| Background:Uric acid,the oxidation end-product of purine nucleotides metabolism in man and higher primates,was a heterocyclic compound of carbon,nitrogen,oxygen,and hydrogen with the formula C5H4N403.Serum uric acid was a slightly soluble material,while in most other mammals,the enzyme uricase(urate oxidase)further oxidates uric acid into allantoin,a more soluble molecule.However,in man and higher primates,mutations in the uricase gene occurred during evolution and,making the enzyme non-functional,resulted in higher levels of uric acid in hominids than in other mammals.Serum uric acid concentrations ?7mg/dL in man and ?6mg/dL in woman was defined as hyperuricemia.The variability in serum uric acid levels is multifactorial and influenced by both environmental and genetic factors.Briefly,both reduced excretion and increased production was responsible for high levels of serum uric acid.Studies in different countries demonstrated the human Uromodulin gene(UMOD)mutation may have a role in serum uric acid metabolism.And most of the genes involved with the renal urate transport system(the uric acid transportasome),generally considered the most influential regulator of serum urate homeostasis.In other hand,increased production of purine metabolism due to disease such as hematologic disorders,disorder of transformation of nucleotides in disease as leukemia,high intake of dietary purine,table sugar and high-fructose corn syrup,excess drinking and obesity,lead to high level of serum uric acid as well.Also,as is well known,most of serum uric acid was eliminated by the kidneys,renal function decline may lead to less elimination of serum uric acid.Hyperuricemia was a non-communicable disease that threatens human health and its prevalence had been increasing in recent decades.A national cross-sectional survey using multistage,stratified sampling in Chinese adults during 2009-2010,reported the prevalence of hyperuricemia was 8.4%,and it was 9.9%in men and 7.0%in women,respectively.Chronic kidney disease,or CKD,a high prevalent chronic disease in developed countries as well in the developing countries.And it was said to have an increment in its prevalence in recent decades.In the United States,a cross-sectional analysis of the most recent National Health and Nutrition Examination Surveys(NHANES 1988-1994 and NHANES1999-2004),reported the prevalence of CKD was 10.0%in 1988-1994 and reached 13%in the year 1999-2004.Furthermore recently the NHANES survey 2009-2010 reported the prevalence of CKD was 14%.In China,a cross-sectional survey of a nationally representative sample of Chinese adults,which was conducted in 2007 to 2010,47204 participants selected from 13 provinces,reported that the prevalence of CKD in China adults was 10.8%.Hypertension another high prevalent chronic disease especially in old people,was said to have a prevalence of 37.6%in the United States adults.In our country,data from the 46239 Chinese adults 20 years old or more,who participated in the 2007-2008 China National Diabetes and Metabolic Disorders Study,reported the prevalence of hypertension in Chinese adults was 26.6%.Serum uric acid was regarded as risk factor of many diseases such as gout,hypertension,cardiovascular disease,diabetes,metabolic syndrome and so on.While,as hypertension and diabetes was well established risk factors of chronic kidney disease.And giving to the association of renal disease and cardiovascular disease,the association of serum uric acid and renal disease was also be interested in recent years.Serum uric acid was said as a risk factor of incident CKD in some health cheek people studies but not in all.On the other hand,some studies demonstrated serum uric acid as an independent risk factor for renal function and renal failure.However,the association of serum uric acid and CKD progression in CKD patients was controversy.Objectives:In this study,we first aimed to examine the prevalence of hyperuricemia and its risk factors in hypertensive patents in China rural areas in a cross-sectional cohort and then examine the relationship between serum uric acid and renal function progression in patients with renal injury in a prospective cohort.Methods:Study populationData of this article was from the China Stroke Primary Prevention Trial,CSPPT study(clinicaltrials.gov identifier:NCT00794885),enalapril maleate and folic acid tablets for primary prevention of stroke in patients with hypertension:A post-marketing,double-blind,parallel controlled trial.The CSPPT study was a multi-community,randomized,double-blind,actively-controlled trial conducted in 32 communities in Jiangsu province and Anhui province.We used data of patients from 20 communities in Jiangsu province,aged 45 to 75 with primary hypertension.Hypertension was defined as seated systolic blood pressure(SBP)?140 mmHg and/or seated diastolic blood pressure(DBP)? 