title: Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction.
abstract: BACKGROUND
  Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI.
  
  
  METHODS
  RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection.
  
  
  RESULTS
  Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats.
  
  
  CONCLUSIONS
  CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.
authors.affiliation: Department of Nephrology, University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil. camila.eleuterio@usp.br
authors.forename: Camila E
authors.initials: CE
authors.lastname: Rodrigues
authors.forename: Talita R
authors.initials: TR
authors.lastname: Sanches
authors.forename: Rildo A
authors.initials: RA
authors.lastname: Volpini
authors.forename: Maria H M
authors.initials: MH
authors.lastname: Shimizu
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Kuriki
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Camara
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Seguro
authors.forename: Lúcia
authors.initials: L
authors.lastname: Andrade
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000517:prevention & control*; D000818:Animals; D002432:Cecum / Q000601:surgery; D016207:Cytokines / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008026:Ligation / Q000009:adverse effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology* / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011677:Punctures / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D017467:Receptors, Erythropoietin / Q000378:metabolism; D018805:Sepsis / Q000150:complications* / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D017467:Receptors, Erythropoietin; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; D011092:Polyethylene Glycols