several studies have reported that hyperuricemia is associated with the development of hypertension and cardiovascular disease ( 1 - 3 ) . in addition , epidemiological studies have shown an association between a high level of serum uric acid and increased vascular events and mortality in patients with hypertension ( 4 ) . more evidences also show that hyperuricemia may have a pathogenetic role in the progression of renal disease ( 5 ) . ( 6 ) showed that an elevated serum uric acid level correlated with the development of renal insufficiency in individuals with normal kidney function . paradoxically , it has been suggested that uric acid have antioxidant activity in experimental studies ( 7 ) . in addition , it has been reported that uric acid administration to healthy volunteers increase their serum antioxidant capacity ( 8) . studies have shown that the relationship between serum uric acid and cardiovascular risk is j - shaped with a nadir in the second quintile ( 3 , 9 ) . this may reflect the association between low serum uric acid and low plasma antioxidant activity ( 10 ) . there are also evidences showing that hyperuricemia seems to induce high blood pressure , renal afferent arteriopathy , a rise in glomerular hydrostatic pressure , and renal scarring ( 11 ) . however , the relationship between the estimated glomerular filtration rate ( egfr ) and serum uric acid has not been studied in people with normal serum levels of uric acid . therefore , we aimed to investigate the association between egfr and uric acid in a general population with physiological serum levels of uric acid . we studied adults who were between 20 - 80 yr old and visited gangnam severance hospital for preventive medicine for a medical examination and health counseling . cross - sectional surveys of adults listed on the electoral roll were undertaken from november 2006 to june 2007 . this study is based on an analysis of the data from 2,170 males and 1,658 females at the time of their first survey . a total of 452 subjects ( 274 men , and 178 women ) were excluded based on the following exclusion criteria : 14 subjects reported the current use of blood uric acid - lowering agents ; 118 subjects had a history of cancer , ischemic heart disease , stroke , respiratory , renal , liver , or rheumatologic disease ; 234 had high levels of uric acid level ( 7 mg / dl for men and 6 mg / dl for women ) ( 12 ) , and 86 had missing medical history , laboratory , or urinalysis data . because some individuals were excluded for multiple reasons , the total number of eligible subjects for the study was 3,376 ( 1,896 men , and 1,480 women ) . participants were asked about health - related behaviors , including cigarette smoking , alcohol consumption , and physical activity as well as current treatments for any type of disease . if subjects were receiving treatment , they were asked to provide the date of diagnosis of the disease and a list of medications being taken . body weight and height were measured in light indoor clothing without shoes to the nearest 0.1 kg and 0.1 cm , respectively . body mass index ( bmi ) was calculated as the ratio of weight ( kg)/height ( m ) . after a 12-hr overnight fast , blood samples were obtained from each subject from the antecubital vein . fasting plasma glucose , total cholesterol , triglyceride , hdl - cholesterol , high sensitivity - c reactive protein ( crp ) , and uric acid were measured using a hitachi 7600 - 110 chemistry analyzer ( hitachi , tokyo , japan ) . kidney function was calculated using the modification of diet in renal disease 7 ( mdrd7 ) equation : gfr ( ml / min per 1.73 m)=170(serum creatinine)(age)(bun)(albumin)(0.762 if female ) ( 13 ) . urine protein was determined at each examination by a single uric stick semi - quantitative analysis ( uriscan urine strip ; yd diagnostics , yong - in , korea ) . the amount of urine protein was reported as absent , trace , 1 + , 2 + 3 + , or 4 + . the results of trace , 1 + , 2 + , 3 + , and 4 + correspond to protein levels of about 10 , 30 , 100 , 300 , and 1,000 mg / dl , respectively . diabetes was defined as a self - reported history of the disease or a fasting plasma glucose level 126 mg / dl . hypertension was defined as a self - reported history of the disorder , systolic blood pressure 140 mmhg , or diastolic blood pressure 90 mmhg . all continuous variables are presented as means ( sd ) or medians ( iqr ) , and the categorical variables are summarized as percentages in each group . due to skewness , crp was log transformed before statistical analyses . pearson and spearman rank correlation coefficients were determined for gfr vs age , bmi , cigarette smoking , regular exercise , systolic and diastolic blood pressure , plasma glucose , crp , non hdl - cholesterol , proteinuria , hypertestion , diabetes , and uric acid in men and women . to examine independent factors of gfr , multivariate linear regression analyses were performed . all statistical tests were 2-sided , and significance was determined at a p value < 0.05 . the study was approved by the institutional review board of gangnam severance hospital , yonsei university , college of medicine in seoul , korea ( 3 - 2008 - 0174 ) . we studied adults who were between 20 - 80 yr old and visited gangnam severance hospital for preventive medicine for a medical examination and health counseling . cross - sectional surveys of adults listed on the electoral roll were undertaken from november 2006 to june 2007 . this study is based on an analysis of the data from 2,170 males and 1,658 females at the time of their first survey . a total of 452 subjects ( 274 men , and 178 women ) were excluded based on