Severity of sepsis-induced acute kidney injury in a novel mouse model is age dependent

Objective: Despite extensive research, the mortality rate of patients with sepsis-induced acute kidney injury (AKI) is unacceptably high, especially in the elderly. Current sepsis models have difficulties in reproducing AKI. This study aimed to develop a novel, clinically relevant mouse model for sepsis-induced AKI by uterine ligation and inoculation of bacteria. In addition, the age dependency of the severity of sepsis and sepsis-induced AKI was studied by validating this model in three different age categories. Design: Experimental animal investigation. Setting: University research laboratory. Subjects: Young (12-14 wks), aged (46-48 wks), and old (70-72 wks) C57BL/6 female mice were used as models for adolescent, adult premenopausal, and elderly postmenopausal women, respectively. Interventions: Uterine ligation and inoculation with 103 colony forming unit Escherichia coli or saline (sham) was performed; in vivo imaging with a luminescent Escherichia coli strain documented the course of infection. Measurements and Main Results: All mice had established Escherichia coli sepsis at 48 hrs postinfection, with higher mortality rate in old (43%) compared to aged (23%) or young (9%) mice. Infected mice had elevated serum or plasma cytokine, chemokine (tumor necrosis factor, interleukin-6, keratinocyte-derived chemokine, monocyte chemoattractant protein 1, and interleukin-10), and NO; concentrations compared to sham mice. AKI was confirmed by renal histology. Serum creatinine concentrations at 48 hrs increased with age (mean +/- SEM; controls 0.18 +/- 0.03 mg/dL, young 0.28 +/- 0.03 mg/dL, aged 0.38 +/- 0.05 mg/dL, and old 0.44 +/- 0.06 mg/dL). Conclusion: The uterine ligation and inoculation model for sepsis-induced AKI starts from a real infectious focus and shows an age-dependent severity of septic AKI that resembles AKI in humans. (Crit Care Med 2012; 40:2638-2646)