90 mmHg,according to Guidelines for Prevention and Treatment of Hypertension in China in the year 2005 and 2003 WHO/ISH Guidelines for hypertension.Patients with diagnosed second hypertension were eliminated.The run-in period was conducted from May,2008 to May,2009,after 3-weeks run-in period,eligible patients were randomized to the two groups.All participants had informed consent.Regular visits were performed every 3 month.The follow-up was until August 26,2013.In this article we first selected patients in Lianyungang in the cross-sectional cohort to examine serum uric acid distribution.Then selected patients in Lianyungang with renal injury defined as baseline eGFR(estimated used the CKD-EPI equation)<60ml/min/1/73m2 or with proteinuria(positive),to examine the association of serum uric acid and renal function progression.Clinical MeasurementsBlood pressure measurements were taken manually 3 times,using standardized sphygmomanometers by well-trained persons,patients with at least 2 times measurements in each visit was regarded as eligible ones.The mean of the measurements is recorded in the database at each visit as the systolic or diastolic blood pressure.Patients attending the clinic trail were randomized to take enalapril or maleate folic acid tablets,and advised to take their regular medications as usual and other antihypertensive drug such as diuretic,calcium channel blockers(CCB)and so on was used as possible.Height and weight of all patients were measured using standardized equipment in the entry and the last visit to calculate body mass index(BMI).Standard epidemiological questionnaire was set to acquire basic demographic characteristics including age,smoking status,alcohol consumption and so on.Blood samples were collected at baseline and the last visit for estimation of biochemical indices.All biochemical investigations were performed at the department of nephrology laboratory service in Nanfang Hospital,Southern Medical University and the participants were asked to fast overnight for at least 8 hours.Serum creatinine at baseline and the last follow-up period was measured using an enzymatic method.Estimated glomerular filtration rate(eGFR)was estimated based on the equation derived from the Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI)creatinine equation:eGFR= 141 xmin(Scr/k,l)a×max(Scr/k,l)-1.209x0.993Agex 1.018[if female]where serum creatinine(Scr)is expressed in mg/dl(if expressed in lmmol/l,divided by 88.4)and age in years,k is 0.7 for females and 0.9 for males,a is-0.329 for females and-0.411 for males,min indicates the minimum of Scr/k or 1,and max indicates the maximum of Scr/k or 1.Uric acid along with glucose,triglyceride,cholesterol and other variables was measured using Automatic biochemical analyzer(AU480,Beckman Coulter,Inc,USA).Hyperuricemia was defined as serum uric acid>7mg/dL in man and>6mg/dL in woman according to some other studies.Diabetes was defined as glucose?7.0mmol/L or patients with diagnosed diabetes or patients having anti-diabetic drugs.And abdominal obesity was defined as waist circumference>90 cm in male and>80 cm in female.Outcome AssessmentThe primary endpoints we focused on this study was composite endpoint defined as creatinine at least 50%increment or developed to ERSD(eGFR<15ml/min/1.73m2)or requirement of dialysis therapy during the follow-up duration.The second endpoints of interest in our study as follow:rapid progression(eGFR slope at least 5ml/min/1.73m2 per year);CKD progression,which was defined according to the Kidney Disease:Improving Global Outcome(KDIGO)2012[1]as follows:a drop in GFR category(>90[G1],60-89[G2],45-59[G3a],30-44[G3b],15-29[G4],<15[G5]mL/min/1.73 m2)accompanied by a 25%or greater drop in eGFR from baseline or a sustained decline in eGFR of more than 5 mL/min/1.73 m2 per year;And eGFR slope in our study was the absolutely decline in the follow-up duration,which was calculated as(eGFR at the final visit-eGFR at baseline)/follow-up years.Statistical AnalysisDistribution serum uric acidWe compared basic characteristics of the study population in sex-stratified serum uric acid quartile in male and female.And variables were presented as mean±SD or median(interquartile range)for continuous variable as possible and percentage for category variable.Crude prevalence of hyperuricemia was reported by age and glomerular groups.Stepwise regression model was used to select the risk factors of high serum uric acid level.Relation between uric acid and renal disease progression:We divided our study population into two groups based on serum uric acid level normal serum uric acid level versus hyperuricemia.Differences in characteristics across the groups were explored using t test(for continuous variables)and ?2 test(for categorical variables).Logistic regression models were used to explore the relationship between renal outcomes(composite endpoint,rapid progression and CKD progression)and serum uric acid,for the endpoint eGFR slope generalized linear models were using.Furthermore,uric acid was presented as hyperuricemia and continuous variable in the multivariable adjusted model analyses.The statistical significance level was set at P<0.05 for all the conclusions obtained through inferential analysis.The statistical analysis was carried out using R software,version 3.1.0(http://www.r-project.org/).Epidata 3.0 was used for data entry and