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      Effect of Specific and Non-Specific Inhibition of COX-2 on Renal Oxygenation before and after Water Diuresis

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          Background/Aims: Water diuresis usually increases medullary oxygenation as a result of increased medullary synthesis of prostaglandins, but it is not clear whether this involves activation of cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2). Methods: The effects of celecoxib, a selective inhibitor of COX-2, and of ibuprofen, a non-specific inhibitor of COX-1 and COX-2, upon renal oxygenation during water diuresis were studied in a double-blind, prospective manner in 13 young women (age 24–34 years) using blood-oxygen level dependent magnetic resonance imaging. Celecoxib 200 mg b.i.d. for 4 days was compared with ibuprofen 80 mg b.i.d. for 4 days and with a placebo. Results: There was no effect of either drug on urinary volume, urinary osmolal concentration, or creatinine clearance. Water diuresis alone elicited a significant increase in oxygenation in borderline areas between cortex and medulla, which was eliminated by celecoxib or ibuprofen. Conclusion: Renal medullary oxygenation is improved by water diuresis in normal young women in a way that is blocked by a selective inhibitor of COX-2 as well as non-selective cyclooxygenase inhibitors. Selective COX-2 may be expected to have significant effects on renal functions.

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          Most cited references 11

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          Acute renal failure with selective medullary injury in the rat.

          Since human acute renal failure (ARF) is frequently the result of multiple rather than single insults, we used a combination of treatments to induce ARF in rats. Uninephrectomized, salt-depleted rats injected with indomethacin developed ARF after administration of radiocontrast. After 24 h, the plasma creatine rose from 103 +/- 3 to 211 +/- 22 mumol/liter (mean +/- SE) and the creatinine clearance dropped from 0.7 +/- 0.1 to 0.2 +/- 0.04 ml/min (P less than 0.001). Severe injury was confined to the outer medulla and comprised necrosis of medullary thick ascending limbs (mTALs), tubular collapse, and casts. Other nephron segments were free of damage except for the proximal convoluted tubules which showed vacuole formation originating from lateral limiting membranes that resembled changes reported in human contrast nephropathy. Cell damage to mTALs included mitochondrial swelling, nuclear pyknosis, and cytoplasmic disruption with superimposed calcification; these changes were most severe in the deepest areas of the outer medulla, away from vasa recta in zones remote from oxygen supply. The fraction of mTALs with severe damage was 30 +/- 7% (range 2-68) and the extent of injury was correlated with a rise in plasma creatinine (r = 0.8, P less than 0.001). Thus, the nature of mTAL injury was similar to the selective lesions observed in isolated kidneys perfused with cell-free medium and was shown to derive from an imbalance between high oxygen demand by actively transporting mTALs and the meager oxygen supply to the renal medulla. Combined multiple renal insults in the rat produce ARF that resembles the clinical syndrome of contrast nephropathy and is characterized by selective mTAL injury conditioned by medullary hypoxia.
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            Changes in renal medullary pO2 during water diuresis as evaluated by blood oxygenation level-dependent magnetic resonance imaging: effects of aging and cyclooxygenase inhibition.

            Hypoxia of the renal medulla has been implicated in the development of renal injury, particularly acute renal failure, and its regulation in humans may therefore be relevant to certain renal disorders. Changes in oxygenation of the renal medulla can now be monitored noninvasively with blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI). Using this method, water diuresis has been shown to improve medullary oxygenation in young persons. Urinary excretion of prostaglandin E2 (PGE2) likewise increases during water diuresis in younger but not in older people. We used BOLD MRI to measure the effects of aging and of inhibiting prostaglandin synthetase on the renal response to water diuresis in healthy human subjects. Nine younger (25 to 31 years) and nine older (59 to 79 years) female volunteers were studied with BOLD MRI during antidiuresis in the postabsorptive state and during water diuresis. Simultaneously, urinary excretion of PGE2 was determined. PG synthetase was inhibited by administering ibuprofen. Renal medullary oxygenation, initially low, greatly improved during diuresis in younger subjects, whereas PGE2 excretion increased. In older women, however, water diuresis elicited no change in oxygenation of renal medulla or PGE2 excretion. Ibuprofen inhibited excretion of PGE2 and blocked the increase in medullary oxygenation normally produced by water diuresis in the young. The increase in oxygenation of the renal medulla accompanying water diuresis depends on PGE2 synthesis. Attenuation of renal PGE2 synthesis in older people is probably responsible, at least in part, for the loss of the ability to improve medullary oxygenation that younger subjects possess. Inability to improve renal medullary oxygenation might predispose to hypoxic renal injury in older patients.
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              Physiology of renal hypoxia.


                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                April 2005
                18 March 2005
                : 99
                : 4
                : p101-p104
                Departments of aMedicine and bRadiology, Beth Israel Deaconess Medical Center and Harvard Medical School, and cDivision of Nephrology, Tufts-New England Medical Center, Boston, Mass., USA
                83767 Nephron Physiol 2005;99:p101–p104
                © 2005 S. Karger AG, Basel

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