uric acid ( ua ) has been formerly considered as a major antioxidant in human plasma with possible beneficial antiatherosclerotic effects ; however , since the beginning of the twentieth century , uric acid has been suggested as a risk factor for cardiovascular diseases . while epidemiologic studies suggested that hyperuricemia ( hu ) is strongly correlated with cardiovascular disease , some clinical evidence has found a significant and specific association between serum uric acid levels and coronary atherosclerosis ; however , there is much controversy concerning this relationship , and some studies in fact came to the opposite conclusions [ 2 , 3 ] . high uric acid levels could potentially increase the risk of cardiovascular disease via several biological mechanisms ; however , recent studies have suggested that endothelial dysfunction is a fundamental mechanism whereby uric acid may affect cardiovascular function . series of animal experiments revealed that in rats , hyperuricemia induced by oxonic acid , a uricase inhibitor , causes hypertension and renal arteriolopathy and impairs nitric oxide generation . moreover , oxidative stress plays an important role in the vascular endothelial dysfunction of hyperuricemia [ 4 , 5 ] . an increase in the levels of adma is likely to be a factor connected with impaired nitric oxide production and resulting in endothelial dysfunction in cardiovascular disease , including hypertension , atherosclerosis , and metabolic syndrome . recent studies suggested adma to be a sensitive marker and even an initiator of endothelial dysfunction . similarly , the second form - symmetric dimethylarginine ( sdma ) has insignificant inhibitory effects on nitric oxide synthase . however , it has recently been suggested that sdma might have an indirect effect on nitric oxide synthesis via inhibiting the transporter that mediates the intracellular uptake and absorption of l - arginine . although previous studies suggested that serum uric acid as well as adma and sdma levels might correlate with cardiovascular risk or renal disease , the relationship between serum uric acid and adma or sdma has not yet been characterized . the goal of this work was to investigate if in adolescents with hyperuricemia serum levels of adma and sdma are increased and if their levels correlate with serum uric acid . additionally we would like to check if serum level of any of these dimethylarginines correlates with hs - crp . the protocol was approved by the bioethics committee of the medical university of bialystok in accordance with the declaration of helsinki . informed consent was obtained from parents of all participants and children older than 16 years of age . ( m35 ; f23 ) with elevated serum uric acid were eligible to participate in the study . patients were recruited from referrals to department of pediatric nephrology , medical university of bialystok , from june 2010 until may 2012 . reference group ( r ) consisted of 27 healthy children ( 12 boys , 15 girls ; aged median 15.8 q1q3 ( 10.817.1 ) ) with normal serum uric acid levels . patients who meet all the following inclusion criteria were enrolled into the study : ( 1 ) age 1018 years , ( 2 ) hyperuricemia defined as serum uric acid above 5.5  mg / dl , ( 3 ) normal renal function ( normal creatinine level , egfr > 90  ml / min/1.73  m , no proteinuria ) , ( 4 ) no clinical and laboratory signs of infection , ( 5 ) not treated with antibiotics within the last 4 weeks , and ( 6 ) signed the informed consent . patients with a history of gouty arthritis , renal stones , protein / creatinine ratio > 0.2 , and diabetes mellitus were excluded . in all adolescents , careful clinical history , underlying comorbidities , and physical examination were assessed . body weight and height were measured using a balance beam scale and pediatric wall - mounted stadiometer . body mass index ( bmi ) was calculated as weight ( kg ) divided by the square of height ( m ) . bmi z - scores , which reflect the sd score for age- and gender - appropriate bmi distribution , were calculated using the following formula : z = [ x  ]/ ; x is the bmi measured in the patient , whereas  and  represent the mean and the standard deviation for age- and gender - matched controls . based on the international norms from the who   with age- ( to the nearest one month ) and gender - specific bmi , bmi cutoffs were the following : overweight  bmi > + 1sd ; obesity  bmi > + 2sd . hypertension ( ht ) on the basis of abpm was defined as mean systolic or diastolic daytime or nighttime bp levels that are 95th percentile . ambulatory blood pressure monitoring ( abpm ) was performed using the oscillometric spacelab device ( spacelab cardionavigator ) . the monitors were programmed to measure bp every 15 minutes during daytime ( 8:0022:00 ) and every 30 minutes during nighttime ( 22:008:00 ) ; however , the periods were corrected according to the patients ' diary . recordings with a minimum 80% of measurement and without brakes longer than 2 hours were considered sufficient . after an overnight fast , five