Endotoxin-induced renal failure - II. A role for tubular hypoxic damage

Endotoxin-induced hypotension and altered renal microcirculation could lead to tubular injury, particularly at the physiologically hypoxic outer medul la. We explored this hypothesis in isolated perfused kidneys and in vivo in rats subjected to endotoxemia. Rat kidneys were removed 15 min after endot oxin injection in vivo (from Escherichia coli 0127:B8, 1 mg/kg i.p.) and pe rfused with oxygenated medium supplemented with 20 amino acids and endotoxi n. Glomerular filtration rate and filtration fraction markedly declined (0. 4 +/- 0.1 ml/min and 1.1 +/- 0.1, respectively) as compared with control ki dneys (0.7 +/- 0.1 ml/min and 1.8 +/- 0.1, n = 8-12 per group; p < 0.05). H ypoxic injury to medullary thick ascending limbs in the innermost outer med ulla increased (47 +/- 9% of tubules vs. 16 +/- 8% in controls, p < 0.05). When rats were preconditioned with an additional endotoxin injection 16 h e arlier (a manipulation that markedly reduces cortical and medullary blood f low), glomerular filtration rate and filtration fraction further declined t o 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 subjecte d to a single or two repeated daily doses of endotoxin (1 mg/kg i.p.) plasm a creatinine comparably rose 41% on the average over 24 h, creatinine clear ance fell by 27% (p < 0.0001), but tubular damage was absent. By contrast, in rats preconditioned with indomethacin and the nitric oxide synthase inhi bitor N-G-nitro-L-arginine methyl ester (10 mg/kg), the addition of endotox in markedly augmented outer medullary hypoxic tubular damage both in S-3 se gments (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 o xide or prostaglandin synthesis, endotoxin may predispose to hypoxic outer medullary tubular damage. Copyright (C) 2000 S. Karger AG, Basel.