sepsis and the kidney.pdf - SASSiT
sepsis and the kidney.pdf - SASSiT
sepsis and the kidney.pdf - SASSiT
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216<br />
klenzak & himmelfarb<br />
Local soluble mediators<br />
Cellular <strong>and</strong> humoral cytokines are integral to organ dysfunction in <strong>sepsis</strong><br />
syndromes, with <strong>the</strong> <strong>kidney</strong> being especially vulnerable to cytokine-mediated<br />
injury. CD14 is expressed by mesangial cells <strong>and</strong> can be stimulated directly by<br />
LPS. The mesangial cells are capable of expressing multiple proinflammatory<br />
cytokines <strong>and</strong> chemokines, IL-1, IL-6, TNF, <strong>and</strong> PAF. Tubular cells are also<br />
capable of releasing proinflammatory cytokines after stimulation by LPS [23].<br />
Studies of isolated <strong>kidney</strong>s perfused ex vivo with LPS do not demonstrate<br />
a decrease in glomerular filtration rate despite increased mRNA expression for<br />
proinflammatory cytokines. In vivo experiments involving LPS stimulation<br />
demonstrate <strong>the</strong> expected renal dysfunction, however, suggesting that <strong>the</strong> ARF in<br />
this setting is caused by host factors outside <strong>the</strong> renal parenchyma [24,25].<br />
Specific mediators of vascular resistance <strong>and</strong> endo<strong>the</strong>lial injury whose expression<br />
is induced by LPS in vivo include PAF, endo<strong>the</strong>lin-1, <strong>and</strong> iNOS. Each of <strong>the</strong>se<br />
soluble proteins has been shown to decrease glomerular filtration rate <strong>and</strong> RBF,<br />
leading to decreased urine output. Animal studies using antagonists to each of<br />
<strong>the</strong>se soluble mediators have demonstrated amelioration of <strong>the</strong> renal injury<br />
[15,19,26].<br />
PAF is a vasoconstrictor that additionally is chemotactic for activated<br />
inflammatory cells, including neutrophils. It can be produced by glomerular<br />
cells <strong>and</strong> by circulating inflammatory cells, such as neutrophils <strong>and</strong> macrophages.<br />
Increases in PAF lead to a reduction in glomerular filtration rate. Blockade of<br />
PAF receptors lessens <strong>the</strong> deterioration of renal function in models of endotoxemia<br />
[26].<br />
Oxidative stress<br />
It has recently been demonstrated that <strong>the</strong>re are high levels of oxidative stress<br />
in patients with ARF in <strong>the</strong> setting of critical illness. These patients demonstrated<br />
diminished thiol content <strong>and</strong> increased carbonyl content in plasma proteins. The<br />
excess burden of protein oxidation is significantly greater in patients with ARF as<br />
compared with critically ill patients with preserved renal function or patients with<br />
dialysis-dependent chronic <strong>kidney</strong> disease. The levels of protein oxidation are<br />
improved by dialysis, but only transiently, <strong>and</strong> oxidized proteins continue to<br />
accumulate during <strong>the</strong> intradialytic period [27]. The oxidative burden in patients<br />
who have ARF in <strong>the</strong> setting of critical illness may be a target for potential<br />
<strong>the</strong>rapies to decrease <strong>the</strong>ir excess mortality.<br />
Endo<strong>the</strong>lium<br />
Endo<strong>the</strong>lial activation induced by circulating cytokines <strong>and</strong> activated complement<br />
is likely a key instigator in <strong>the</strong> evolution of <strong>sepsis</strong>-associated ARF.<br />
The changes induced in endo<strong>the</strong>lial function by this stimulation enhance <strong>the</strong>