Acute Ischemic Renal Failure: Review of Experimental Studies on Pathophysiology and Potential Protective Interventions

More than 70% of acute renal failure in man is of circulatory nature and results from hypoxic injury to the kidney. Since intrarenal hemodynamic and metabolic events cannot be accurately assessed in human acute renal failure, various experimental models of renal hypoperfiision or complete interruption of renal blood supply, such as norepinephrine-induced acute renal faiure or clamping of the renal artery, have been employed to obtain more direct insight into the pathophysiological events and consequences of hypoxia, although none of these models may truly mimic human acute renal failure. In addition, the severity of experimental acute renal failure, that is, oliguric or nonoliguric acute renal failure resulting from renal hypoperfusion, depends not only on the model employed but also largely on the experimental conditions. In the hemodynamic models a vascular component is incriminated in the initial phase, and persistent tubular tissue dysfunction in the maintenance phase of ischemic acute renal failure. Hypoxic vascular injury will lead to vasoconstriction; a decrease in glomerular filtration pressure, glomerular capillary surface area, and permeability; and thus to a decrease in glomerular filtration rate. In contrast to previous concepts which incriminated the renal cortex as the main target tissue of hypoxic injury, in recent years attention has been focused on impaired medullary perfusion as the most prominent pathophysiological event leading to the decrease in total renal blood flow and glomerular filtration rate. Medullary congestion may result from hypoxic cell swelling with vascular compression. Cell swelling may also lead to tubular compression in addition to tubular obstruction by cast formation. Impaired cell volume regulation is due to decreased ATP supply and membrane damage occurring predominantly in the outer medulla, which operates normally at the brink of oxygen supply and is therefore most susceptible to hypoxic injury. Accumulation of intra-cellular and intramitochondrial calcium, greatly enhanced during reperfusion of the hypoxic tissue, will further impair cellular energy supply. Activated phospholipases are suspected to aggravate membrane damage, to which oxygen radical formation during reflow will mainly contribute. Our experimental data suggest that phar-macologic agents such as furosemide or calcium entry blockers, although they do not prevent qualitatively medullary cell injury, in general convert oliguric into nonoliguric acute renal failure with corresponding protection from severely impaired cellular energy metabolism and reversal of mitochondrial calcium overload. The osmotic diuretic mannitol additionally will preserve tubular integrity by its action as a potent hydroxyl radical scavanger.