title: Pre-existing renal disease promotes sepsis-induced acute kidney injury and worsens outcome.
abstract: While it is known that risk of death from sepsis is higher in patients with pre-existing chronic kidney disease its mechanism is unknown. To study this we established a two-stage mouse model where renal disease was first induced by folic acid injection followed by sub-lethal cecal ligation and puncture to induce sepsis. Septic mice with pre-existing renal disease had significantly higher mortality, serum creatinine, vascular permeability, plasma vascular endothelial growth factor (VEGF) levels, bacteremia, serum IL-10, splenocyte apoptosis and more severe septic shock when compared to septic mice without pre-existing disease. To evaluate the contribution of vascular and immunological dysfunction, we treated the folate-septic mice with soluble Flt-1 to bind VEGF and chloroquine to reduce splenocyte apoptosis. These treatments together resulted in a significant improvement in kidney injury, hemodynamics and survival. Our study shows that the sequential mouse model mimics human sepsis frequently complicated by pre-existing renal disease and might be useful in evaluating preventive and therapeutic strategies.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1268, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.forename: Asada
authors.initials: A
authors.lastname: Leelahavanichkul
authors.forename: Xuzhen
authors.initials: X
authors.lastname: Hu
authors.forename: Karen L
authors.initials: KL
authors.lastname: Sidransky
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Peter S T
authors.initials: PS
authors.lastname: Yuen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Star
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D003401:Creatine / Q000097:blood; D004195:Disease Models, Animal; D006439:Hemodynamics; D016753:Interleukin-10 / Q000097:blood; D007674:Kidney Diseases / Q000150:complications / Q000382:microbiology* / Q000473:pathology*; D051379:Mice; D018805:Sepsis / Q000150:complications / Q000473:pathology*; D012772:Shock, Septic / Q000209:etiology; D013154:Spleen / Q000473:pathology; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D003401:Creatine