the study was performed within the framework of the verona diabetes study , an observational longitudinal study on chronic complications in type 2 diabetic outpatients attending the diabetes clinic at the university hospital of verona ( 24 ) . data included in this analysis are based on a cohort of 1,449 white type 2 diabetic outpatients , who were recruited over the period of january 2000 to january 2002 and then followed up until december 2007 . these participants represent ~40% of the whole cohort of type 2 diabetic individuals ( n = 3,924 ) who regularly attended our diabetes clinic during the years 20002002 , after excluding 1 ) patients with overt proteinuria or an estimated glomerular filtration rate ( egfr ) < 60 ml / min/1.73 m ( n = 701 ) ; 2 ) those who had a previous history of cardiovascular disease ( defined as angina , myocardial infarction , ischemic stroke , and coronary revascularization ) , severe chronic obstructive pulmonary disease , and malignancies ( n = 727 ) ; and 3 ) those who had incomplete baseline laboratory data for analysis ( n = 1,047 ) . baseline demographics , blood pressure , plasma lipids , and hba1c were not significantly different between the 1,449 participants of the study and those ( n = 1,047 ) who had incomplete laboratory data ( data not shown ) . all participants were periodically seen ( every 69 months ) for routine medical examinations of glycemic control and chronic complications of diabetes . more details about the study design and recruitment methods have been reported elsewhere ( 9 ) . bmi was calculated by dividing weight in kilograms by the square of height in meters . a physician measured blood pressure in duplicate with a mercury sphygmomanometer ( at the right upper arm using an appropriate cuff size ) after the patient had been seated quietly for at least 5 min . subjects were considered to have arterial hypertension if their blood pressure was 140/90 mmhg or if they were taking any antihypertensive medications . detailed information in our informatic database regarding specific classes of antihypertensive medications ( e.g. , ace inhibitors , angiotensin receptor blockers , or diuretics ) currently is available in a subset of 632 participants . information on comorbid conditions and smoking history was obtained from all patients by interviews during medical examinations . serum uric acid ( uricase / peroxidase enzymatic method ) , creatinine ( measured using a jaff rate - blanked and compensated assay ) , and other biochemical blood measurements were determined by standard laboratory procedures ( dax 96 ; bayer diagnostics , milan , italy ) . both intra- and interassay hba1c was measured by an automated high - performance liquid chromatography analyzer ( bio - rad diamat , milan , italy ) ; the upper limit of normal for our laboratory was 5.8% . mol / l ( 7.0 mg / dl ) in men and 386 mol / l ( 6.5 mg / dl ) in women or if they were on allopurinol therapy . these cutoff values of the serum uric acid level are those commonly used to define hyperuricemia in our clinical laboratory . egfr was estimated from the four - variable modification of diet in renal disease ( mdrd ) study equation , as follows : egfr = 175.0  ( serum creatinine )  ( age )  1.212 ( if black )  0.742 ( if female ) ( 25 ) . egfr also was estimated from the ckd  epidemiology collaboration ( ckd - epi ) creatinine equation ( 26 ) . urinary albumin excretion was measured from an early - morning urine sample on at least two consecutive occasions as the albumin - to - creatinine ratio ( acr ) by an immunonephelometric method . microalbuminuria was defined as an acr > 2.5 and < 30 mg / mmol for men and > 3.5 and < 30 mg / mmol for women ( 1,25 ) . for this study , incident ckd was defined as the occurrence of an egfr < 60 ml / min/1.73 m or persistent macroalbuminuria ( i.e. , acr 30 mg / mmol for both sexes in at least two of three consecutive samples ) in participants with normal or near - normal kidney function at baseline . the unpaired t test and the  test with yates correction for continuity ( for categorical variables ) were used to compare the baseline characteristics of participants stratified by the presence or absence of sex - specific hyperuricemia ( table 1 ) . a multivariable logistic regression analysis also was used to identify the factors independently associated with the development of incident ckd . three forced - entry multivariable logistic regression models were performed . in all these models , the first model was adjusted for age ( years ) and sex ( male versus female ) ; the second model was further adjusted for bmi ( kg / m ) , hba1c ( % ) , diabetes duration ( years ) , smoking history ( yes or no ) , systolic blood pressure ( yes ; mmhg ) , antihypertensive treatment ( yes or no ) , insulin therapy ( yes or no ) , egfr ( ml / min/1.73 m ) , and albuminuria ( mg / mmol ) . in the third model , we additionally adjusted for the changes of systolic blood pressure and hba1c at the end of follow - up plus the same set of covariates that were included in the second model . these covariates were chosen as potential confounding factors on the basis of their significance in univariate analyses or on the basis of their biological plausibility . baseline clinical and biochemical characteristics of patients with type 2 diabetes and normal kidney function stratified by sex - specific hyperuricemia bmi was calculated by dividing weight in kilograms by the square of height in meters . a physician measured blood pressure in duplicate with a mercury sphygmomanometer ( at the right upper arm using an appropriate cuff size ) after the patient had been seated quietly for at least 5 min . subjects were considered to have arterial hypertension if their blood pressure was 140/90 mmhg or if they were taking any antihypertensive medications . detailed information in our informatic database regarding specific classes of antihypertensive medications ( e.g. , ace inhibitors , angiotensin receptor blockers , or diuretics ) currently is available in a subset of 632 participants . information on comorbid conditions and smoking history was obtained from all patients by interviews during medical examinations . serum uric acid ( uricase / peroxidase enzymatic method ) , creatinine ( measured using a jaff rate - blanked and compensated assay ) , and other biochemical blood measurements were determined by standard laboratory procedures ( dax 96 ; bayer diagnostics , milan , italy ) . both intra- and interassay hba1c was measured by an automated high - performance liquid chromatography analyzer ( bio - rad diamat , milan , italy ) ; the upper limit of normal for our laboratory was 5.8% . 386 mol / l ( 6.5 mg / dl ) in women or if they were on allopurinol therapy . these cutoff values of the serum uric acid level are those commonly used to define hyperuricemia in our clinical laboratory . egfr was estimated from the four - variable modification of diet in renal disease ( mdrd ) study equation , as follows : egfr = 175.0  ( serum creatinine )  ( age )  1.212 ( if black )  0.742 ( if female ) ( 25 ) . egfr also was estimated from the ckd  epidemiology collaboration ( ckd - epi ) creatinine equation ( 26 ) . urinary albumin excretion was measured from an early - morning urine sample on at least two consecutive occasions as the albumin - to - creatinine ratio ( acr ) by an immunonephelometric method . microalbuminuria was defined as an acr > 2.5 and < 30 mg / mmol for men and > 3.5 and < 30 mg / mmol for women ( 1,25 ) . for this study , incident ckd was defined as the occurrence of an egfr < 60 ml / min/1.73 m or persistent macroalbuminuria ( i.e. , acr 30 mg / mmol for both sexes in at least two of three consecutive samples ) in participants with normal or near - normal kidney function at baseline . skewed variables were logarithmically transformed to improve normality prior to analysis . the unpaired t test and the  test with yates correction for continuity ( for categorical variables ) were used to compare the baseline characteristics of participants stratified by the presence or absence of sex - specific hyperuricemia ( table 1 ) . a multivariable logistic regression analysis also was used to identify the factors independently associated with the development of incident ckd . three forced - entry multivariable logistic regression models were performed . in all these models , the first model was adjusted for age ( years ) and sex ( male versus female ) ; the second model was further adjusted for bmi ( kg / m ) , hba1c ( % ) , diabetes duration ( years ) , smoking history ( yes or no ) , systolic blood pressure ( yes ; mmhg ) , antihypertensive treatment ( yes or no ) , insulin therapy ( yes or no ) , egfr ( ml / min/1.73 m ) , and albuminuria ( mg / mmol ) . in the third model , we additionally adjusted for the changes of systolic blood pressure and hba1c at the end of follow - up plus the same set of covariates that were included in the second model . these covariates were chosen as potential confounding factors on the basis of their significance in univariate analyses or on the basis of their biological plausibility . baseline clinical and biochemical characteristics of patients with type 2 diabetes and normal kidney function stratified by sex - specific hyperuricemia the 1,449 patients ( 888 men , mean age 66 years ) with type 2 diabetes included in the study had a mean baseline serum uric acid level of 284  81 mol / l with a significant difference between sexes ( 298  80 vs. 261  77 mol / l in men and women , respectively , p < 0.001 ) . they also had a mean baseline egfr of 82  14 ml / min/1.73 m , and 80.5% ( n = 1,166 ) of patients had normal albuminuria and 19.5% ( n = 283 ) had microalbuminuria ; by study design , no participants had macroalbuminuria . approximately 85% of participants had hypertension at baseline ( defined as blood pressure 140/90 mmhg or drug treatment ) . clinical and biochemical characteristics of participants grouped according to the presence or absence of hyperuricemia are summarized in table 1 . patients with hyperuricemia ( n = 159 [ 11% ] ) had a shorter duration of diabetes , higher bmi , higher systolic blood pressure , higher triglycerides , and lower values of hba1c , hdl cholesterol , and baseline egfr than their counterparts without hyperuricemia . in addition , they were less likely to be smokers and were more likely to have hypertension and to be treated with antihypertensive agents . detailed information regarding specific classes of antihypertensive drugs currently was available only in a subset of 632 subjects . no significant differences were found in the use of ace inhibitors , angiotensin receptor blockers , or diuretics in the hyperuricemic versus normouricemic group ( data not shown ) . frequency of microalbuminuria also tended to be greater in those with hyperuricemia , but the difference did not achieve statistical significance . sex distribution , age , ldl cholesterol , and the proportion of patients using insulin did not differ between the groups . during a mean follow - up of 5 years , 194 ( 13.4% ) patients developed incident ckd ( 148 developed an egfr < 60 ml / min/1.73 m , 29 developed persistent macroalbuminuria , and 17 developed both conditions ) . during the follow - up , 36 subjects died of any cause , of whom 5 had developed incident ckd ; they were considered alive for statistical analyses . of note , a significantly greater proportion ( p < 0.001 ) of patients with hyperuricemia developed incident ckd ( 29.5% ) during the follow - up in comparison with those without hyperuricemia ( 11.4% ) ( table 1 ) . at the end of the follow - up period , the rates of hypertension were 93.7% ( 127 new patients developed incident hypertension ) in the normouricemic group and 98.1% ( 5 patients developed incident hypertension ) in the hyperuricemic group , respectively . at the end of follow - up , mean hba1c was 7.51  1.2% and 7.27  1.2% in the normouricemic and the hyperuricemic groups , respectively . conversely , mean values of plasma lipids slightly decreased in both groups at the end of follow - up ( ldl cholesterol 2.88  0.7 and 2.62  0.6 mmol / l , triglycerides 1.36  0.7 and 1.59  0.9 mmol / l , and hdl cholesterol 1.32  0.3 and 1.21  0.3 mmol / l , respectively ) . as shown in table 2 , in univariate logistic regression analysis , the presence of hyperuricemia ( included as a categorical variable ) roughly doubled the risk of developing ckd ( or 2.55 [ 95% ci 1.713.85 ] , p < 0.001 ) . the significant association between hyperuricemia and the risk of incident ckd was consistent in all subgroups evaluated ( fig . 1 ) . association between hyperuricemia ( included as a categorical variable ) and incident ckd in patients with type 2 diabetes association of sex - specific hyperuricemia with the development of incident ckd within subgroups . also shown in table 2 , after adjusting for age and sex ( model 1 ) , hyperuricemia was associated with subsequent development of ckd . results remained essentially unchanged after additionally adjusting for bmi , diabetes duration , smoking status , systolic blood pressure , hba1c , egfr , albuminuria , and use of insulin or antihypertensive agents ( model 2 ) . the association between hyperuricemia and incident ckd remained statistically significant even when we additionally adjusted for changes of hba1c and systolic blood pressure at the end of follow - up ( model 3 ) . almost identical results also were observed when analyses were repeated with serum uric acid as a continuous variable ( table 3 ) . in such cases , a 1-sd increment ( i.e. , 81 mol / l ) in the serum uric acid level was associated with a 21% increased risk of incident ckd after adjusting for potential confounders ( model 2 ) . similar results were found after additional adjustment for changes of hba1c and systolic blood pressure at the end of follow - up ( model 3 ) . association between serum uric acid levels ( included as a continuous variable ) and incident ckd in patients with type 2 diabetes results remained essentially unchanged when we used the newer ckd - epi equation ( instead of the mdrd study equation ) to estimate gfr in our patient cohort . also , in this case , elevated levels of serum uric acid , either as a dichotomous variable ( adjusted or 2.74 [ 95% ci 1.734.33 ] , p < 0.001 ) or as a continuous variable ( 1.25 [ 1.051.49 ] , p = 0.01 ) , were closely associated with an increased risk of incident ckd , independently of age , sex , bmi , diabetes duration , smoking status , systolic blood pressure , hba1c , egfr , albuminuria , and use of insulin or antihypertensive agents . in all multivariable regression models , together with elevated uric acid levels , other independent predictors of incident ckd were older age , use of antihypertensive drugs ( or hypertension when it was included as a categorical variable in the regression models ) , lower egfr , and higher albuminuria at baseline ( see supplementary tables 13 ) . several ( 1217 ) , but not all ( 1820 ) , prospective studies have suggested a significant association of hyperuricemia with the development and progression of kidney disease in mainly nondiabetic populations . however , prospective data on the relationship between hyperuricemia and adverse renal outcomes in patients with type 2 diabetes are scarce ( 23 ) . in a post hoc analysis of 1,342 patients with type 2 diabetes and ckd participating in the renaal trial , miao et al . ( 23 ) reported that losartan lowered serum uric acid by 0.16 mg / dl ( p = 0.031 ) compared with placebo during the first 6 months and that the risk of renal events , defined as a doubling of serum creatinine or end - stage renal disease , was significantly decreased by 6% per 0.5 mg / dl decrement in uric acid . the authors concluded that a part of the losartan 's renoprotective effect could be attributed to its effect on serum uric acid ( 23 ) . to our knowledge , this is the first large prospective study specifically aimed at examining the association of serum uric acid levels with the risk of incident ckd in patients with type 2 diabetes and normal or near - normal kidney function . in this 5-year observational study , we found that hyperuricemia is strongly associated with an increased incidence of ckd ( i.e. , defined as egfr < 60 ml / min/1.73 m or overt proteinuria ) in a cohort of 1,449 white type 2 diabetic individuals with a baseline egfr > 60 ml / min/1.73 m ( ~80% normoalbuminuric ) . of note , this association seems to be independent of a broad number of risk factors and confounders , including hba1c , hypertension , egfr , and albuminuria . in continuous analyses , a 1-sd increment ( i.e. , 81 mol / l ) in the serum uric acid level was associated with a 21% increased risk of incident ckd . overall , our findings are corroborated by previous observations of two small prospective studies showing a strong , graded relationship between elevated uric acid levels and the risk of early decline in renal function in nonproteinuric patients with type 1 diabetes ( 21,22 ) . it still is unclear whether hyperuricemia is a risk factor for , or simply a marker of , kidney disease , because of its complex interrelationships with other established risk factors , especially hypertension , or important comorbidities . of note , in this study we excluded patients who had a previous history of malignancy , severe chronic obstructive pulmonary disease , and cardiovascular disease . moreover , we found that elevated uric acid levels were associated with an increased risk of incident ckd , independently of a broad spectrum of established risk factors , including hypertension , diabetes - related variables , and renal function measures . thus , it is conceivable that hyperuricemia might confer an excess risk over and above the risk attributable to underlying established risk factors . the recognition of the biological mechanism(s ) linking hyperuricemia to the development and progression of kidney disease is beyond the scope of this study . however , putative underlying mechanisms may include chronic inflammation , endothelial dysfunction , vascular smooth muscle proliferation , and impaired nitric oxide generation ( 2729 ) . furthermore , experimental evidence suggests that hyperuricemia may exert adverse effects on oxidative metabolism , platelet adhesiveness , and aggregation ( 2729 ) . in animal models , elevated uric acid levels can lead to arteriolopathy of preglomerular vessels , impaired autoregulation , glomerular hypertension , as well as endothelial dysfunction ( 30 ) . kidney damage in hyperuricemic rats is not dependent on blood pressure and instead involves the renin - angiotensin and cyclooxygenase-2 systems ( 29,30 ) . our data indicate that serum uric acid is an independent risk factor for the development of ckd , thus supporting the view that the measurement of serum uric acid levels in patients with type 2 diabetes might be helpful in the risk prediction of ckd . two small prospective , randomized , controlled trials involving nondiabetic and diabetic patients