Early renal medullary hypoxic injury from radiocontrast and indomethacin

Abstract

We evaluated the acute changes in cortical and outer medullary oxygen tension and the alterations in renal function and morphology within the first 90 minutes after the administration of indomethacin and iothalamate to anesthetized Sprague-Dawley rats. Both agents were found to produce marked and protracted outer medullary hypoxia averaging 12 +/- 4 and 9 +/- 2 mm Hg, respectively (mean +/- SE). Given together to salt depleted uninephrectomized rats they produced an early hypoxic injury localized selectively in the outer medulla. This lesion progressed from 3 +/- 1% of medullary thick ascending limbs (mTALs) at 15 minutes to 22 +/- 7% at 24 hours. Condensed "dark" cells were observed at 15 minutes, probably representing a type of early injury. Residual red cell mass, quantified in the outer medullary vasculature of perfusion-fixed kidneys and presumably reflecting stasis, was substantially increased in iothalamate treated rats. Red cell mass in the interbundle zone correlated with mTAL necrosis. Taken together, these results show an early period of medullary hypoxia, accompanied by a selective injury to mTALs in the central interbundle zone with apparent stasis. These findings contrast sharply with the ischemia-reflow pattern of renal damage and emphasize the important role of medullary hypoxia in the genesis of acute renal failure in this model.

Promising novel therapy with hydrogen gas for emergency and critical care medicine

“…Injection of contrast medium promotes secretion of endothelin, a vasoconstrictor peptide produce by endothelial cells, by the renal parenchyma and the resulting vasoconstriction reduces renal tissue blood flow and oxygen supply 9. Also, the osmotic pressure is elevated by infusion of contrast medium, which increases the amount of NaCl reaching the ascending limb of the loop of Henle, and increased sodium reabsorption accelerates renal oxygen consumption.…”

Renal Parenchymal Hypoxia, Hypoxia Adaptation, and the Pathogenesis of Radiocontrast Nephropathy

“…The decline in outer medullary Po 2 , despite enhanced regional blood flow (outlined next), only emphasizes the important role for increased reabsorptive activity in the consequent regional hypoxia. Indeed, as shown in Figure 1, the inhibition of transport activity with the loop diuretic furosemide abruptly reverses radiocontrast-induced medullary hypoxemia (7,18). Furosemide-related attenuation of medullary hypoxemia takes place despite the profound regional vasoconstriction induced by this agent (19), again emphasizing the crucial role of regulated tubular transport activity in the determination of medullary oxygenation.…”

“…Using oxygen microelectrodes, Brezis and colleagues (7) found that after the injection of the high-osmolar ionic agent sodium iothalamate, cortical Po 2 declined from 40 to 25 mmHg. In the already hypoxic outer medulla, Po 2 fell from 26 mmHg at baseline to mean levels as low as 9 mmHg.…”

“…In vivo, administration of radiocontrast agents resulted in proximal tubular vacuolar changes and brush border simplification (flattening/loss of microvilli) (5,6). Nevertheless, these tubular anatomic findings seem to represent exposure to radiocontrast rather than true indicators of CIN and lack correlation with kidney dysfunction (7). Moreover, electron microscopy, at least in animal models, revealed that the "vacuolar" changes were in fact basolateral membrane outpouchings with otherwise intact cellular structures (8).…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…These include sepsis that induces renal vasoconstriction through the release of endothelin and the use of radiocontrast imaging dyes that increase oxygen consumption for solute reabsorption and reduce regional inner medullary blood flow. [54][55][56][57][58][59][60][61] More generalized reductions in blood flow represent another major cause of AKI. These can result from hemorrhage, decompensated liver cirrhosis, treatment with non-steroidal anti-inflammatory drugs, congestive heart failure, and renal artery occlusion or stenosis.…”