diverse systemic and renal hemodynamic responses. The 0127:B8 serotype attenuates renal medullary vasodilation during hypotension, exerts transient cortical vasodilation, and following repeated exposure induces profound renal vasoconstriction. NO and endothelin participate in LPS-induced vascular responses that may predispose to hypoxic tubular damage.

              Author and article information

              Nephron Exp Nephrol
              Cardiorenal Medicine
              S. Karger AG
              October 2000
              31 July 2000
              : 8
              : 4-5
              : 275-282
              aDepartment of Medicine, Hadassah University Hospital, Mt. Scopus, and Hebrew University Medical School and bNephrology Unit, Bikur Holim Hospital, Jerusalem, Israel; cDepartment of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass., USA
              20679 Exp Nephrol 2000;8:275–282
              © 2000 S. Karger AG, Basel

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              Figures: 3, Tables: 4, References: 28, Pages: 8
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