Sepsis Survival Alters Kidney Resident Macrophage Populations and Sensitizes to Subsequent Ischemic Kidney Injury

Background: Acute kidney injury (AKI) is one of the most common readmission diagnoses following hospitalization for severe sepsis.Mechanisms of kidney injury among sepsis survivors remain poorly understood. Persistent immune reprogramming weeks to months after murine polymicrobial sepsis predisposes to chronic brain dysfunction and new lung injury. Immune reprogramming after sepsis may also predispose to AKI, but models of secondary AKI after sepsis are lacking. We have developed a model of secondary AKI in murine sepsis survivors. Methods: Adult male C57BL6/J mice underwent sepsis induced by cecal ligation and puncture (CLP) or a sham procedure. Three weeks later, mice underwent unilateral (pre-injury) nephrectomy with mild contralateral ischemia-reperfusion injury (IRI, 15 min clamp). Mice were euthanized 48 h after IRI. Pre-injury kidney resident immune populations were measured by flow cytometry and confirmed histologically by immunofluorescence staining. Response to IRI was assessed by mortality, blood urea nitrogen (BUN), and histologic injury. Results: There were no differences in baseline BUN or histology in mice 3 wk following CLP compared with sham controls before IRI. However, explanted pre-IRI kidneys from post-sepsis mice demonstrated a 3.5-fold reduction in CD11c+ macrophages (P<0.001), a 2.4-fold increase in CD11b+ monocyte/macrophages (P<0.001), and a 4.6-fold increase in neutrophils (Ly6G+, P<0.001) relative to sham. These changes occurred diffusely throughout the kidney interstitium on immunofluorescence staining. Post-sepsis mice had a 1.9-fold increase in BUN 48 hours after IRI relative to sham controls (P=0.04) and a higher histologic injury score (P<0.001). Post-sepsis mice had higher mortality following IRI. Conclusion: Mice surviving sepsis induced by CLP are sensitized to subsequent ischemic kidney injury. Sepsis survival is associated with a dramatic shift in kidney resident macrophages with loss of the CD11c+ population. This is unique to the kidney, as previous work has not shown loss of resident macrophage in the lung or brain. Kidney resident macrophages are protective in models of chronic kidney disease and their loss may be a mechanism through which prior sepsis predisposes to enhanced kidney injury. Funding: NIDDK Support, Private Foundation Support