Title: AKI and CKD Worsen Outcomes in Experimental Sepsis: Creating a Reverse-translational Model of Acute Peritoneal Infection and Recovery in an Immunocompromised Rodent

Abstract

AbstractIntroductionInfection is a leading cause of morbidity and mortality in individuals with kidney disease. Both acute kidney injury (AKI), and chronic kidney disease (CKD) are clinical states that have been associated with higher risk of incident infection, and poor outcomes once infection has been established. A variety of host-and pathogen-specific factors are implicated as potential causes for these disparate outcomes including an altered host microbiome, innate and adaptive immune defects, and poor renal clearance and cytokines. However, there remains significant difficulty in modeling both human kidney disease and infection into an animal host. Likewise, there remains a poor understanding of the mechanisms underlying the unique immunodeficiency imparted by AKI and CKD, and if either condition imparts disparate risk.MethodsC57BL/6J mice were given vehicle or aristolochic acid (AA) to create AKI (control, AKI groups) or CKD (control, CKD groups). Donor mice from all four groups underwent sterile cecal dissection and creation of cecal slurry (CS) preparations, which was later injected into separate mice in a matched host-recipient manner, at either high or lower doses. Animals were clinically monitored for either 24- or 72-hours after inoculation, then euthanized. Animal survival, sepsis severity, temperature, weights, and transcutaneous glomerular filtration rate (tGFR) were tracked longitudinally throughout the study. Histology for kidney injury, peripheral blood flow cytometry for leukocyte counts, plasma cytokines, and typical markers for organ injury were determined.ResultsCompared to controls, animals with AKI experienced much more severe sepsis across virtually all tracked metrics, and no animals with AKI survived high-dose CS injection past 24-hours. AKI mice manifested with a peripheral defect in leukocytes early after sepsis, with severe and persistent cytopenias, and a dramatically heightened early pro-inflammatory cytokine response. Septic CKD mice also had worse outcomes than controls, though less severe, and occurring later than in animals with AKI. Interestingly, animals with AKI had worse clinical outcomes and evidence of organ injury than mice with CKD at any dose or time-point after inoculation, despite a higher mean baseline measured GFR.ConclusionsRodents with established AKI and CKD experience worse clinical outcomes and organ injury versus controls in a CS model intraperitoneal live-bacterial infection. Additionally, mice with AKI experienced earlier and more severe morbidity and mortality than animals with CKD.