The Urate-lowering Efficacy And Renal Effect Of Febuxostat In Hyperuricemic Patients With Chronic Kidney Disease Stages 3-5

Objective:1.First stage:To explore the prevalence and risk factors of hyperuricemia?HUA?in patients with chronic kidney disease?CKD?stages 3-5 and investigate the effect of uric acid on renal function during the past 15 years.2.Second stage:To investigate the urate-lowering efficacy and renal effect of febuxostat in hyperuricemic patients with CKD stages 3-5.Methods:1.First stage:Patients with CKD stages 3-5 who admitted to the Department of renal medicine,Affiliated Hospital of Qingdao University from January 2000 to December 2014were recruited.The prevalence of HUA in patients with CKD stages 3-5 were analyzed statistically,the risk factors of HUA and the effect of uric acid on the estimated glomerular filtration rate?eGFR?were analyzed by regression analysis.2.Second stage:We conducted a prospective,randomized,controlled trial of CKD stages 3-5 patients with hyperuricemia from June 2015 to June 2016.Patients were randomly assigned to either the febuxostat group?treatment group?or the allopurinol group?control group?.Patients in treatment group received febuxostat 40 mg/d after study initiation,and it was changed to 20 mg/d if serum uric acid?sUA?<360?mol/L.Patients in control group were administered a dose of 100 mg/d of allopurinol.Serum uric acid,serum creatinine and other clinical parameters were measured at baseline and 1⁶ months after treatment.The rate of achieving target sUA level and the change of eGFR in two groups were performed using SPSS 21.0.Results:1.First stage:?1?The prevalence of HUA was 55.6%,and there was no significant difference between male and female in the 3547 patients who met the inclusion criteria??²=0.184,P=0.683?.The prevalence of HUA for CKD stage 3,4,5 was 42.6%,59.1%,61.2%,respectively.?2?The independent risk factors of HUA in patients with CKD stages3-5 were hypertension,increased BMI,increased total cholesterol,increased CKD stage and decreased HDL-C?P<0.05?.?3?In patients with CKD stages 3-5,multiple regression analysis showed that after adjusting for confounding factors,each 100?mol/L-higher uric acid at baseline led to a change in the rate of the baseline eGFR decline of 1.49ml·min^-1·?1.73 m²?^-1[95%confidence interval?CI?:-2.20^-1.05].?4?In 348 hyperuricemic patients with CKD stage 3,Logistic regression analysis showed that persistent HUA was associated with a higher risk for eGFR decreasing more than 10 ml·min^-1·?1.73 m²?^-1 1 year later[hazard ratio?HR?=2.645,95%CI:1.388⁵.039,P=0.003].2.Second stage:A total of 98 patients met the inclusion criteria and completed the trial.The treatment group and the control group were 51 cases and 47 cases,respectively.There was no significant difference between the two groups in age,sex,BMI,blood pressure,serum creatinine,eGFR,sUA and renal disease?P>0.05?.?1?At month 1⁶,there were significant differences between the two groups in the the rate of achieving target sUA level?P<0.001?;?2?At month 1 and month 3,no statistical difference was observed in the change of eGFR between the two groups?P=0.624,P=0.319?.At month 6,the changes in eGFR were+2.23 ml·min^-1·?1.73m²?^-11 and-4.36 ml·min^-1·?1.73m²?^-11 in the treatment and control group,respectively.The difference between the two groups was significant?P=0.037?;?3?In patients with CKD stages 3-5,generalized estimating equation showed that after adjusting for confounding variables,the rate of eGFR increased 1.149ml·min^-1·?1.73 m²?^-1?P=0.003?and 24-hour urinary protein decreased 0.019 g/d?P=0.037?per 60?mol/L decreased in sUA;?4?Febuxostat 40 mg/d can make 92.2%of the patients with CKD stages 3-5 meet the target sUA levels within 1 month,and the dosage of febuxostat was allowed to decrease to 20 mg/d,which was able to keep target sUA levels in90.2%of the patients within half a year and no serious adverse effects appeared.Conclusion:The prevalence of HUA in patients with CKD stages 3-5 was high.HUA is an independent risk factor for renal function deterioration.Urate-lowering efficacy and delaying progression of renal function of febuxostat exceeded that of allopurinol in patients with CKD stages 3-5 and HUA.Febuxostat 20 mg/d may be the effective and safe maintenance dose to maintain target sUA levels in patients with CKD stages 3-5,and whether it can be used as the best long-term maintenance dose should be further studied.