the following exclusion criteria : 14 subjects reported the current use of blood uric acid - lowering agents ; 118 subjects had a history of cancer , ischemic heart disease , stroke , respiratory , renal , liver , or rheumatologic disease ; 234 had high levels of uric acid level ( 7 mg / dl for men and 6 mg / dl for women ) ( 12 ) , and 86 had missing medical history , laboratory , or urinalysis data . because some individuals were excluded for multiple reasons , the total number of eligible subjects for the study was 3,376 ( 1,896 men , and 1,480 women ) participants were asked about health - related behaviors , including cigarette smoking , alcohol consumption , and physical activity as well as current treatments for any type of disease . if subjects were receiving treatment , they were asked to provide the date of diagnosis of the disease and a list of medications being taken . body weight and height were measured in light indoor clothing without shoes to the nearest 0.1 kg and 0.1 cm , respectively . body mass index ( bmi ) was calculated as the ratio of weight ( kg)/height ( m ) . after a 12-hr overnight fast , blood samples were obtained from each subject from the antecubital vein . fasting plasma glucose , total cholesterol , triglyceride , hdl - cholesterol , high sensitivity - c reactive protein ( crp ) , and uric acid were measured using a hitachi 7600 - 110 chemistry analyzer ( hitachi , tokyo , japan ) . kidney function was calculated using the modification of diet in renal disease 7 ( mdrd7 ) equation : gfr ( ml / min per 1.73 m)=170(serum creatinine)(age)(bun)(albumin)(0.762 if female ) ( 13 ) . urine protein was determined at each examination by a single uric stick semi - quantitative analysis ( uriscan urine strip ; yd diagnostics , yong - in , korea ) . the amount of urine protein was reported as absent , trace , 1 + , 2 + 3 + , or 4 + . the results of trace , 1 + , 2 + , 3 + , and 4 + correspond to protein levels of about 10 , 30 , 100 , 300 , and 1,000 mg / dl , respectively . diabetes was defined as a self - reported history of the disease or a fasting plasma glucose level 126 mg / dl . hypertension was defined as a self - reported history of the disorder , systolic blood pressure 140 mmhg , or diastolic blood pressure 90 mmhg . all continuous variables are presented as means ( sd ) or medians ( iqr ) , and the categorical variables are summarized as percentages in each group . due to skewness , crp was log transformed before statistical analyses . pearson and spearman rank correlation coefficients were determined for gfr vs age , bmi , cigarette smoking , regular exercise , systolic and diastolic blood pressure , plasma glucose , crp , non hdl - cholesterol , proteinuria , hypertestion , diabetes , and uric acid in men and women . to examine independent factors of gfr all statistical tests were 2-sided , and significance was determined at a p value < 0.05 . the study was approved by the institutional review board of gangnam severance hospital , yonsei university , college of medicine in seoul , korea ( 3 - 2008 - 0174 ) . the average age was 46.5 yr for men , 45.4 yr for women , and the mean level of serum uric acid was 5.2 mg / dl for men and 4.1 mg / dl for women . approximately 39.2% of men and 5.3% of women were current smokers , while 64.6% of men and 48.7% of women exercised regularly . in multivariate linear regression analysis , age , dm , cigarette smoking , fasting plasma glucose , non - hdl cholesterol , and uric acid were found to be independent variables that were significantly associated with gfr in men . non hdl - cholesterol and uric acid were found to be independent variables associated with gfr in women ( table 2 ) . multiple stepwise regression models were used to evaluate the association of gfr with uric acid ( tables , 3 , 4 ) . the association of gfr with uric acid was negative after adjusting for age , dm , cigarette smoking , fasting plasma glucose and now hdl - cholesterol ( table 4 ) . it has been observed an increase in uric acid of 1 mg / dl is independently association with a decrease in gfr of about 5 ml / min/1.73 m in men and about 6 ml / min/1.73 m in women in table 4 . in the present study , we found an association between increased uric acid levels and decreased gfr in koreans with normal serum levels of uric acid . , hyperuricemia might develop when the production of uric acid increases or the excretion of uric acid declines , or both ( 15 ) . several studies have shown that an increase in uric acid is associated with hypertension , cerebral vascular disease and chronic kidney disease ( ckd ) ( 2 , 16 , 17 ) . experimental animal studies and in vitro studies have identified the mechanisms in which elevated uric acid levels might cause nephrotoxicity . afferent arteriopathy , mild tubulointerstitial fibrosis , glomerular hypertrophy , and glomerulosclerosis occur in hyperuricemic rats ( 18 ) . however , despite several epidemiological , experimental , and prospective cohort studies , it is still controversial whether hyperuricemia can be considered to be a risk factor for the progression of ckd . sturm et al . ( 19 ) reported that uric acid levels are not independent predictors of the progression of ckd . ( 20 ) reported that a high level of serum uric acid was more predictive for the development of renal dysfunction than proteinuria . one of the reasons for the controversy over whether hyperuricemia is a risk factor for the progression of ckd is that uric acid may function as an antioxidant ( 21 ) . uric acid can chelate transition metals and can scavenge singlet oxygen and superoxide radicals ( 22 ) . gfr has been suggested to be an indicator of early