Acute and Chronic Kidney Disease Worsen Outcomes in Experimental Sepsis.

Abstract

Infection is a leading cause of morbidity in individuals with acute and chronic kidney disease (AKD, CKD). However, there is significant difficulty in modeling infection into an animal host with preexisting kidney disease. We report a novel method of peritoneal infection induced via cecal slurry inoculation deployed into mice with experimental aristolochic acid-induced AKD and CKD. AKD, CKD, and paired control mice were injected with sham, low, or higher doses of donor-recipient matched cecal slurry solution. Animal survival, sepsis severity, and change in glomerular filtration rate was tracked longitudinally throughout the study. Histology for kidney injury, flow cytometry, plasma cytokines, and evidence of indirect organ injury from sepsis were also assessed. Infected AKD mice experienced significantly heightened sepsis severity, with 100% mortality by 24 hours after high cecal slurry doses versus no mortality in control mice. Additionally, AKD mice receiving lower cecal slurry doses developed dramatically increased pro-inflammatory cytokines and persistent cytopenias. Infected CKD mice also had worse outcomes than paired CKD-controls, though less severe than in AKD mice. Interestingly, animals with AKD had worse outcomes than mice with CKD after any cecal slurry dose or time-point after inoculation, despite higher baseline kidney function and less uremic sequela. These data confirm that acute bacterial infection can be modeled in animals with established kidney disease; and suggest that the clinical state of kidney disease (AKD versus CKD) may influence host susceptibility to infection more than the degree of kidney failure alone.