The Research Of Early Renal Impairment In Adefovir Dipivoxil For Long-term Treatment In Chronic Hepatitis B Patients

ResearchBackgroundHepatitis B virus(HBV)infection is a serious clinical problem in the world,According to the national epidemiological survey of hepatitis B in 2006,there are about 90 million people with chronic HBV infection in china,The number of patients with chronic hepatitis B(CHB)is 20 million,and CHB is still one of the most common infectious diseases in china.Antiviral therapy is currently recognized as the most effective treatment for CHB.Nucleoside(acid)analog(NAs)is a class of drugs widely used in antiviral treatment of CHB,which has long been used to inhibit the replication of HBV virus,prevent hepatitis attack and delay the progression of liver fibrosis.However,due to the NAs can not completely remove HBV,CHB patients need long-term NAs antiviral treatment,long-term use of antiviral drugs security issues become the focus of attention.At present,the approved antiviral drugs are classified into interferons and nucleosides(acids)analogues.At present in the domestic market of the nucleoside(acid)compounds with lamivudine(lamivudine,LAM),adefovir dipivoxil(adefovir dipivoxil,ADV),telbivudine(telbivudine,LDT),entecavir(entecavir,ETV)and tenofovir(tenofovir disoproxil,fumarate,TDF),It has the advantages of less side effects and convenient taking.It can successfully inhibit the replication of hepatitis B virus and control the disease.However,with the extension of the application time,the defects of each drug also appeared.According to the Chinese hepatitis B follow-up and clinical research platform data in December 2014,31.66% of patients with chronic hepatitis B treated with oral nucleoside analogue antiviral therapy received adefovir dipivoxil monotherapy or adefovir dipivoxil treatment.Clinical studies have shown that long-term ADV treatment can lead to renal tubular injury,renal dysfunction,hyperphosphatemia and Vankoni syndrome.The expert consensus on antiviral therapy for chronic hepatitis B patients with kidney injury and its high risk indicates that 2-9 years after ADV treatment,about 15% of the patients suffered from renaltubular injury.Thus,ADV has adverse effects on renal function in patients with HBV infection,but the observation indicators of renal injury are inconsistent,especially the lack of early renal injury research.At present,there is insufficient understanding of kidney damage in liver diseases,and serum creatinine(Cr)is often used to reflect renal impairment.In fact,blood Cr is not a sensitive indicator of early renal damage.The guidelines for the prevention and treatment of chronic hepatitis B(2015)suggest that the increase of creatinine(Cr)often indicates that renal function damage has been more serious,and the recovery of renal function is also difficult.In 2002,NKF-K/DOQI and 2012 KDIGO guidelines for chronic kidney disease pointed out that serum creatinine alone was not sufficient to evaluate renal function,and eGFR was the best indicator of renal function.The decline of eGFR in chronic kidney disease was paralleled with renal function impairment.Therefore,eGFR is a sensitive and practical index for evaluating early renal function impairment.Because cystatin C is independent of any external factors and is only cleared by glomerular filtration,it is an endogenous marker reflecting changes in glomerular filtration rate.Objective:This study excluded renal toxicity,diabetes,hypertension,hyperlipidemia,hyperuricemia,retrospective analysis of HBV infection effect of long-term ADV treatment in renal injury factors,at the same time,the incidence of treatment before renal injury were observed in HBV antiviral infection,to provide reference for the clinical management of patients with ADV treatment.Method:From February 2014 to February 2017 in Southwest Hospital infectious disease department patients,screening compliance with admission and discharge standard cases.Telephone follow-up to further improve the data.Inclusion of ADV 10mg/d monotherapy or ADV10mg/d combined with LAM1 00mg/d or ETV 0.5mg/d antiviral therapy and follow-up in our hospital for more than 2 years CHB.Inclusion criteria: Patients with HBV infection related disease diagnostic criteria and treatment indications in accordance with the guidelines for the prevention and treatment of chronic hepatitis B(2010 Edition);aged 13~78 years;at least 2 years of continuous use;followed up 1 times every 3~6 months.Exclusion criteria:(1)with malignant tumor;(2)with HCV or HIV infection;(3)associated with other diseases of the urinary system;(4)associated with other liver diseases(such as liver cancer,autoimmuneliver disease,drug-induced