sepsis and the kidney.pdf - SASSiT

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216 klenzak & himmelfarb Local soluble mediators Cellular and humoral cytokines are integral to organ dysfunction in sepsis syndromes, with the kidney being especially vulnerable to cytokine-mediated injury. CD14 is expressed by mesangial cells and can be stimulated directly by LPS. The mesangial cells are capable of expressing multiple proinflammatory cytokines and chemokines, IL-1, IL-6, TNF, and PAF. Tubular cells are also capable of releasing proinflammatory cytokines after stimulation by LPS [23]. Studies of isolated kidneys perfused ex vivo with LPS do not demonstrate a decrease in glomerular filtration rate despite increased mRNA expression for proinflammatory cytokines. In vivo experiments involving LPS stimulation demonstrate the expected renal dysfunction, however, suggesting that the ARF in this setting is caused by host factors outside the renal parenchyma [24,25]. Specific mediators of vascular resistance and endothelial injury whose expression is induced by LPS in vivo include PAF, endothelin-1, and iNOS. Each of these soluble proteins has been shown to decrease glomerular filtration rate and RBF, leading to decreased urine output. Animal studies using antagonists to each of these soluble mediators have demonstrated amelioration of the renal injury [15,19,26]. PAF is a vasoconstrictor that additionally is chemotactic for activated inflammatory cells, including neutrophils. It can be produced by glomerular cells and by circulating inflammatory cells, such as neutrophils and macrophages. Increases in PAF lead to a reduction in glomerular filtration rate. Blockade of PAF receptors lessens the deterioration of renal function in models of endotoxemia [26]. Oxidative stress It has recently been demonstrated that there are high levels of oxidative stress in patients with ARF in the setting of critical illness. These patients demonstrated diminished thiol content and increased carbonyl content in plasma proteins. The excess burden of protein oxidation is significantly greater in patients with ARF as compared with critically ill patients with preserved renal function or patients with dialysis-dependent chronic kidney disease. The levels of protein oxidation are improved by dialysis, but only transiently, and oxidized proteins continue to accumulate during the intradialytic period [27]. The oxidative burden in patients who have ARF in the setting of critical illness may be a target for potential therapies to decrease their excess mortality. Endothelium Endothelial activation induced by circulating cytokines and activated complement is likely a key instigator in the evolution of sepsis-associated ARF. The changes induced in endothelial function by this stimulation enhance the
inflammatory process by increasing the production of inflammatory mediators. Endothelial activation is an early host response to circulating pathogens, and likely is triggered by activated and adherent neutrophils and their degradation products. The release of cytokines from the activated endothelium may be an early and aggressive defense. The dysfunctional endothelium is more severely damaged and results in the leaky capillaries associated with sepsis. The process by which endothelium evolves from activated and physiologic to damaged and dysfunctional is relatively unknown and represents a key area for research and a potential target for therapy. Coagulation cascade sepsis and the kidney 217 The activation of coagulation and deposition of fibrin in the tissues is a welldefined component of the MOSF in sepsis. Increased expression of tissue factor in response to LPS and TNF stimulation of inflammatory and endothelial cells may contribute to organ injury in sepsis, including renal injury. Tissue factor binds activated factor VII. This complex activates factor X, which cleaves prothrombin to thrombin, which in turn cleaves fibrinogen to fibrin. The activation of the coagulation cascade increases the tissue inflammatory response. Fibrin is often deposited in the intravascular space in animal models of sepsis, including the glomerular capillaries. For these reasons, anticoagulant therapies, or therapies that interfere with initiation of coagulation, are of potential interest in ameliorating MOSF, including renal failure. In a primate model of sepsis, animals were treated with site-inactivated factor VIIa, which serves as a competitive inhibitor of tissue factor, to block the initiation of the coagulation cascade. The treated animals showed preserved renal function at 48 hours, less metabolic acidosis, and better urine output. Histologic examination of the kidneys demonstrated less tubular injury, inflammatory cell infiltration, and fewer fibrin clots than in untreated animals [28]. Activated protein C improves outcomes in sepsis, and it is currently unclear whether it also attenuates sepsis-associated ARF [29]. Management of sepsis-associated acute renal failure Renal replacement therapy The introduction of hemodialysis for the treatment of severe ARF lowered the mortality rate from greater than 90% to approximately 50%. The widespread availability of continuous renal replacement therapies (CRRT) has led to a growing interest in its use for the possible removal of proinflammatory cytokines in sepsis, in addition to its use in volume and urea clearance. The use of CRRT is favored in patients with pressor-dependence because of its better hemodynamic tolerability than intermittent hemodialysis. Additionally, CRRT offers potentially improved adequacy through clearance of solute. After intermittent
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