title: Inflammatory Kidney and Liver Tissue Response to Different Hydroxyethylstarch (HES) Preparations in a Rat Model of Early Sepsis.
abstract: BACKGROUND
  Tissue hypoperfusion and inflammation in sepsis can lead to organ failure including kidney and liver. In sepsis, mortality of acute kidney injury increases by more than 50%. Which type of volume replacement should be used is still an ongoing debate. We investigated the effect of different volume strategies on inflammatory mediators in kidney and liver in an early sepsis model.
  
  
  METHODS
  Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) and assigned to three fluid replenishment groups. Animals received 30mL/kg of Ringer's lactate (RL) for 2h, thereafter RL (75mL/kg), hydroxyethyl starch (HES) balanced (25mL/kg), containing malate and acetate, or HES saline (25mL/kg) for another 2h. Kidney and liver tissue was assessed for inflammation. In vitro rat endothelial cells were exposed to RL, HES balanced or HES saline for 2h, followed by stimulation with tumor necrosis factor-α (TNF-α) for another 4h. Alternatively, cells were exposed to malate, acetate or a mixture of malate and acetate, reflecting the according concentration of these substances in HES balanced. Pro-inflammatory cytokines were determined in cell supernatants.
  
  
  RESULTS
  Cytokine mRNA in kidney and liver was increased in CLP animals treated with HES balanced compared to RL, but not after application of HES saline. MCP-1 was 3.5fold (95% CI: 1.3, 5.6) (p<0.01) and TNF-α 2.3fold (95% CI: 1.2, 3.3) (p<0.001) upregulated in the kidney. Corresponding results were seen in liver tissue. TNF-α-stimulated endothelial cells co-exposed to RL expressed 3529±1040pg/mL MCP-1 and 59±23pg/mL CINC-1 protein. These cytokines increased by 2358pg/mL (95% CI: 1511, 3204) (p<0.001) and 29pg/ml (95% CI: 14, 45) (p<0.01) respectively when exposed to HES balanced instead. However, no further upregulation was observed with HES saline. PBS supplemented with acetate increased MCP-1 by 1325pg/mL (95% CI: 741, 1909) (p<0.001) and CINC-1 by 24pg/mL (95% CI: 9, 38) (p<0.01) compared to RL. Malate as well as HES saline did not affect cytokine expression.
  
  
  CONCLUSIONS
  We identified HES balanced and specifically its component acetate as pro-inflammatory factor. How important this additional inflammatory burden on kidney and liver function is contributing to the sepsis-associated inflammatory burden in early sepsis needs further evaluation.
authors.affiliation: Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Schimmer
authors.affiliation: Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.|Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Urner
authors.affiliation: Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Voigtsberger
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Christa
authors.initials: C
authors.lastname: Booy
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Birgit
authors.initials: B
authors.lastname: Roth Z'Graggen
authors.affiliation: Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.|Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.|Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Beck-Schimmer
authors.affiliation: Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.|Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Schläpfer
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006895:Hydroxyethyl Starch Derivatives / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D006895:Hydroxyethyl Starch Derivatives; D014409:Tumor Necrosis Factor-alpha