hepatitis);(5)hypertension,diabetes mellitus(6;)with thyroid disease;(7)by taking other drugs on renal damage caused by [3940].In addition,the data of HBV infection patients who were treated in the infectious diseases department of Southwest Hospital in 2014 without antiviral therapy were collected,and the incidence of renal injury was analyzed by a cross-sectional analysis.The main outcome measures were renal injury indexes,including serum creatinine(Cr),Cystatin C(Cys C),and estimated glomerular filtration rate(eGFR).The early impairment of renal function is defined in this dissertation as follows: 2 consecutive detection of mild renal dysfunction,namely blood Cr>106 mol / L or mol compared to the baseline and elevated levels of >44.2 / L or cystatin C(Cys-C)1.05mg/L or eGFR(CKD-EPI,MDRD)= 90ml/(min,1.73m2)[20].Or 1 moderately decreased renal function,blood Cr>177 mol / L C(Cys-C)or cystatin 1.53mg/L or eGFR(CKD-EPI,MDRD)= 60ml/(min,1.73m2).The main indexes affecting the renal function included gender,age,duration of ADV use,combined use of other antiviral drugs,blood glucose(GLU)and serum uric acid(UA)in the use of ADV.HBsAg,HBe Ag,HBV DNA,ALTBy statistical methods of independent samples t test,Mann-Whitney U test,chi square test,two yuan logistics regression analysis and ROC curve analysis of gender,age and ADV combined with other antiviral drug use time,when using ADV,HBsAg,HBeAg,HBV,DNA,ALT and other factors on early renal injuryResult:In this study,a total of 1187 patients receiving ADV antiviral therapy were retrospectively collected.870 patients who did not meet the inclusion and exclusion criteria were excluded,and 317 patients were analyzed for antiviral treatment group.According to the standard of early renal damage defined in this study,they were divided into 2 groups: 118 cases of renal injury,199 cases of non renal injury.A total of 495 patients with HBV infection who had not been treated with antiviral therapy were enrolled in this study.The patients were excluded from diabetes,hypertension,hyperuricemia and chronic kidney disease.In the antiviral group,the average age was 40.52 years in 317 patients,187 in males,58.99% in,51.2 in ALT,27.7% in HBeAg,81.43% in HBVDNA,and 45.7% in males.73 patients received ADV monotherapy,156 received ADV+LAM treatment,and 88 received ADV+ETV treatment.The average duration of antiviral therapy was 6.43 years,and the overall incidenceof kidney injury was about 37.22%.No antiviral group 495 patients,male 293 cases,accounting for 59%,with an average age of 35.4 years,the average duration of about 9.98 years,the average BMI27.16;the average ALT 58.65U/L,higher than normal in 155 cases,accounting for 31.3%;the average HBVDNA value of 5.37E+5,HBVDNA below the detection limit of 112 cases,accounting for 22.62%;the positive rate of HBeAg was 30.5%.The overall renal injury incidence rate was 8.48%.Most of the renal function damage was mild,accounting for more than 92%.In patients with early renal injury,Cystatin C and eGFR were found to be abnormal,with only 16 cases with abnormal creatinine,and all of them had abnormal cystatin C or / and eGFR.Independent samples t test and Mann-Whitney U test: the incidence of kidney injury in patients with chronic hepatitis B treated with long-term use of ADV was significantly higher than that of HBV infected patients who did not use drugs.Chi square test: age and ADV duration results have significant differences,no significant difference in other factors;two logistics regression analysis: age,ADV duration were the dependent variables whether early renal damage has significant effect;ROC curve analysis:age ADV and medication time of early renal injury has obvious sensitivity and the corresponding Youden index were 0.616,0.422,corresponding critical value were 47.5 years old and 3.175 years.Conclusion:1.The incidence of early renal injury in patients with chronic hepatitis B treated with ADV for long-term use in this region was significantly higher than that in HBV patients who did not receive antiviral therapy,suggesting that long-term ADV treatment can lead to kidney injury,but most of them are mild renal damage.2.Cystatin C and eGFR are good indicators to monitor early renal damage in patients with long-term anti HBV treatment of ADV.3.age and ADV use time are risk factors of early renal injury,and age is more predictive of renal damage than ADV medication time.47.5 years old can be used as the critical reference age for renal damage;3.175 years antiviral therapy can be used as the critical reference age for renal damage.4.gender,whether combined use of other antiviral drugs,HBsAg,HBeAg,HBV,DNA,ALT and other factors have no significant impact on early renal injury.