milliliters of venous , peripheral blood was collected from each patient and reference participants during routine laboratory testing . the biochemical workup included serum creatinine ( measured by jaffe reaction ) , urea , fasting plasma glucose ( fpg ) , lipid profile , and serum uric acid concentration . the estimated glomerular filtration rate ( egfr ) was calculated from the updated schwartz formula : gfr ( ml / min/1.73  m ) = ( 0.41  height in cm)/creatinine in mg / dl . adma and sdma were measured in serum using elisa method ( immundiagnostik ag , bensheim , germany ) according to the manufacturer 's guidelines . the intra- and interassay coefficients of variance ( cvs ) for adma were 6.57.0% and 6 - 7% and for sdma 4.87.5% and 6 - 7% , respectively . serum hs - crp was assessed by particle - enhanced immunonephelometry using a standard cardiophase hs - crp for bnii ( dade behring diagnostics , marburg , germany ) and expressed in mg / l . the intra - assay and interassay coefficient of variation for hs - crp were 4.2% and 6.8% , respectively . all continuous variables were tested for normal distribution by the kolmogorov - smirnov , with lilliefors correction and shapiro - wilk tests . as most of the studied parameters were not normally distributed , descriptive statistics were calculated as median with the interquartile range . mann - whitney u test was used to compare continuous variables , and -test with yates correction was used to compare categorical variables between two groups . the correlations between sdma , adma , and other studied variables were assessed using spearman correlation test . two multiple linear regression models were created including the sdma and adma as dependent variables . statistical significance was determined at p < 0.05 level . overall median age of all children with hyperuricemia was 16.15 q1q3 ( 1417 )  yrs . the age and sex of studied children did not differ from healthy controls ( p > 0.05 ) . median bmi z - score in both examined groups was 1.08 ( q1q3 : 0.361.64 ) in studied children and 0.2 ( q1q3 : 0.20.8 ) in reference group ( p < 0.01 ) . total cholesterol values were significantly higher in studied patients ( median : 162  mg / dl ) than in reference group ( median : 142  mg / dl ; p < 0.05 ) . no significant differences between those two groups were observed regarding fpg , triglycerides , hdl , and ldl . when compared to healthy controls , hyperuricemic patients showed increased serum sdma ( p < 0.01 ) , but not serum adma levels ( table 1 ) . serum adma and sdma correlated positively with ua ( r = 0.34 , p < 0.01 ) ( r = 0.31 , p < 0.01 ) , respectively , and hs - crp ( r = 0.20 , p < 0.05 ) ( r = 0.36 , p < 0.01 ) , respectively ( figure 1 ) . the positive correlation was observed between serum adma and bmi z - score ( r = 0.36 , p < 0.01 ) , tg ( r = 0.46 , p < 0.01 ) , total cholesterol level ( r = 0.28 , p < 0.01 ) , and ldl - cholesterol ( ldl - c ) ( r = 0.33 , p < 0.01 ) in hyperuricemic patients . additionally sdma correlated positively with creatinine level ( r = 0.27 , p < 0.01 ) and systolic ( r = 0.32 , p < 0.01 ) and diastolic blood pressure ( r = 0.25 , p < 0.01 ) during a day and negatively with egfr ( r = 295 , p < 0.01 ) . no correlation between serum sdma and adma was found . the factors that were found to have a significant correlation with serum sdma and adma in the single regression analyses were used as explanatory variables to create the multiple regression models . to reduce the impact of multicollinearity we removed some correlated variables . next we eliminated a few more nonsignificant ( in the model ) variables .   in multivariable analysis , serum adma was associated with serum uric acid , tg , and ldl - c independent of age , gender , and parameters of renal function ( table 2 ) . on the other hand serum sdma was associated with serum uric acid , serum creatinine , hs - crp , and systolic blood pressure . in this cross - sectional study , we found that in adolescents with increased serum uric acid levels , serum sdma is significantly elevated . we also confirmed positive correlation of serum sdma with uric acid , creatinine , and hs - crp and negative with egfr . additionally positive correlation between sdma and systolic and diastolic blood pressure was found . it is interesting to note that we created multivariable linear regression model and found that serum uric acid , triglycerides , and ldl - cholesterol accounted for more than 37% of the variations in serum sdma . taken together , the results of this study demonstrate that serum sdma is an independent determinant of renal function but also takes part in cardiovascular disease in pediatric patients with hyperuricemia . another important finding is that we have not found significant increase in serum adma between subjects with hyperuricemia and reference group ; however , serum adma correlated positively with serum uric acid , bmi z - score , triglycerides , total cholesterol , ldl - c , and hs - crp . to our best knowledge this is the first clinical study on the association between the serum sdma , adma , ua , and hs - crp in adolescents with hyperuricemia . in many previous reports the association of serum uric acid with endothelial dysfunction was reported by zoccali et al .   