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Critical Care

, 18:488

First Online: 03 September 2014Received: 18 March 2014Accepted: 04 August 2014


IntroductionAcute kidney injury AKI is a common and feared complication of sepsis. The pathogenesis of sepsis-induced AKI is largely unknown, and therapeutic interventions are mainly supportive. In the present study, we tested the hypothesis that pharmacological inhibition of Toll-like receptor 4 TLR4 would improve renal function and reduce renal damage in experimental sepsis, even after AKI had already developed.

MethodsSheep were surgically instrumented and subjected to a 36-hour intravenous infusion of live Escherichia coli. After 12 hours, they were randomized to treatment with a selective TLR4 inhibitor TAK-242 or vehicle.

ResultsThe E. coli caused normotensive sepsis characterized by fever, increased cardiac index, hyperlactemia, oliguria, and decreased creatinine clearance. TAK-242 significantly improved creatinine clearance and urine output. The increase in N-acetyl-beta-D-glucosaminidas, a marker of tubular damage, was attenuated. Furthermore, TAK-242 reduced the renal neutrophil accumulation and glomerular endothelial swelling caused by sepsis. These effects were independent of changes in renal artery blood flow and renal microvascular perfusion in both cortex and medulla. TAK-242 had no effect per se on the measured parameters.

ConclusionsThese results show that treatment with a TLR4 inhibitor is able to reverse a manifest impairment in renal function caused by sepsis. In addition, the results provide evidence that the mechanism underlying the effect of TAK-242 on renal function does not involve improved macro-circulation or micro-circulation, enhanced renal oxygen delivery, or attenuation of tubular necrosis. TLR4-mediated inflammation resulting in glomerular endothelial swelling may be an important part of the pathogenesis underlying Gram-negative septic acute kidney injury.

AbbreviationsAKIacute kidney injury

ANOVAanalysis of variance

ATNacute tubular necrosis

BUNblood urea nitrogen

CIcardiac index

GBMglomerular basement membrane

GFRglomerular filtration rate

HRheart rate



MAPmean arterial blood pressure

MPAPmean pulmonary arterial blood pressure


NOnitric oxide

NOxsum of nitrite and nitrate

pCO2partial pressure of carbon dioxide

PMNpolymorphonuclear leukocyte

TLR4Toll-like receptor 4

Electronic supplementary materialThe online version of this article doi:10.1186-s13054-014-0488-y contains supplementary material, which is available to authorized users.

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Autor: Johan Fenhammar - Mats Rundgren - Kjell Hultenby - Jakob Forestier - Micael Taavo - Ellinor Kenne - Eddie Weitzberg - Stefa


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