Acute and Chronic Kidney Disease Worsen Outcomes in Experimental Sepsis

Abstract

Key Points Acute kidney disease (AKD) and CKD are common conditions associated with high rates of incident infection, and poor outcomes once infection have been established.We successfully modeled AKD and CKD in rodents and then administered a cecal slurry solution to create peritonitis and tracked sepsis severity, end organ injury, and inflammatory changes.Our results indicate that AKD mice are more susceptible to infection than CKD mice, developing an aggravated inflammatory response and suggests that this condition predisposes to disparate infection risk. Background Infection is a leading cause of morbidity in individuals with acute kidney disease (AKD) and 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 (CS) inoculation deployed into mice with experimental aristolochic acid–induced AKD and CKD. Methods AKD, CKD, and paired control mice were injected with sham, low, or higher doses of donor–recipient matched CS solution. Animal survival, sepsis severity, and change in GFR were tracked longitudinally throughout the study. Histology for kidney injury, flow cytometry, plasma cytokines, and evidence of indirect organ injury from sepsis were also assessed. Results Infected AKD mice experienced significantly heightened sepsis severity, with 100% mortality by 24 hours after high CS doses versus no mortality in control mice. In addition, AKD mice receiving lower CS doses developed dramatically increased proinflammatory cytokines and persistent cytopenias. Infected CKD mice also had worse outcomes than paired CKD controls, although less severe than in AKD mice. Interestingly, animals with AKD had worse outcomes than mice with CKD after any CS dose or time point after inoculation, despite higher baseline kidney function and less uremic sequela. Conclusions 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.