in 217 individuals with mild untreated hypertension who underwent measurement of endothelium - dependent brachial artery vasodilation . the authors reported that compared with participants whose serum ua was 3.5  mg / dl , endothelium - dependent vasodilation was 33% worse among those with serum ua levels of 5.5  mg / dl . furthermore , experimental studies showed that hyperuricemic rats developed endothelial dysfunction , but early l - arginine supplementation could prevent both the systemic and glomerular hypertension . taken together , these data suggest that higher levels of serum ua indicate the presence of endothelial dysfunction and might contribute to an increase in cardiovascular risk . it was shown that reduced no bioavailability and oxidative stress contribute to endothelial dysfunction [ 21 , 22 ] . asymmetric dimethylarginine ( adma ) is an endogenous modulator of endothelial function and oxidative stress , and increased levels of this molecule have been reported in some metabolic disorders and cardiovascular diseases . very little was found in the literature on role of adma in patients with futures of metabolic syndrome . .   found that adma levels were significantly increased in the metabolic syndrome ; however , the levels of adma were modestly correlated only with waist circumference but not with the other components of metabolic syndrome . in experimental study korandji et al .   analyzed the relationship between dimethylarginine compounds and oxidative stress levels and cardiovascular function in fructose - hypertensive rats . the authors suggested that elevated levels of adma could in part be secondary to the early development of oxidative stress associated with development of hypertension . to our best knowledge no data concerning the relationship between the adma and uric acid in humans were published . several clinical studies have shown that adma levels are increased in hypertensive patients , atherosclerosis , and hypercholesterolemia . they found a positive correlation between adma and hs - crp and tg / hdl ratio in patients with metabolic syndrome . patients in whom adma concentrations decreased at followup had lower tg / hdl and ldl / hdl ratios when compared to patients with increase / stabilization of adma . similarly kanazawa et al .   found significantly positive association between adma and bmi , blood pressure , ldl , hdl and cholesterol independent of age . in obese women studied by krzyzanowska et al . adma correlated with high - sensitivity c - reactive protein at baseline and after weight loss , but no association with blood pressure or plasma lipids was observed .   in reviewing the literature , median serum sdma levels in hu patients was significantly higher compared to the controls , similarly like hs - crp , wich was also confirmed in our previous study in similar population . the results of this study showed that similarly adma and sdma correlated positively with serum hs - crp . similarly we still do not know too much about the effect of sdma on the l - arginine - no pathway . closs et al .   showed that sdma had no effect on the inducible nos extracted from macrophages . the results of tojo et al .   experimental study suggested that sdma might be a potent competitor of l - arginine transport and thereby have an indirect inhibitory effect of no synthesis by limiting arginine availability to nos . in human studies it was shown that sdma was associated with inflammatory markers in patients with chronic kidney disease . sdma was independently associated with increased cardiovascular and total mortality in patients undergoing coronary angiography in studies by meinitzer et al .   and schulze et al . . in contrast to studies presented above zoccali et al .   did not confirm sdma as a predictor of cardiovascular outcome in patients with chronic kidney disease . both adma and sdma were significantly elevated in patients with chronic renal failure ; however , the increase was more pronounced for sdma .   in conclusion , increased circulating methylarginines have been linked to some features of the metabolic syndrome ; however , it is still difficult to answer the question about their role in this process . the results of the present study have demonstrated increased sdma , but not adma levels in adolescents with hyperuricemia and their correlation with serum uric acid levels . however , at the moment it is difficult to answer the question if it is just coexistence of these factors or any mechanism linking uric acid and methylated arginines really exists . our study has limitations ; it is a single - center , cross - sectional study , and confirmation in other cohorts is necessary to validate our findings . third , the study design did not allow to answer the question if sdma is a new player or an innocent bystander in chronic inflammation in patients with hyperuricemia .