with hyperuricemia and ckd , who were randomly assigned to treatment with allopurinol or to continue with the usual therapy for 1224 months , demonstrated that the allopurinol group showed less kidney dysfunction compared with patients in the control group ( 31,32 ) . future larger , randomized controlled trials on drugs that lower serum uric acid need to be conducted to evaluate the causal relationship between serum uric acid and the development and progression of diabetic kidney disease . first , because our cohort comprises white , type 2 diabetic individuals who were followed at an outpatient diabetes clinic , our results may not necessarily be generalizable to other diabetic populations . other potential limitations of our study include a possible selection bias of excluding the patients who had missing laboratory data at baseline and an inability to adjust for certain specific antihypertensive agents . however , in the subset of 632 participants in which such information currently was available in our informatic database , we did not find any significant difference in the use of ace inhibitors , angiotensin receptor blockers , or thiazide diuretics between those with and those without hyperuricemia . in addition , we used an egfr ( i.e. , the four - variable mdrd study equation and the ckd - epi creatinine equation ) instead of a directly measured gfr to define kidney function . it is known that current gfr estimates have greater inaccuracy in populations without known ckd than in those with kidney disease . nonetheless , current gfr estimates facilitate the detection , evaluation , and management of ckd , and many organizations recommend the use of prediction equations for the evaluation of kidney function in large epidemiologic studies and in clinical practice ( 1,10,25,26 ) . finally , whether these observations also can be extended to nonwhite ethnic groups remains to be determined . strengths of our study include its prospective design , the large number of participants from both sexes , the long duration of follow - up , the complete nature of the dataset , and the ability to adjust for a wide range of known risk factors and potential confounders . in addition , our patients were free of diagnosed cardiovascular disease , severe chronic obstructive pulmonary disease , and malignancies ; the evaluation of patients with such complications would almost certainly have confounded interpretation of the data . in summary , this study demonstrated an association between hyperuricemia and the risk of incident ckd , independent of several potential confounders , including hypertension , egfr , and albuminuria , in a large cohort of type 2 diabetic patients with a baseline egfr > 60 ml / min/1.73 m and without a previous history of cardiovascular disease . additional studies are needed to examine the reproducibility of our results and to further elucidate the biological mechanisms underlying the relationship between hyperuricemia and incident ckd in type 2 diabetes . the advantage(s ) of treating hyperuricemia in type 2 diabetes in order to reduce the risk of adverse renal outcomes remains to be demonstrated .
objectiverecent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations . 
 data on the relationship between hyperuricemia and the risk of incident chronic kidney disease ( ckd ) in type 2 diabetic patients with normal or near - normal kidney function are lacking . 
 we determined whether baseline serum uric acid levels predict the subsequent development of ckd in patients with type 2 diabetes.research design and methodswe followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident ckd ( defined as overt proteinuria or estimated glomerular filtration rate [ egfr ] < 60 ml / min/1.73 m2).resultsduring a 5-year follow - up period , 194 ( 13.4% ) patients developed incident ckd . 
 the cumulative incidence of ckd was significantly greater in patients with hyperuricemia than in those without hyperuricemia ( 29.5 vs. 11.4% , p < 0.001 ) . 
 in univariate logistic regression analysis , the presence of hyperuricemia roughly doubled the risk of developing ckd ( odds ratio [ or ] 2.55 [ 95% ci 1.713.85 ] , p < 0.001 ) . after adjusting for age , sex , bmi , smoking status , diabetes duration , 
 systolic blood pressure , antihypertensive treatment , insulin therapy , hba1c , egfr , and albuminuria , hyperuricemia was associated with an increased risk of incident ckd ( adjusted or 2.10 [ 1.163.76 ] , p < 0.01 ) . 
 in continuous analyses , a 1-sd increment in the serum uric acid level was significantly associated with a 21% increased risk of ckd.conclusionsin type 2 diabetic individuals with preserved kidney function , hyperuricemia seems to be an independent risk factor for the development of incident ckd .