Analysis Of Association Between Opioid Analgesics And The Risk Of Hospital-acquired Acute Kidney Injury In Adults:A Large Multicenter Retrospective Study

Background:Acute kidney injury(AKI)is common and associated with increased risk of death and other poor outcomes in hospitalized patients.It is considered as a new "global health problem" because of its high incidence,high mortality.Exposure to nephrotoxic medications has been recognized as one of the reasons for Hospital-acquired Acute Kidney Injury(HA-AKI)in adults.Opioid analgesics are important analgesics,which have been widely used in the world in recent years.The use of opioid analgesics has been linked with increased risk of adverse events,including respiratory depression,constipation and death.Despite its widely usage in the world,the correlation between opioid analgesics use and acute kidney injury was underrecognized and underreported.We need a large-scale epidemiological study on the relationship between the use of opioid analgesics and risk of AKI.Objective:In the current analysis,we aim to examine the clinical use of opioid analgesics among hospitalized adults in China,and to assess the potential association between the use of opioid analgesics and risk of HA-AKI,and to further explore the correlation between dosage of opioid analgesics and risk of HA-AKI.Study participants and Methods:Study participants:EACH2(Epidemiology of AKI in Chinese Hospitalized patient 2)study is a large-scaled,retrospective cohort study conducted in 25 regional hospitals,including nine children’s hospitals,from 15 provinces across China.EACH2 contained 3,044,223 patients.We selected adult patients who had two or more serum creatinine(SCr)tests in a 7-day window within the first 30 days of their hospitalization.The selected adults had available prescription data and available diagnostic information.Patients who were diagnosed as End-stage renal disease(ESRD)or CA-AKI,receiving renal replacement therapy(including hemodialysis and peritoneal dialysis)or renal transplantation were excluded.Patients whose baseline estimated glomerular filtration rate(eGFR)≤ 15 ml/min/1.73m2 were also excluded.Definition of AKI:AKI was considered as an increase in SCr by 26.5 μmol/L(0.3 mg/dl)within 48 hours or a 50%increase in SCr from the baseline within seven days according to the Kidney Disease Improving Global Outcomes(KDIGO)criteria.Patients who developed AKI but did not meet CA-AKI criteria were identified as having hospital-acquired HA-AKI.Opioid analgesics exposure and other drugs exposure definition:We defined drug exposure as any prescription of the specified drug that study subjects received within the first 30 days of hospitalization prior to the onset date of HA-AKI in patients with HA-AKI and that study subjects received before the last creatinine test in those without HA-AKI.Opioid analgesics exposure was identified with the ATC code:tramadol(N02AX02),dezocine(N02AX03),morphine(N02AA01),oxycodone(N02AA05),pethidine(N02AB02),fentanyl(N02AB03).Statistical Analysis:Characteristics of study population stratified by use of each kind of opioid analgesics was compared using Man-Whitney U test for continuous variables and Pearson χ2 tests for categorical variables.We used Kaplan-Meier method to derive the curves of cumulative hazzards of HA-AKI by strata of exposure to opioid analgesics use within the first 30 days of their hospitalization.We estimated the effect of drug use on the risk of HA-AKI using Time-varing Cox proportional risk regression model with adjustment for age,gender,baseline eGFR,comorbidities,operation procedures,need for ICU treatment and concomitant use of nephrotoxic drugs,and Charlson’s comorbidity score,hospital,division and other factors.In order to further decrease the confounding bias,we tended to use propensity score matching methods to establish new matched cohort and use time-varing cox proportional risk regression analysis to estimate the effect of drug use on the risk of HA-AKI.In addition,we performed several other sensitivity analyses to further evaluate the consistency of our findings.Results:Of the 174408 hospitalized adults,816(15.24%),601(11.2%),660(14.94%),627(4.78%),353(5.25%),254(4.49%)AKI events were identified from 5356 morphine users,5369 pethidine users,4417 fentanyl users,13131 dezocine users,6729 tramadol users and 5653 oxycodone users,respectively.Compared with non-users,significantly increased risk of HA-AKI was observed among morphine users(HR=1.57,95%CI 1.42-1.74)and pethidine users(HR=1.52,95%CI 1.36-1.70),after adjusting for age of patients,gender of patients,baseline eGFR,comorbidities,clinical procedures,need for ICU therapy,concomitant use of nephrotoxic drugs,hospital,division and other factors.The associations were consistent in subgroups and multiple sensitivity analyses.In addition,the effect of morphine or pethidine on the increased risk of HA-AKI was dose-dependent.Compared with non-users,the use of fentanyl,dizocine,tramadol or oxycodone was not significantly associated with the risk of HA-AKI in adults.Subgroup analysis showed that adults without receiving intensive care or operation during hospitalization were more susceptible to morphine-related AKI.While,pethidine users without receiving operation had a higher susceptibility to pethidine-related AKI.Conclusions:Our study identified that morphine and pethidine use was independent risk factors for HA-AKI in adults.While the use of fentanyl,dezocine,tramadol,or oxycodone was not significantly associated with the risk of HA-AKI in adults.The effect of morphine or pethidine on the increased risk of HA-AKI was dose-dependent.These findings should remind physicians of potential risk in using these tow subtypes of opioid analgesics in adults.Our study may also help to promote rational prescriptions of morphine and pethidine in adults worldwide.