sepsis and the kidney.pdf - SASSiT
sepsis and the kidney.pdf - SASSiT
sepsis and the kidney.pdf - SASSiT
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inflammatory process by increasing <strong>the</strong> production of inflammatory mediators.<br />
Endo<strong>the</strong>lial activation is an early host response to circulating pathogens, <strong>and</strong><br />
likely is triggered by activated <strong>and</strong> adherent neutrophils <strong>and</strong> <strong>the</strong>ir degradation<br />
products. The release of cytokines from <strong>the</strong> activated endo<strong>the</strong>lium may be an<br />
early <strong>and</strong> aggressive defense. The dysfunctional endo<strong>the</strong>lium is more severely<br />
damaged <strong>and</strong> results in <strong>the</strong> leaky capillaries associated with <strong>sepsis</strong>. The process<br />
by which endo<strong>the</strong>lium evolves from activated <strong>and</strong> physiologic to damaged <strong>and</strong><br />
dysfunctional is relatively unknown <strong>and</strong> represents a key area for research <strong>and</strong> a<br />
potential target for <strong>the</strong>rapy.<br />
Coagulation cascade<br />
<strong>sepsis</strong> <strong>and</strong> <strong>the</strong> <strong>kidney</strong> 217<br />
The activation of coagulation <strong>and</strong> deposition of fibrin in <strong>the</strong> tissues is a welldefined<br />
component of <strong>the</strong> MOSF in <strong>sepsis</strong>. Increased expression of tissue factor<br />
in response to LPS <strong>and</strong> TNF stimulation of inflammatory <strong>and</strong> endo<strong>the</strong>lial cells<br />
may contribute to organ injury in <strong>sepsis</strong>, including renal injury. Tissue factor<br />
binds activated factor VII. This complex activates factor X, which cleaves<br />
prothrombin to thrombin, which in turn cleaves fibrinogen to fibrin. The activation<br />
of <strong>the</strong> coagulation cascade increases <strong>the</strong> tissue inflammatory response. Fibrin<br />
is often deposited in <strong>the</strong> intravascular space in animal models of <strong>sepsis</strong>, including<br />
<strong>the</strong> glomerular capillaries. For <strong>the</strong>se reasons, anticoagulant <strong>the</strong>rapies, or <strong>the</strong>rapies<br />
that interfere with initiation of coagulation, are of potential interest in ameliorating<br />
MOSF, including renal failure. In a primate model of <strong>sepsis</strong>, animals were<br />
treated with site-inactivated factor VIIa, which serves as a competitive inhibitor<br />
of tissue factor, to block <strong>the</strong> initiation of <strong>the</strong> coagulation cascade. The treated<br />
animals showed preserved renal function at 48 hours, less metabolic acidosis, <strong>and</strong><br />
better urine output. Histologic examination of <strong>the</strong> <strong>kidney</strong>s demonstrated less<br />
tubular injury, inflammatory cell infiltration, <strong>and</strong> fewer fibrin clots than in untreated<br />
animals [28]. Activated protein C improves outcomes in <strong>sepsis</strong>, <strong>and</strong> it is<br />
currently unclear whe<strong>the</strong>r it also attenuates <strong>sepsis</strong>-associated ARF [29].<br />
Management of <strong>sepsis</strong>-associated acute renal failure<br />
Renal replacement <strong>the</strong>rapy<br />
The introduction of hemodialysis for <strong>the</strong> treatment of severe ARF lowered <strong>the</strong><br />
mortality rate from greater than 90% to approximately 50%. The widespread<br />
availability of continuous renal replacement <strong>the</strong>rapies (CRRT) has led to a<br />
growing interest in its use for <strong>the</strong> possible removal of proinflammatory cytokines<br />
in <strong>sepsis</strong>, in addition to its use in volume <strong>and</strong> urea clearance. The use of CRRT<br />
is favored in patients with pressor-dependence because of its better hemodynamic<br />
tolerability than intermittent hemodialysis. Additionally, CRRT offers<br />
potentially improved adequacy through clearance of solute. After intermittent