verification.Data were entered twice by two different people,and inconsistencies were checked with the original records.ResultsSeum uric acid distribution:20192 patients in the run-in period form Lianyungang,Jiangsu province and 15486 eligible participants was in the randomized period,935 participants with missing variable such as uric acid,creatinine and other variables was exclude.Finally,14551 participants was include in the analysis,5679(39.0%)was male,mean uric acid level was 295(SD:79.5)?mol/L,334(SD:81)?mol/L in male and 270(SD:67)?mol/L in female.The prevalence of hyperuricemia was 10.8%,and 13.4%in male and 9.2%in male.And with age increase,serum uric acid level and prevalence of hyperuricemia increase in male but not in male.However,with glomerular filtration decline,serum uric acid level and prevalence of hyperuricemia increased in both gender.In participants with glomerular less than 60ml/min/1.73m2,the prevalence in male and female was 48.9%and 40.5%,respectively.In stepwise regression model,age,smoking and drinking status,education level,physical activity,blood pressure,creatinine,glomerular filtration rate,proteinuria,fasting glucose,triglyceride,high density cholesterol,diuretic use,calcium and phosphorus was related to serum uric acid level in man;age,smoking status,blood pressure,glomerular filtration rate,proteinuria,fasting glucose,triglyceride,high density cholesterol,cholesterol,diuretic use,calcium and phosphorus was related to that of female.Uric acid and renal disease progression:Among the 1729 patients were selected in our study,49 with one or more basic value missing,78(4.2%)of all-caused death in the 4.3 year(SD,0.3)follow-up duration,197(12.3%)loss follow-up,and patents with missing data such as serum uric acid or serum creatinine missing was eliminated.Finally 1405 patients were enrolled in our analysis.590(42.5%)was male,with a mean age of 60(standard deviation:8.0)years,mean glomerular filtrated rate was 85.6ml/min/1.73m2 and mean serum uric acid level was 317.9?mol/L.In baseline,we found body mass index,waist circumference,serum creatinine,serum uric acid level was higher in hyperuricemia patients compared to that in the normal serum uric acid group.Also,there was more percentage in anti-hypertensive drug use and diuretic use in the hyperuricemia group.No statistic significant was found in age,serum glucose level in the two groups due to serum uric acid level.In a mean 4.3(0.2)years follow-up,74(percentage:5.4%),174(percentage:12.4%)and 148(percentage:10.5%)of the patients developed composite endpoints,KDIGO CKD progression and rapid progression.And the median of eGFR slope was-1.05(range:-2.64-0.48)ml/min/1.73m2 per year.In the smoothing curve,liner association was found between serum uric acid level and the primary outcome,KDIGO CKD progression and rapid progression.Furthermore,in consistently with the smoothing curve,in multivariable adjusted logistic regression model,the risk for primary outcome,KDIGO CKD progression and rapid progression was 1.32(95%confidence interval:1.12-1.56,P<0.001),1.15(95%confidence interval:1.03-1.30,P=0.016)and 1.12(95%confidence interval:0.99-1.28,P=0.081),respectively with per 1 mg/dL increment in serum uric acid level.In sensitive analysis,uric acid was divided into hyperuricmia and normal serum uric acid level,and in multivariable adjusted logistic regression model,the result was inconsistently with that of serum uric acid as continuous variable.In hyperuricmia group,the risk for primary outcome,KDIGO CKD progression and rapid progression was 1.92(95%confidence interval:1.09-3.40,P=0.025),1.60(95%confidence interval:1.07-2.39,P=0.021)and 1.46(95%confidence interval:0.93-2.30,P=0.096),respectively.While no significant association was found between uric acid residual and renal outcomes in the regression models.Furthermore,we studied the interaction effect of concomitant variable on serum uric acid,the concomitant variable such as sex,age,body mass index,waist circumference,diabetes,high density cholesterol and triglyceride.And in multivariable adjusted logistic regression model,age and waist circumference was found to have an effect on serum uric acid,in the elder people 60 years old and more and abdominal obesity people,the risk for primary outcome,KDIGO CKD progression and rapid progression was 1.54(95%confidence interval:1.23-1.91,P for interaction:0.043)and 1.56(95%confidence interval:1.25-1.96,P for interaction 0.033),respectively.While uric acid residual analysis no significant association was found.The concomitant variable include in the multivariable adjusted regression model was sex,age,baseline glomerular filtrated rate,proteinuria,fasting glucose,diuretic use,baseline and the last blood pressure.Conclusion:Liner association was found between serum uric acid and kidney disease progression and serum uric acid was an independent predict factor for renal function progression in rural Chines hypertensive patient with kidney disease.Furthermore,there was a detrimental interaction of uric acid with old age and abdominal obesity on renal function progression. |
PDF Full Text Request