The Ratio of Plasma Interleukin-18 Is a Sensitive Biomarker for Acute Kidney Injury After Liver Transplantation W.-C. Sung, H.-P. Yu, Y.-F. Tsai, P.C.-H. Chung, C.-C. Lin, and W.-C. Lee ABSTRACT Background. Acute kidney injury (AKI) is common after liver transplantation (OLT) and is associated with high morbidity and mortality. Previous studies have shown that interleukin-18 (IL-18) levels are associated with AKI. The purpose of this study was to determine whether plasma IL-18 levels were early predictors for AKI after liver transplantation. Methods. Plasma samples were obtained from 26 patients who underwent OLT at induction of anesthesia (T1), 1 hour after the surgical incision (T2), the time of reperfusion (T3), as well as 1 (T4), 2 (T5), and 4 hours (T6) after reperfusion. Samples were also obtained at 24 hours after surgery (T7). The AKI criteria were taken according to the Acute Kidney Injury Network criteria. Results. Twelve patients (46%) developed AKI after OLT. The area under the receiver operating curve of plasma IL-18 concentrations (T4/T1) to predict AKI occurrence was 0.842 at T5, 0.905 at T6, 0.726 at T7, and 0.726 at T5 to T7. Conclusion. Plasma IL-18 concentrations taken 1 hour after reperfusion were predictive of AKI. Therefore, changing IL-18 ratio may be an early predictor for AKI after OLT.

A

CUTE KIDNEY INJURY (AKI) is a common and serious complication after orthotopic liver transplant (OLT) [1]. The side effects of post-transplant AKI include required renal replacement therapy, prolonged mechanical ventilation, extended stay in the intensive care unit, and an increased infection rate [2]. In addition, AKI is an independent risk factor for 1-year mortality after OLT [2]. The etiology of AKI is multifactorial and includes hepatorenal syndrome, intra- and postoperative hypotension, massive blood loss, sepsis, nephrotoxic medications, hepatitis C, and volume depletion [1,3]. The diagnosis of AKI is based on serum creatinine (SCr) and urine output. However, such indicators are poor for predicting early renal dysfunction. In recent years, novel biomarkers of AKI have been developed to detect renal injury, including neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) [4,5]. Urine IL-18 has been identified as an early biomarker of AKI [6]. Previous studies have demonstrated that urine IL-18 can predict AKI 4 to 24 hours after surgery and is associated with mortality [4,7]. Plasma IL-18 is a proinflammatory cytokine and is associated with mortality, inflammation, and sepsis [8,9]. This study was performed to evaluate whether the ratio of plasma IL-18 was an early predictor of AKI during OLT. 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.055 816

MATERIALS AND METHODS Study Design and Patients We prospectively examined the course of 26 patients who had undergone OLT from October 1, 2010 until October 31, 2011. Patients who were younger than 18, had end-stage renal disease, and could not to complete the inform-consent sheet were excluded. This study was approved by the Chang Gung Memorial Hospital institutional research ethics review board. Plasma samples were obtained to analyze SCr and IL-18 at the induction of anesthesia (T1), 1 hour after the surgical incision (T2), reperfusion (T3), as well as 1 (T4), 2 (T5), and 4 hours (T6) after reperfusion. The samples were also collected at 24 hours after surgery (T7). The levels of plasma IL-18 were measured using a

From the Department of Anesthesiology, Chang Gung Memorial Hospital (W.-C.S., H.-P.Y., Y.-F.T., P.C.-H.C., C.-C.L.); College of Medicine (W.-C.S., H.-P.Y., Y.-F.T., P.C.-H.C., C.-C.L., W.-C.L.); Graduate Institute of Clinical Medical Sciences, Chang Gung University (Y.-F.T.); Division of Transplantation and Liver Surgery, Department of General Surgery, Chang Gung Memorial Hospital (W.-C.L.), Taoyuan, Taiwan. Address reprint requests to Dr Huang-Ping Yu, Department of Anesthesiology, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Tao-Yuan, Taiwan 333. E-mail: yuhp2001@ adm.cgmh.org.tw ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 816e817 (2014)

RATIO OF PLASMA INTERLEUKIN-18

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Table 1. Prediction of the Ratio of Plasma IL-18 for AKI at Different Time Points 95% CI for OR Outcome

AKI AKI AKI AKI

at at at at

T5 T6 T7 T5w7

Parameter

IL-18 IL-18 IL-18 IL-18

T4/T1 T4/T1 T4/T1 T4/T1

P Value

OR

Lower

Upper

AUROC

.031 .022 .048 .048

16.87 30.84 19.93 19.93

1.30 1.65 1.03 1.03

218.30 577.13 386.46 386.46

0.842 0.905 0.726 0.726

Abbreviations: IL-18, interleukin-18; AKI, acute kidney injury; OR, odds ratio; CI, confidence interval; AUROC, area under the receiver operating curve; T1, anesthesia induction; T4, 1 h after reperfusion; T5, 2 h after reperfusion; T6, 4 h after reperfusion; T7, 24 h after surgery; IL-18 T4/T1, (IL-18 concentration at 1 h after reperfusion)/(IL-18 concentration at the time of anesthesia induction).

human IL-18 enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, Minn, United States). AKI was defined according to the criteria of the Acute Kidney Injury Network, including an increase in serum creatinine of 150% or 0.3 mg/dL above the baseline within 48 hours after OLT [10].

serum IL-18 levels are associated with acute renal ischemia and ischemia-reperfusion injury [11,12]. Previous studies have also shown that IL-18 plays a role in the process of renal tubulointerstitial fibrosis by promoting tubular proximal epithelial cell injury and activation [13]. Li et al [14] found that the IL-18 promoter at position G-137C is associated with an increased risk of early renal glomerular injury after liver transplantation. These studies have suggested that IL-18 levels may play a role in kidney injury. Previous study revealed that urine IL-18 can predict AKI at 4 to 6 hours after cardiopulmonary bypass and 12 to 24 hours after kidney transplantation [4]. In our study, we used the ratio of plasma IL-18 to predict AKI during OLT. We found that the ratio of plasma IL-18 can predict AKI 1 hour after reperfusion of the liver graft. This time is earlier than that of previous studies using the absolute concentration of urine IL-18. In conclusion, the ratio of plasma IL-18 may be an alternative early predictor of AKI during OLT.

Statistical Analysis All analyses were performed using SPSS statistical software package 17.0 (SPSS Inc., Chicago, IL). Binary logistic regression was calculated to determine the significance and odds ratios and whether the ratio of plasma IL-18 was a predictor of AKI during OLT. The area under the receiver operator curve was used to assess the continuous variable of plasma IL-18 each time. As in other studies, a P value

The ratio of plasma interleukin-18 is a sensitive biomarker for acute kidney injury after liver transplantation.

Acute kidney injury (AKI) is common after liver transplantation (OLT) and is associated with high morbidity and mortality. Previous studies have shown...
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