title: Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep.
abstract: BACKGROUND
  Acute 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.
  
  
  METHODS
  Sheep 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  These 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.
authors.forename: Johan
authors.initials: J
authors.lastname: Fenhammar
authors.forename: Mats
authors.initials: M
authors.lastname: Rundgren
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Jakob
authors.initials: J
authors.lastname: Forestier
authors.forename: Micael
authors.initials: M
authors.lastname: Taavo
authors.forename: Ellinor
authors.initials: E
authors.lastname: Kenne
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Eriksson
authors.forename: Volkan
authors.initials: V
authors.lastname: Ozenci
authors.forename: Annika
authors.initials: A
authors.lastname: Wernerson
authors.forename: Robert
authors.initials: R
authors.lastname: Frithiof
mesh_terms: D058186:Acute Kidney Injury / Q000382:microbiology / Q000517:prevention & control*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D012079:Renal Circulation / Q000187:drug effects*; D018805:Sepsis / Q000150:complications / Q000188:drug therapy*; D034561:Sheep, Domestic; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D013449:Sulfonamides; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate