all newly diagnosed type 1 diabetic patients , consecutively admitted to the steno diabetes center between 1 september 1979 and 31 august 1984 , were included in an inception cohort ( n = 277 ) , described previously in detail ( 4 ) . a total of 270 patients had blood samples taken at baseline . in seven cases , uric acid was not determined ; therefore , 263 patients ( 156 men ) were available for analysis . uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria . patients were treated according to set principles and guidelines as described previously ( 4,5 ) . a1c was measured from venous blood samples , with a normal range of 4.16.4% ( 4 ) . each patient had a 24-h urinary albumin excretion rate ( uaer ) measured at least once per year . uaer was quantitated by using automated immunotopical nephelometric analysis until 1984 ( 6 ) and by using enzyme immunoassay from 1984 to 1997 ( 7 ) ( sensitivity 1.1 mg / l ; coefficient of variation [ cv ] 8% ) . from 1997 , the dako turbidimetric method was used to measure uaer with a cv of 5% . a very close correlation between radial immunodiffusion and enzyme immunoassay ( r = 0.99 ) as well as between enzyme immunoassay and the turbidimetric method ( r = 0.99 ) was documented , and absence of any systematic error between methods was verified by bland - altman plots before any change in methods was imposed . persistent microalbuminuria and macroalbuminuria were defined as uaer of 30300 mg/24 h and > 300 mg/24 h , respectively , in at least two of three consecutive samples , with 30% increase in uaer above the baseline level ( 4 ) . uric acid was measured from samples that had been stored in freezers at 20c by colorimetric slide test ( vitros 5.1 fs ; ortho clinical diagnostics ) , with a cv of 1.3 and 1.5% , respectively , in samples from the lowest and highest quartiles of the uric acid levels . measurements were from samples taken 3 years after onset of diabetes in all subjects , i.e. , after initial glycemic stabilization , and prior to development of persistent microalbuminuria . at the time of sampling , only two patients received antihypertensive treatment ( both treated with diuretics ; one additionally treated with an ace inhibitor ) . the normal range of uric acid was 200450 arterial blood pressure was measured at least once per year with a standard mercury sphygmomanometer and was performed with the patient in a seated position after 10 min rest . smoking history was determined via questionnaire , and patients were classified as smokers if they were smoking more than one cigarette per day . variables with skewed distribution are median ( interquartile range ) ; all other values are given as means  sd . for non  normally distributed variables , comparisons between groups were performed using the mann - whitney u test , whereas one - way anova or unpaired student 's t tests were used for normally distributed variables . a  test was used for comparison between groups of noncontinuous variables . to evaluate uric acid as a causal determinant of development of persistent micro- or macroalbuminuria in an explanatory model , a cox proportional hazards regression model was used , including baseline levels of variables that either previously had been shown to be associated with the level of uric acid or were correlated with uric acid in the present study , correcting for different lengths of follow - up . uric acid was entered in the model as a continuous variable . because both sex and age can affect the outcome ( development of nephropathy ) and the independent variable ( uric acid ) these models allow for adjustment for sex differences , which is practical because the different reference intervals between sexes can be disregarded when only evaluating risk without firm cutoff values . the cumulative incidence of persistent micro- and macroalbuminuria was calculated based on the entire follow - up period with a life - table method . groups were compared using the log - rank test . statistical significance was assumed for p < 0.05 . all statistical calculations were performed with spss for windows , version 15.0 ( spss , chicago , il ) . variables with skewed distribution are median ( interquartile range ) ; all other values are given as means  sd . for non  normally distributed variables , comparisons between groups were performed using the mann - whitney u test , whereas one - way anova or unpaired student 's t tests were used for normally distributed variables . a  test was used for comparison between groups of noncontinuous variables . to evaluate uric acid as a causal determinant of development of persistent micro- or macroalbuminuria in an explanatory model , a cox proportional hazards regression model was used , including baseline levels of variables that either previously had been shown to be associated with the level of uric acid or were correlated with uric acid in the present study , correcting for different lengths of follow - up . because both sex and age can affect the outcome ( development of nephropathy ) and the independent variable ( uric acid ) , sex and age were entered as fixed variables in the models . these models allow for adjustment for sex differences , which is practical because the different reference intervals between sexes can be disregarded when only evaluating risk without firm cutoff values . the cumulative incidence of persistent micro- and macroalbuminuria was calculated based on the entire follow - up period with a life - table method . groups were compared using the log - rank test . statistical significance was assumed for p < 0.05 . all statistical calculations were performed with spss for windows , version 15.0 ( spss , chicago , il ) . the 263 patients were followed for a median of 18.1 years ( interquartile range 1.021.8 ) . of these this resulted in a cumulative incidence