Fig. 14.16 ). Several factors predispose these cells to toxic and ischemic injury, including elevated intracellular concentrations of various molecules that are resorbed or secreted across the proximal tubule, exposure to high concentrations of luminal solutes that are concentrated by the resorption of water from the glomerular filtrate, and a high rate of oxygen consumption, which is required to generate the ATP that is needed for transport and reabsorption functions.
Ischemia causes numerous structural alterations in epithelial cells. Loss of cell polarity is an early reversible event caused by ischemia. It leads to the redistribution of membrane proteins (e.g., Na+,K+-ATPase) from the basolateral to the luminal surface of tubular cells, resulting in decreased sodium reabsorption by proximal tubules and hence increased sodium delivery to distal tubules. The latter, through a tubuloglomerular feedback mechanism, contributes to afferent arteriolar vasoconstriction and a decrease in GFR, further worsening the perfusion (discussed below). Injury to the epithelial cells causes detachment of the damaged cells from the basement membranes, and their shedding into the urine. If sufficient tubular debris builds up, it can block the outflow of urine (obstruction by casts), increasing intratubular pressure and thereby exacerbating the decline in GFR. Additionally, fluid from the damaged tubules may leak back into the interstitium, resulting in decreased urine output, increased interstitial pressure, and collapse of the tubules. Ischemic tubular cells also express chemokines, cytokines, and adhesion molecules such as P-selectin that recruit leukocytes (interstitial inflammation) and can participate in tissue injury. Necrotic tubular cells also may elicit an inflammatory reaction that contributes to the tubular injury and functional derangements.
Tubular injury is exacerbated by severe hemodynamic alterations that cause reduced GFR. The major one is intra-renal vasoconstriction, which results in both reduced glomerular plasma flow and reduced oxygen delivery to the tubules in the outer medulla (thick ascending limb and straight segment of the proximal tubule) (see
Fig. 14.16 ). Although a number of vasoconstrictor pathways have been implicated in this phenomenon (e.g., renin-angiotensin, thromboxane A2, sympathetic nerve activity), the current opinion is that vasoconstriction is mediated by sublethal endothelial injury, leading to increased release of the endothelial vasoconstrictor endothelin and decreased production of vasodilatory nitric oxide and prostaglandins. Finally, some evidence points to a direct effect of ischemia or toxins on the glomerulus, causing a reduced effective glomerular filtration surface.
The patchiness of tubular necrosis and maintenance of the integrity of the basement membrane along many segments allow repair of the injured foci and recovery of function if the precipitating cause is removed. This repair is dependent on the capacity of reversibly injured epithelial cells to proliferate and differentiate.
Fig. 14.16 Postulatedsequenceinischemicortoxictubularinjury.
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MORPHOLOGYIschemic ATI ischaracterizedbylesionsinthestraightportionsoftheproximaltubuleandtheascendingthicklimbs,butnosegmentoftheproximalordistaltubulesisspared.Thereisoftenavarietyoftubular injuries, includingattenuationofproximaltubularbrushborders,blebbingandsloughingofbrushborders,vacuolizationofcells,anddetachmentoftubularcellsfromtheirunderlyingbasementmembraneswithsloughingofcellsintotheurine(