Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury

Abstract

The present study aimed to evaluate whether levels of urinary L-type fatty acid-binding protein (L-FABP) could be used to monitor histological injury in acute kidney injury (AKI) induced by cis-platinum (CP) injection and ischemia reperfusion (IR). Different degrees of AKI severity were induced by several renal insults (CP dose and ischemia time) in human L-FABP transgenic mice. Renal histological injury scores increased with both CP dose and ischemic time. In CP-induced AKI, urinary L-FABP levels increased exponentially even in the lowest dose group as early as 2 hours, whereas blood urea nitrogen (BUN) levels increased at 48 hours. In IR-induced AKI, BUN levels increased only in the 30-minute ischemia group 24 hours after reperfusion; however, urinary L-FABP levels increased more than 100-fold, even in the 5-minute ischemia group after 1 hour. In both AKI models, urinary L-FABP levels showed a better correlation with final histological injury scores and glomerular filtration rates measured by fluorescein isothiocyanate-labeled inulin injection than with levels of BUN and urinary N-acetyl-D-glucosaminidase, especially at earlier time points. Receiver operating characteristic curve analysis demonstrated that urinary L-FABP was superior to other biomarkers for the detection of significant histological injuries and functional declines. In conclusion, urinary L-FABP levels are better suited to allow the accurate and earlier detection of both histological and functional insults in ischemic and nephrotoxin-induced AKI compared with conventional renal markers.

Figure 1

Histological evaluation of CP- and IR-induced AKI. CP with different dose injections (0, 5, 10, 20 mg/kg) and different ischemia times (0, 5, 15, 30 minutes) were conducted. Representative histology in CP (A)- and IR (B)-induced AKI are shown. Stepwise increases of total ATN score in CP (C)- and IR (D)-induced AKI along with CP dose and ischemia time were found. [n = 5 ∼ 10 per group, ^#P < 0.05 versus saline (CP) or sham (IR) group]. OSOM, outer stripe of outer medulla. Original magnifications, ×200.

Figure 2

Renal biomarkers in CP- and IR-induced AKI. Renal biomarkers of BUN (A, B), urinary L-FABP (C, D), and urinary NAG (E, F) in response to CP with different dose injections (0, 5, 10, 20 mg/kg) and different ischemia times (0, 5, 15, 30 minutes) are shown. (n = 5 ∼ 10 per group, ^#P < 0.05 versus sham or saline group).

Figure 3

Correlation of renal biomarkers with histological injury and functional decline in AKI. R² values were calculated with the renal biomarkers at each time point and the ATN score at 72 hours in CP-AKI (A, n = 30) or 24 hours in IR-AKI (B, n = 22). R² values were also calculated with the renal biomarkers at each time point and measured GFR at 72 hours in CP-AKI (C, n = 13) or at 24 hours in IR-AKI (D, n = 12). ^#P < 0.001. ROC curve analysis for detecting moderate to severe histological injuries in CP and IR AKI was performed with renal biomarkers at 24 hours (E) or 72 hours (I) after CP injection (n = 30) and 3 hours (F) or 24 hours (J) after IR (n = 22). The areas under the ROC curve were calculated with the renal biomarkers at each time point in CP-AKI (M, n = 30) and IR-AKI (N, n = 22). ROC curve analysis for detecting the functional change of GFR >25% decrease in CP- and IR-induced AKI was performed with renal biomarkers at 24 hours (G) or 72 hours (K) after CP injection (n = 13) and 3 hours (H) or 24 hours (L) after IR (n = 12). The areas under the ROC curve were calculated with the renal biomarkers at each time point in CP-AKI (O, n = 13) and IR-AKI (P, n = 12).