Clinical implication of urinary midkine as a sensitive biomarker of acute kidney injury

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Although acute kidney injury (AKI) is the most important predictor of the prognosis of the patients treated in the field of ICU, there have been no sensitive biomarkers to diagnose AKI before the rising of serum creatinine. Recently, several urinary biomarkers such as NGAL, IL-18, KIM-1, NHE3, KC, and L-FABP are reported as a candidate of new sensitive biomarker of AKI.We reported that midkine(MK), a heparin-binding growth factor, was induced in the diseased kidneys and promoted chemotaxis of leukocytes in the animal models of an ischemic renal reperfusion injury(Sato W., et. al., J Immunol 2001 ; 167 : 3463-3469). The enhanced expression of MK was detected mainly in the proximal tubules after ischemic injuries. Here, we evaluated whether human MK is shed into urine from the tubular epithelial cells, and may serve as a potent urinary biomarker of acute kidney injuries in human.Western blot analysis showed that the increased expression of MK was detected in the culture media from cultur … More ed human tubular epithelial(HK2)cells treated with hypoxia, but not from HK2 cells treated with 20 μM BSA. There were no differences in the MK expression in the cell lysates.For the measurement of urinary MK, 583 patients, including controls (n=33), patients with different forms of acute tubular necrosis (ATN) (n=33), and patients with other chronic renal diseases(n= 517), were studied. Urinary MK level was determined by enzyme-linked immunoassay.The urinary MK levels were significantly higher in patients with ATN compared to levels in patients with other chronic renal diseases or controls. For concentration in urine of MK, the receiver-operating characteristic(ROC)curve analysis for diagnosis of ATN showed that sensitivity was 97.0 %, and specificity was 91.1 % for a cut-off value of 70.0 pg/ml.We have confirmed that urinary MK level serves as a sensitive biomarker of ATN facilitating the early diagnosis of the disease. We obtained the patent(2008-048954, Ref : K20070222)for "Clinical examination for the early diagnosis of AKI : Urinary MK measurement". Less