Pathogenetic and Regenerative Mechanisms in Acute Tubular Necrosis

Vascular Contribution The pathophysiology of ischemic renal injury is complex. There is clearly an important vascular component to the injury, not only at the level of total renal perfusion but also at the microvascular level where the heterogeneity of blood flow, arteriolar vasoconstriction, and capillary obstruction limit oxygen delivery to renal tubular cells whose oxygen needs are quite high. Within the kidney small vessel disease secondary to atherosclerosis, atheroemboli, or vasculitis or an imbalance between vasoconstrictive and vasodilatory factors can contribute to compromised oxygen delivery to epithelial cells leading to tubular cell necrosis. The heterogeneity of blood flow plays an important role in the pathophysiology of ischemic renal failure. Vascular congestion in the outer medulla [1] and decreased blood flow [2] to this region are features of experimental ischemic acute renal failure in rats. This vascular congestion may be the result, at least in part, of swelling of endothelial or tubular epithelial cells, resulting in interference with flow through the vasa recta and may further compromise of blood flow. The vulnerability of the tubules in the outer medulla is also enhanced by the vasa recta counter current exchange of oxygen which results in a marked drop-off in oxygen tension with increasing distance into the medulla from the cortex [3]. The S3 segment of the proximal tubule, the pars recta, traverses this region and is very sensitive to ischemic injury. In a number of studies that we and others have carried out in which unilateral or bilateral renal ischemia is induced by either transient complete cessation of renal blood flow [4] or partial reduction in blood flow [4–6], cell injury and necrosis is most apparent in the S3 segment. Adherence of the leukocyte to the vascular endothelium may play an essential role in compromising flow in the microvessels supplying the S3 segment. Leukocyte-endothelial cell adherence depends upon adhesion molecules on both the leukocyte and the endothelial cell. Elevated syst mic tumor necrosis factorα and IL-1 levels after ischemia and reperfusion provide a possible mechanism of upregulation of intercellular adhesion molecule-1 (ICAM-1) in the post-ischemic tissue [7]. In addition, other endothelial adhesion molecules are upregulated with ischemia and reperfusion. Some of these are well characterized such as E-selectin, but others identified in vitro in hypoxia-exposed endothelial cells are incompletely characterized. Ischemia/reperfusion is associated with complement activation, and increased levels of tissue lipid mediators, such as leukotrienes and platelet-activating factor, which are chemotactic for neutrophils. Adherent and activated leukocytes release reactive oxygen species, proteases, elastases, myeloperoxidase, leukotrienes, and other enzymes that damage the ischemic tissue directly, enhance additional inflammatory cell infiltration, increase vascular permeability and upregulate adhesion molecule expression promoting further inflammation and increased vasoconstriction. Postischemic kidneys undergo in reased injury when perfused with activated neutrophils [8]. The administration of a monoclonal antibody directed Plenary Lectures