Pre-existing renal disease promotes sepsis-induced acute kidney injury and worsens outcome.
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.
Doi
Kent
K
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1268, USA.
Leelahavanichkul
Asada
A
Hu
Xuzhen
X
Sidransky
Karen L
KL
Zhou
Hua
H
Qin
Yan
Y
Eisner
Christoph
C
Schnermann
Jürgen
J
Yuen
Peter S T
PS
Star
Robert A
RA
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
D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D003401:Creatine