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214 klenzak & himmelfarb in the setting of hyperdynamic sepsis. Although the role of hypoperfusion needs elucidation in the setting of sepsis, these studies certainly support the hypothesis that mediators of cellular injury, rather than lack of blood, play a larger role in the pathophysiology of ARF [6]. Vasopressors and acute renal failure In the setting of hypodynamic septic shock, compensatory increases in systemic vascular resistance become disabled, leading to pressor desensitivity and refractory hypotension without local autoregulation of the vital organs. Clinical concerns regarding the use of vasopressor therapies, which are known to induce vasoconstriction in the setting of ARF, are set aside by the supremacy of increasing systemic blood pressure to levels that continue to perfuse the remainder of the vital organs. Norepinephrine infusion may, in fact, increase RBF. Several animal studies have demonstrated increases in RBF with the use of norepinephrine infusion [7–12]. Recent work by Di et al [13] demonstrated that norepinephrine infusion in septic sheep induced an increase in RBF, countering concern that vasoconstrictors worsen blood delivery to the renal parenchyma in the setting of vasodilatory shock. Nitric oxide synthase In contrast, in hyperdynamic shock RBF is preserved, with apparent redistribution of flow from cortex to medulla, maintaining oxygen delivery to the most vulnerable portions of the renal parenchyma, while also decreasing the work of the tubules. This redistribution of blood flow coincides with an increase in nitric oxide (NO) in the medulla [14]. Inducible NO synthase (iNOS) can be expressed locally, in glomerular mesangial cells and endothelial cells, after stimulation with proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, and endotoxin [15]. Nonselective or selective blockade of NOS decreases RBF while increasing mean arterial pressure. This suggests that iNOS plays a role in maintaining RBF in the setting of shock through its vasodilatory effects at the afferent arteriole. Despite increases in iNOS, renal vasoconstriction can be seen in the setting of systemic vasodilation. The mechanism of vasodilation by NO is dependent on the synthesis of cyclic guanosine monophosphate by soluble guanylate cyclase. Studies of lipopolysaccharide (LPS) stimulation in mice leading to shock and ARF have demonstrated a decrease in cyclic guanosine monophosphate to basal levels at 24 hours, despite an early rise in and sustained iNOS levels, suggesting that desensitization of soluble guanylate cyclase results in loss of regulatory vasodilation in the kidney [16]. NOS inhibition in animal models of endotoxemia results in glomerular thrombosis and declines in creatinine clearance. The glomerular thrombosis in the setting of NOS inhibition seems related to the antithrombotic qualities of
sepsis and the kidney 215 NOS, by inhibiting leukocyte interactions with endothelial cells and inhibiting platelet aggregation [17]. Soluble and local mediators Endothelins The production of endothelins, which are potent vasoconstrictors, by endothelial, mesangial and tubular cells is stimulated by proinflammatory cytokines, including TNF. The vasoconstrictors vasopressin and angiotensin II also stimulate endothelin release. Endothelins cause vigorous constriction of the afferent and efferent arterioles, and mesangial cell contraction. The effects of endothelin may be secondary to its induction of platelet-activating factor (PAF) synthesis in the mesangium or thromboxane A 2 by the endothelium. Additionally, endothelin induces some vasodilators, counteracting its vasoconstricting effect, including prostacyclin, NO, and prostaglandin E 2 . Two endothelin receptors are active in the renal parenchyma: the endothelin-A receptor is found mainly in the vascular compartment, and the endothelin-B receptor is found mainly in the tubular compartment. In an animal model of glycerol-mediated toxic renal injury, selective antagonism of the endothelin-A receptor lessened the reduction in glomerular filtration rate [18]. Preliminary evidence suggested that the endothelin-B receptor was integral to clearing endothelin-1, and probably plays a beneficial role in ischemia. Studies of selective endothelin-A receptor blockade and nonselective endothelin receptor blockade (both endothelin-A receptor and endothelin-B receptor) demonstrated improved outcomes only for the selective blockade in a chronic ischemia animal model, further supporting the beneficial effects of intact endothelin-B receptor function [19]. Tumor necrosis factor and interleukin-1 Major mediators of cytokine-induced renal injury include TNF and IL-1, both of which promote further cytokine release, induce vasoconstriction, neutrophil aggregation, production of reactive oxygen species, and induction of tissue factor and promotion of thrombosis [20]. When infused into animal models, TNF and IL-1 result in renal damage and decrease RBF and glomerular filtration rate [21]. TNF is produced and circulated systemically, whereas IL-1 is expressed in the glomerular endothelial cells early in animal models of sepsis. These pleiotropic cytokines are capable of inducing mesangial and endothelial production of PAF, endothelin, adenosine, NO, and prostaglandin E 2 . The migration of activated neutrophils into the kidney in the setting of up-regulation of adhesion molecule expression by activated endothelial cells leads to further endothelial damage and is likely a seminal event in the pathogenesis of ARF. Ischemic animal models of ARF demonstrate a protective effect of monoclonal antibodies to adhesion molecules [22].
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