The Diagnostic Value Of Circulating Kidney Injury Molecule 1 For Renal Dysfunction During Long-term Adefovir Therapy In Chronic Hepatitis B

Objective: Renal dysfunction has been reported in chronic hepatitis B(CHB)patients treated with adefovir dipivoxil(ADV).However,its incidence and clinical importance may be underappreciated given the lack of long-term follow-up and data outside of a clinical trial setting.Most routine renal function was generally estimated by the rise of creatinine,blood urea nitrogen in serum and the decrease of estimated glomerular filtration rate(eGFR)in clinic,which failed to identify the precision and specificity of in the diagnosis of renal dysfunction and structural injury.Kidney injury molecule-1(KIM-1)has been demonstrated to be a sensitive,specific and early biomarker for monitoring renal function.Previous studies have confirmed that KIM-1 can be detected in the blood in human,rat,and mouse with acute kidney injury or chronic kidney disease.In current investigation,we aimed to examine serum KIM-1 to elucidate whether serum KIM-1 can be used as a marker to diagnose renal impairment in CHB patients with long-term ADV treatment.Methods:CHB patients who treated with ADV or entecavir monotherapy more than 6 months were enrolled from January 2010 and August 2015 in the Third Hospital of Hebei Medical University.All the patients had a baseline eGFR?80mL/minute.ADV group and entecavir(ETV)group were matched by their baseline characteristics for age(± 5years),sex,and baseline eGFR classification.Two groups of patients were evaluated serum Cystatin C at the baseline and the last follow-up.At the same time,serum KIM-1concentrations were measured by enzyme linked immunosorbent assay(ELISA).Statistical analysis was performed by SPSS 17.0 software package.Measurement data expressed as mean±SD or median(range).Use Student t test if the data were normally distributed and homogeneity of variance.Use Kruskal Wallis H rank sum test if the data were not normally distributed.Count data used Chi-square test.Bivariate correlation analysis was assessed by Spearman correlation test.The diagnostic performance of serum KIM-1was assessed by using the Receiver operating characteristic(ROC)curve.Clinical data were analyzed by single and muti-factor Cox proportional hazard regression.The odds ratio and 95%confidence interval were calculated by an unconditional Cox proportional hazard regression model.Results:1 Baseline Clinical CharacteristicsA total of 81 CHB patients prescribed ADV and 81 CHB patients prescribed ETV monotherapy were included in the data analysis.In ADV group,30 cases were treated with ADV and 51 cases were treated with ADV combined with lamivudine or ETV.ADV monotherapy group and combination therapy group in age,gender and baseline eGFR had no significant difference(P>0.05).The ADV group and ETV group were well-matched with a similar mean age,similar proportion of male patients,and similar baseline eGFR classification(P>0.05).2 ADV-related nephrotoxicityThe levels of serum Cystatin C,eGFR and serum KIM-1 in ADV monotherapy group have no significant difference compared with ADV combination therapy group(P>0.05).There was a statistically significant difference in the number of incidences and severity of decrease in eGFR in the ADV group versus the ETV group.eGFR decreased 10%-20% from baseline in 11/81(13.58%)patients,20%-30% in 5/81(6.17%),and ? 30% in 2/81(2.47%)in patients treated with ADV.Of the patients on ADV,8(9.9%)developed mildly impaired renal function.In the ETV group,serum creatinine,serum Cystatin C and eGFR remained stable over the treated period(P>0.05).Serum KIM-1 showed a significant increase in ADV group compared to ETVgroup(P<0.01).Serum KIM-1 was positively correlated with serum Cystatin C(r=0.47,P<0.01)and negatively correlated with eGFR(r=-0.45,P<0.01).The area under the receiver-operating characteristic curve(AUC-ROC)of serum KIM-1 for identifying renal injury from all these populations,including both ADV group and ETV group,was 0.94(95% confidence interval [95%CI],0.87 to 1.02;P<0.01),while the AUC-ROC of serum creatinine was only0.81(95%CI,0.61 to 1.02;P<0.01).The cutoff of serum KIM-1 as the diagnosis of renal injury was 166.5pg/mL,and sensitivity and speciality rate were 88% and 95% respectively.3 Predictive factors for serum KIM-1 abnormalitySerum KIM-1 abnormality is no less than 166.5pg/mL.Univariate analysis showed that baseline eGFR < 90mL/min per 1.73m~2 and ADV treatment were associated with the development of serum KIM-1 abnormality.Multivariate analysis indicated that baseline eGFR < 90mL/min per 1.73m~2 was significant predictor of serum KIM-1 abnormality.Conclusions:1 Serum KIM-1 is a diagnostic biomarker of renal impairment during long-term adefovir therapy for chronic hepatitis B patients.