stages of kidney dysfunction ( 23 ) . therefore , we investigated the association between gfr and uric acid in a population with normal serum levels of uric acid . in multivariate linear regression analysis , age , cigarette smoking , fasting blood sugar , dm , and uric acid were independently and negatively associated with gfr in men , but not in women . non - hdl cholesterol and uric acid were independently and negatively associated with gfr in both men and women . ( 24 ) reported that a decrease in gfr was correlated with an increase in uric acid in patients with hypertension . however , in our study , gfr was not significantly correlated with hypertension in either men or women . galvan et al . reported that hyperuricemia develops frequently in subjects with insulin resistance , because insulin stimulates sodium and uric acid reabsorption in the proximal tubule ( 25 ) . gfr was negatively associated with fasting blood sugar and dm in men , but not in women . the reason for this difference is unclear ; however , the uricosuric effect of estrogen could be one possible reason for this difference ( 25 ) . recently , chonchol et al . ( 26 ) reported that high uric acid levels are strongly associated with the risk of kidney disease progression and a decrease in estimated gfr based on a prospective community - based cardiovascular health study of 4,610 participants . however , it is also possible that hyperuricemia is just a bystander to kidney disease . one reason for this hypothesis is the fact that uric acid is excreted by the proximal tubular cells . when gfr decreases , both enteric excretion and fractional urinary excretion increase , but these processes do not fully compensate for the decrease in gfr , and hyperuricemia is induced ( 15 ) . the other reason that hyperuricemia could just be a bystander to kidney disease is that uric acid is an antioxidant in the extracellular setting ( 22 ) . our study showed that an increase in uric acid of 1 mg / dl is independently associated with a gfr decrease of about 5 ml / min/1.73 m in men and about 6 ml / min/1.73 m in women . although it is possible that a high level of uric acid could simply be a result of low gfr , several studies have provided evidences that uric acid might actually play a role in the development or progression of renal disease . kang et al . ( 5 ) showed that uric acid induced renal hypertrophy , glomerulosclerosis and interstitial fibrosis in animal study . 27 ) reported that serum uric acid level was associated with a decline in renal function in a prospective study . siu et al . ( 11 ) reported that allopurinol therapy was able to significantly decrease the probability of kidney function deterioration in a prospective trial of 54 hyperuricemic patients with ckd . ( 28 ) showed that treatment with allopurinol improved not only uric acid levels but also gfr in patients with normal renal function . these results suggest that uric acid might have play a pathologic role in kidney disease progression . our findings are consistent with previous results showing a negative association between egfr and the serum level of uric acid . however , several organizations recommend the use of equations that estimate gfr to evaluate renal function in epidemiologic studies ( 29 ) . second , a dipstick can be inaccurate for detecting proteinuria , because the number of false - positives can be increased by a comorbid illness in older people or by menstruation in women . however , in our study , we used this variable only as an adjustment variable . a third limitation was that the influence of hypertensive drugs as confounding variables was not examined . diuretics such as thiazides increase serum uric acid by stimulating uric acid reabsorption in the proximal tubule ( 30 ) . last , this was a cross - sectional study ; therefore , it is not clear whether the observed serum levels of uric acid contribute to the development of ckd . the potential therapeutic effects of lowering uric acid levels in ckd patients should be investigated in future prospective studies . in conclusion , uric acid is independently and negatively associated with gfr in both men and women with normal serum levels of uric acid . this suggests that a high level of uric acid is a valuable predictor of a gfr decrease , and our findings have important clinical and public health implications .
several studies have reported that hyperuricemia is associated with the development of hypertension and cardiovascular disease . increasing 
 evidences also suggest that hyperuricemia may have a pathogenic role in the progression of renal disease . 
 paradoxically , uric acid is also widely accepted to have antioxidant activity in experimental studies . 
 we aimed to investigate the association between glomerular filtration rate ( gfr ) and uric acid in healthy individuals with a normal serum level of uric acid . 
 we examined renal function determined by gfr and uric acid in 3,376 subjects ( 1,896 men ; 1,480 women ; aged 20 - 80 yr ) who underwent medical examinations at gangnam severance hospital from november 2006 to june 2007 . 
 determinants for renal function and uric acid levels were also investigated . in both men and women , 
 gfr was negatively correlated with systolic and diastolic blood pressures , fasting plasma glucose , total cholesterol , uric acid , log transformed c reactive protein , and log transformed triglycerides . in multivariate regression analysis , 
 total uric acid was found to be an independent factor associated with estimated gfr in both men and women . 
 this result suggests that uric acid appears to contribute to renal impairment in subjects with normal serum level of uric acid .