of persistent microalbuminuria of 32.2% ( 95% ci 25.738.7 ) and a cumulative incidence of macroalbuminuria of 12.6% ( 7.317.9 ) . clinical characteristics of the diabetic patients at baseline , defined as 3 years after onset of diabetes , are summarized in table 1 . characteristics of 263 type 1 diabetic patients followed from onset of diabetes divided into patients with persistent normoalbuminuria , patients who later progressed to microalbuminuria , and patients who later progressed to microalbuminuria and further to macroalbuminuria data are mean  sd or median ( interquartile range ) unless otherwise indicated . however , within the normal range , a significant difference in the means  sd level of uric acid 3 years after onset of diabetes and before any patient developed micro- or macroalbuminuria was found when comparing the three groups . in a one - way anova test comparing the mean levels of uric acid in the three groups p = 0.063 ( table 1 ) . looking at the differences between each group separately , the mean level of serum uric acid was significantly higher in patients who eventually progressed to persistent macroalbuminuria ( 239.1  61 mol / l ) versus patients remaining normoalbuminuric ( 209.4  57.8 mol / l ) or later progressing to microalbuminuria only ( 210.7  55.9 mol / l ) ; p < 0.05 for all comparisons . importantly , no differences in serum creatinine were apparent among groups ( table 1 ) . when comparing patients progressing to microalbuminuria as a combined group irrespective of later or no progression to macroalbuminuria versus patients remaining normoalbuminuric , no difference in the mean  sd level of uric acid 3 years after onset of diabetes was found ( 219.8  58.7 mol / l in patients later progressing to persistent micro- or macroalbuminuria vs. 209.4  56.8 mol / l in patients with persistent normoalbuminuria ; p = 0.194 ) . in a cox proportional hazards model with sex and age as fixed covariates , uric acid was not independently associated with subsequent development of persistent microalbuminuria ( hazard ratio [ hr ] 1.05 [ 95% ci 0.661.69 ] per 100 mol / l increase in uric acid level ; p = 0.83 ) . adjustments for baseline level of bmi , glycemic control , uaer , serum creatinine , serum cholesterol , and mean arterial blood pressure did not change the estimate significantly . in a cox proportional hazards model with sex and age as fixed covariates , uric acid was independently associated with subsequent development of persistent macroalbuminuria ( hr 2.37 [ 95% ci 1.045.37 ] per 100 mol / l increase in uric acid level ; p = 0.04 ) . adjustment for baseline level of bmi , glycemic control , uaer , serum creatinine , serum cholesterol , and mean arterial blood pressure did not change the estimate significantly ( adjusted hr 2.93 [ 1.256.86 ] per 100 mol / l increase in uric acid level ; p = 0.013 ) . in patients with uric acid levels in the highest quartile ( > 249 mol / l but within the normal range ) , the cumulative incidence of persistent macroalbuminuria was 22.3% ( 10.334.3 ) compared with 9.5% ( 3.815.2 ) in patients with uric acid in the three lower quartiles ( crude log - rank test , p = 0.006 ; after bonferroni correction , p = 0.012 ) ( fig . 1 ) . cumulative incidence of persistent macroalbuminuria in 263 type 1 diabetic patients with onset of diabetes from 1979 to 1984 . divided by quartiles of uric acid 3 years after onset of type 1 diabetes , comparing patients with uric acid in the highest quartile ( > 249 mol / l ) with patients with uric acid in the three lower quartiles ( > 249 mol / l ) ; p = 0.006 . when comparing patients progressing to microalbuminuria as a combined group irrespective of later or no progression to macroalbuminuria versus patients remaining normoalbuminuric , no difference in the mean  sd level of uric acid 3 years after onset of diabetes was found ( 219.8  58.7 mol / l in patients later progressing to persistent micro- or macroalbuminuria vs. 209.4  56.8 mol / l in patients with persistent normoalbuminuria ; p = 0.194 ) . in a cox proportional hazards model with sex and age as fixed covariates , uric acid was not independently associated with subsequent development of persistent microalbuminuria ( hazard ratio [ hr ] 1.05 [ 95% ci 0.661.69 ] per 100 mol / l increase in uric acid level ; p = 0.83 ) . adjustments for baseline level of bmi , glycemic control , uaer , serum creatinine , serum cholesterol , and mean arterial blood pressure did not change the estimate significantly . in a cox proportional hazards model with sex and age as fixed covariates , uric acid was independently associated with subsequent development of persistent macroalbuminuria ( hr 2.37 [ 95% ci 1.045.37 ] per 100 mol / l increase in uric acid level ; p = 0.04 ) . adjustment for baseline level of bmi , glycemic control , uaer , serum creatinine , serum cholesterol , and mean arterial blood pressure did not change the estimate significantly ( adjusted hr 2.93 [ 1.256.86 ] per 100 mol / l increase in uric acid level ; p = 0.013 ) . in patients with uric acid levels in the highest quartile ( > 249 mol / l but within the normal range ) , the cumulative incidence of persistent macroalbuminuria was 22.3% ( 10.334.3 ) compared with 9.5% ( 3.815.2 ) in patients with uric acid in the three lower quartiles ( crude log - rank test , p = 0.006 ; after bonferroni correction , p = 0.012 ) ( fig . 1 ) . cumulative incidence of persistent macroalbuminuria in 263 type 1 diabetic patients with onset of diabetes from 1979 to 1984 . divided by quartiles of uric acid 3 years after onset of type 1 diabetes , comparing patients with uric acid in the highest quartile ( > 249 mol / l ) with patients with uric acid in the three lower quartiles ( > 249 mol / l ) ; p = 0.006 . in the present prospective observational study of an inception cohort followed from onset of type 1 diabetes and for a median of 18 years , uric acid was not a predictor of persistent microalbuminuria . in contrast , we demonstrate that the level of uric acid early in the course of type 1 diabetes is significantly and independently associated with later development of persistent macroalbuminuria . a significantly higher proportion of patients developing overt nephropathy among patients with serum uric acid in the highest quartile at baseline was found . these results support the idea that uric acid may be involved in the pathogenesis of microvascular complications in diabetes . hyperuricemia may be a marker of or by itself be responsible for microvascular disease through stimulation of the renin angiotensin system and inhibition of endothelial nitric oxide ( 8) . animal models of induced hyperuricemia have demonstrated an association with renal disease ( 911 ) . in humans , hyperuricemia has been associated with hypertension and , recently , with initiation and progression of nondiabetic renal disease ( 3,8,12 ) . in those with diabetes , rosolowsky et al . ( 13 ) have reported from a cross - sectional study that serum uric acid in the high - normal range was associated with impaired renal function in patients with type 1 diabetes and normo- or microalbuminuria . thus far , no studies have evaluated the impact of uric acid on the development of diabetic kidney disease . in our present study of 263 type 1 diabetic patients followed from onset of diabetes , we were able to demonstrate that the level of uric acid early in the course of type 1 diabetes is significantly associated with later development of diabetic kidney disease , but we could not establish an association with persistent microalbuminuria . however , patients progressing to microalbuminuria may be a more heterogenous group than previously assumed , which could explain why the level of uric acid was not elevated in the microalbuminuric patients as such . our findings in the present study emphasize the importance of the use of a solid and robust end point when evaluating risk markers for disease . the patients in our inception cohort are unselected , all type 1 diabetic patients irrespective of age at diagnosis were included , and our population has a higher mean age than other studies of type 1 diabetic patients . consequently , our results can not be directly generalized to patients with type 1 diabetes , and earlier onset of disease but must be validated in such populations . as only two patients received antihypertensive treatment at the time of sampling for measurement of uric acid , the level of uric acid is unlikely to be confounded by use of diuretics in our population . clearly , a more precise method , such as ambulatory blood pressure measurements over 24 h ( 14 ) , reduces variability in measurement and makes estimates more precise . genetic factors influencing the level of uric acid ( 15 ) or other unknown factors not measured in our study may have an impact on the relationship between uric acid and the development of diabetic nephropathy . the possibility of sublimation of the frozen and stored samples can not be ruled out . however , if sublimation occurred , this would affect all samples , and patients with high values would still have high values within the same population , although at a lower level . diabetic kidney disease is strongly associated with cardiovascular mortality ( 16 ) and may reflect a more generalized vascular process ( 17 ) . elevated uric acid not only has been demonstrated to be associated with kidney disease but also has been linked to endothelial dysfunction , development of hypertension , and cardiovascular disease irrespective of renal involvement ( 3 ) . elevated uric acid may be a candidate for a common link between micro- and macrovascular disease in diabetic patients . in conclusion , we found levels of circulating uric acid in the higher end of the normal range to be an independent predictor for development of overt diabetic nephropathy , thus supporting the concept that uric acid may be involved in the pathogenesis of diabetic microvascular complications . consequently , our study suggests that a long - term treatment trial with allopurinol is warranted .
objectiveexperimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease . whether uric acid has a causal role in the development of diabetic nephropathy is not known . 
 the objective of the present study is to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria.research design and methodsthis prospective observational follow - up study consisted of an inception cohort of 277 patients followed from onset of type 1 diabetes . of these , 
 270 patients had blood samples taken at baseline . in seven cases , 
 uric acid could not be determined ; therefore , 263 patients ( 156 men ) were available for analysis . 
 uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria.resultsduring a median follow - up of 18.1 years ( range 1.021.8 ) , 23 of 263 patients developed persistent macroalbuminuria ( urinary albumin excretion rate > 300 mg/24 h in at least two of three consecutive samples ) . in patients with uric acid levels in the highest quartile ( > 249 mol / l ) , 
 the cumulative incidence of persistent macroalbumnuria was 22.3% ( 95% ci 10.334.3 ) compared with 9.5% ( 3.815.2 ) in patients with uric acid in the three lower quartiles ( log - rank test , p = 0.006 ) . in a cox proportional hazards model with sex and age as fixed covariates , uric acid was associated with subsequent development of persistent macroalbuminuria ( hazard ratio 2.37 [ 95% ci 1.045.37 ] per 100 mol / l increase in uric acid level ; p = 0.04 ) . 
 adjustment for confounders did not change the estimate significantly.conclusionsuric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy .