The Research Of Urinary IGFBP7~*TIMP-2 For Early Prediction Of Acute Kidney Injury Associated With Actue On Chronic Hepatitis B Liver Failure

Objective:To evaluate these two biomakers IFGBP7 (insulin-like growth factor binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinases-2) ability of prediction of AKI after HBV-ACLF(Hepatitis B virus associated acute-on-chronic liver failure), we detect the urinary IFGBP7 and TIMP-2.Methods:1. Research objectSixty-one ACHBLF patients (minimum age:21 years) and eleven CHB (chronic hepatitis B) patients were enrolled from the patients in Infectious Disease Department of The First Affiliated Hospital of Nanchang University from Sep.2015 to Jan.2016. 61 ACHBLF patients were divided into two groups:AKI group including 15 cases suffer from AKI (acute kidney injury) of which 14 cases male and 1 female, median age 46 years old (IQR, 38-51); non-AKI group including 46 cases of which 40 male and 6 female, median age 46.5 years old (IQR,38-52); 21 CHB patients were regard as CHB group, including 16 male and 5 female, median age 45 years old (IQR, 32-52). All of them should conform to Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection(2012),61 ACHBLF patients should conform to the Guidelines for treatment of hepatic failure(2012). This research etcenrolled 21 healthy subjects as control group,14 male and 7 female, median age 42 years old (IQR,29-50). Exclude combined with these disease can affect IFGBP7 and TIMP-2, such as other virus hepatitis, tumor of intestine, primary liver cancer, diabetes mellitus type 2.2.Methods:Collect the entrants' urine samples at 8:00 and 20:00 everyday, from the day confirmed HBV-ACLF till suffer AKI(according to Diagnosis and management of acute kidney injury in patients with cirrhosis:revised consensus recommendations of the International Club of Ascites). These entrants', without AKI, urine samples should collected till 30 days after the enrollment. Healthy subjects' urine samples should be gathered once. Centrifuged the urine samples, stored at?-80?. AKI groups:choose consecutive 5 days urine samples just before the point of clinical definite of AKI. Non-AKI groups:randomly select consecutive 5 days urine samples. Through ELISA method to detect the urinary IFGBP7 and TIMP-2. Gather the SCr dates, calculate eGFR dates at the same time.Results:There are 61 ACHBLF patients,15 of them concurrented AKI,7 cases of AKI 1, 4 cases of AKI2,4 cases of AKI3(according to diagnostic standard Diagnosis and management of acute kidney injury in patients with cirrhosis:revised consensus recommendations of the International Club of Ascites).The IGFBP7* TIMP-2 median concentration at the start point of AKI group is 0.24 (ng/ml) 2/1000(IQR,0.17-0.30), at the 36 hours before the confirme of AKI the level of IGFBP7*TIMP-2 is 0.28 (ng/ml) 2/1000(IQR,0.25-0.51) and begin to rise. At 24 hours before the confirme of AKI point, IGFBP7*TIMP-2 median concentration is 1.75 (ng/ml) 2/1000(IQR,0.95-2.35), it had significantly rose. The IGFBP7*TIMP-2 concentration at the above there points of Non-AKI group are 0.19 (ng/ml) 2/1000(IQR,0.17-0.22),0.21 (ng/ml) 2/1000(IQR,0.17-0.23),0.21 (ng/ml) 2/1000(IQR,0.17-0.24). The level of IGFBP7*TIMP-2 in control group are 0.18 (ng/ml) 2/1000(IQR,0.13-0.19),0.21 (ng/ml) 2/1000(IQR,0.19-0.26),0.21 (ng/ml) 2/1000(IQR,0.17-0.24). There's no significant differences in non-AKI group and control group. Thus we speculate that IGFBP7*TIMP-2 can predict AKI before clinical definite of AKI.The level of IGFBP7*TIMP-2 in AKI1 group is 0.25 (ng/ml) 2/1000 (IQR, 0.20-0.85), AKI2 group 0.27 (ng/ml) 2/1000(IQR,0.21-1.08), AKI3 group 0.26 (ng/ml) 2/1000(IQR,0.18-2.03), so we think that IGFBP7*TIMP-2 can predict the severity of the AKI.Ability to predict this event(i.e., development of moderate or severe AKI) was assessed using the area under the receiver operating characteristic curve(AUC-ROC) for urinary. The seventh specimen collection point(just 36 hours before the confirme of AKI) AUC 0.896 (95% CI 0.789,0.960 P<0.001), meanwhile, the AUC of SCr 0.714 (95% CI 0.582,0.824 P<0.001), eGFR AUC 0.613(95% CI 0.477,0.737 P<0.001). The AUC of IGFBP7*TIMP-2 was higher compared to the AUC of SCr, eGFR.5.In this study, IGFBP7*TIMP-2 median concentration of control gorup is 0.19 (ng/ml) 2/1000(IQR,0.15-0.25), blank group is 0.11 (ng/ml) 2/1000(IQR,0.09-0.18). Two sets of data between a statistically significant difference (P< 0.05). So, we think HBV can enhance the concentration of IGFBP7*TIMP-2.Conclusions:Both TIMP-2 and IGFBP7 are markers of cellular stress in the early phase of tubular cell injury caused by a wide variety of insults (inflammation, ischemia, oxidative stress, drugs, and toxins). Therefore, both markers are involved in the process of G1 cell-cycle arrest that prevents cells from dividing in the case of damage to the DNA until such damage can be repaired. Importantly, both biomarkers appear as "alarm" proteins for other nearby cells in a paracrine fashion. These two biomarkers performed better in prediction of AKI. In HBV-ACLF patients act TIMP2 and IGFBP7 as a sensitive predictor of AKI and may help to predict development of moderate or severe AKI.