Discovery and validation of miR-452 as an effective biomarker for acute kidney injury in sepsis

Rationale: Sepsis is the cause of nearly half of acute kidney injury (AKI) and, unfortunately, AKI in sepsis is associated with unacceptably high rates of mortality. Early detection of AKI would guide the timely intervention and care of sepsis patients. Currently, NephroCheck, based on urinary [TIMP2]*[IGFBP7], is the only FDA approved test for early detection of AKI, which has a relatively low sensitivity for sepsis patients. Methods: In vitro, BUMPT (Boston University mouse proximal tubular cell line) cells were treated with lipopolysaccharides (LPS). In vivo, sepsis was induced in mice by LPS injection or cecal ligation and puncture (CLP). To validate the biomarker potential of miR-452, serum and urinary samples were collected from 47 sepsis patients with AKI, 50 patients without AKI, and 10 healthy subjects. Results: miR-452 was induced in renal tubular cells in septic AKI, and the induction was shown to be mediated by NF-κB. Notably, serum and urinary miR-452 increased early in septic mice following LPS or CLP treatment, prior to detectable renal dysfunction or tissue damage. Sepsis patients with AKI had significantly higher levels of serum and urinary miR-452 than the patients without AKI. Spearman's test demonstrated a remarkable positive correlation between urinary miR-452 and serum creatinine in sepsis patients (r=0.8269). The area under the receiver operating characteristic curve (AUC) was 0.8985 for urinary miR-452. Logistic regression analysis showed a striking 72.48-fold increase of AKI risk for every 1-fold increase of urinary miR-452 in sepsis patients. The sensitivity of urinary miR-452 for AKI detection in sepsis patients reached 87.23%, which was notably higher than the 61.54% achieved by urinary [TIMP2]*[IGFBP7], while the specificity of urinary miR-452 (78.00%) was slightly lower than that of [TIMP2]*[IGFBP7] (87.18%). Conclusions: miR-452 is induced via NF-κB in renal tubular cells in septic AKI. The increase of miR-452, especially that in urine, may be an effective biomarker for early detection of AKI in sepsis patients.