Serum uric acid in pediatric metabolic assessment: the scientific rationale for routine screening and the urgent need for age- and sex-specific diagnostic thresholds

Abstract

Serum uric acid (SUA) is the terminal product of purine catabolism in humans, generated through the sequential action of xanthine oxidoreductase on hypoxanthine and xanthine (Figure 1). Classically, elevation above accepted adult thresholds of 416 μmol/L (7.0 mg/dL) in males and 357 μmol/L(6.0 mg/dL) in females defines hyperuricemia and confers risk for gouty arthritis and nephrolithiasis. Over the past two decades, a growing body of epidemiological, pathophysiological, and interventional evidence has substantially broadened this picture. Elevated SUA is now consistently associated with hypertension, insulin resistance, metabolic syndrome, chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) in both adults and children, though the nature and direction of these relationships vary across outcomes and, in several domains, causality remains an active area of scientific debate. [1][2][3] Serum uric acid homeostasis reflects the balance between purine metabolism, dietary and metabolic influences, and renal excretion. Hyperuricemia may result from increased uric acid production, reduced renal clearance, or both. In children, obesity, chronic kidney disease, fructose-rich diets, purine-rich foods, malignancies associated with increased cell turnover, and tumor lysis syndrome are among the principal contributors, as shown in Figure 1. These mechanisms converge on hepatic purine metabolism, where xanthine oxidase catalyzes the final steps leading to uric acid formation, providing the biological rationale for the use of xanthine oxidase inhibitors and uricase-based therapies in selected clinical settings. Despite this evidence, SUA measurement remains largely absent from the routine pediatric metabolic panel in most international clinical guidelines. Its use in children is predominantly restricted to acute clinical contexts such as oncological tumor lysis syndrome and overt gouty arthritis endpoints that represent the extreme and late expression of what is often a prolonged subclinical process.Population data indicate that hyperuricemia affects a substantial and growing proportion of children globally, driven by the parallel epidemics of childhood obesity and increased dietary fructose consumption. 5,6 A pooled analysis of over 54,000 Chinese children and adolescents documented a hyperuricemia prevalence of 24.8% in 2016-2019, up from 16.7% in the preceding survey cycle. 5 , and prevalence estimates exceeding 50% have been reported in obese pediatric cohorts in some regions. 6 A critical obstacle to clinical action is the absence of validated, age-and sex-specific reference intervals for SUA in children. The adult diagnostic thresholds currently in use are not derived from pediatric populations, do not account for the progressive rise in SUA across childhood, and do not reflect the sex divergence that emerges only after puberty. 7,8 Applying fixed adult cut-offs to children of all ages and both sexes results in systematic misclassification, contributing in part to the clinical inertia that has surrounded this biomarker in pediatric practice.The physiological basis of this age-and sex-dependent variation is well characterized and merits explicit statement before the epidemiological evidence is reviewed. SUA is relatively low in infancy, typically 2.2-2.5 mg/dL, reflecting a fractional excretion of uric acid (FE-UA) that exceeds 10% in the first months of life; FE-UA declines to approximately 8% by one year of age, after which SUA in most children stabilizes in the range of 3.5-4.5 mg/dL. 9,10 Renal tubular urate handling continues to mature throughout childhood, and after puberty, FE-UA falls further in boys but not in girls, resulting in the higher SUA concentrations characteristic of adolescent males relative to females. 10 These maturational changes in renal urate handling, superimposed on the progressive rise in body weight and dietary purine intake across childhood, together explain why no single adult-derived threshold can be validly applied at any point across the pediatric age range, and why the age-and sex-stratified data reviewed below are indispensable rather than merely preferable. This editorial argues that the cumulative evidence now supports incorporating SUA into routine pediatric metabolic screening in defined high-risk groups. In advancing this argument, we deliberately separate two distinct claims that are frequently conflated in the literature: SUA as a validated risk marker, for which the observational, mechanistic, and, in the case of hypertension, interventional evidence is now substantial, and SUA as a clinically actionable screening parameter with demonstrated downstream benefit, for which prospective screening-outcome trials in children do not yet exist. The recommendations that follow rest on the former claim; they should not be read as asserting the latter, and we return to this distinction explicitly before presenting the proposed framework. We review the epidemiological and interventional evidence linking elevated SUA to pediatric cardiometabolic and renal outcomes, examine existing data on age-and sex-specific reference intervals, consider the global applicability and practical implications of screening, and propose a minimum framework for clinical implementation.Estimating the true prevalence of childhood hyperuricemia is complicated by the lack of a universally accepted pediatric definition, but available data consistently indicate that elevated SUA is common and rising. Rao et al. (2022), pooling data from 11 population-based Chinese studies comprising 54,580 participants aged 3-19 years, reported a prevalence that increased markedly with age from 3.7% at ages 3-5 years to 35.5% at ages 12-15 years and with weight status, reaching 64.5% among children with extreme obesity. 5 A multicenter European clinical series of 13,890 children found hyperuricemia in 12.6% of the overall pediatric population, with obesity and CKD the most frequent associated conditions. 9 These figures must be interpreted in the context of considerable definitional heterogeneity. Across published studies, thresholds used to define pediatric hyperuricemia range from 5.5 mg/dL (327 μmol/L) to 7.0 mg/dL (416 μmol/L), with several studies using percentile-based cut-offs rather than fixed values. Dai et al. (2021), studying 5,439 healthy children aged 5-14 years in Southeast China using stringent exclusion criteria, demonstrated that the 97.5th percentile SUA in 14-year-old boys reaches 530.1 μmol/L, substantially above the adult male threshold of 416 μmol/L, while the corresponding value in girls is 439.0 μmol/L. 7 Before age 10, SUA did not differ significantly between sexes, with 97.5th percentile values ranging from approximately 397-406 μmol/L in boys and 381-403 μmol/L in girls aged 5-9 years. 7 These findings demonstrate that applying adult-derived thresholds to children across all age groups produces systematic misclassification in both directions, depending on age and sex. Dietary fructose, independent of total caloric intake, represents a quantitatively important and modifiable driver of SUA elevation in children. Fructose undergoes rapid hepatic phosphorylation via fructokinase, transiently depleting adenosine triphosphate and accelerating purine catabolism, with urate as the terminal product (Figure 1). High-fructose corn syrup and sugar-sweetened beverages, whose consumption in children has increased substantially across multiple world regions, therefore promote hyperuricemia through a mechanism distinct from purine-rich dietary protein, partly explaining the burden of elevated SUA in children who are not overtly obese. 11The associations reviewed in this editorial should not be taken to imply that an elevated SUA in a child is invariably a marker of cardiometabolic risk. Childhood hyperuricemia is aetiologically heterogeneous, and a purely metabolic interpretation risks overlooking rarer but clinically important causes. Persistent or early-onset hyperuricemia, particularly when accompanied by a family history of gout or nephrolithiasis at an unusually young age, should prompt consideration of inherited disorders of purine metabolism or renal urate handling, including uromodulin-associated kidney disease, glycogen storage disease type I, fructose-1,6-bisphosphatase deficiency, hereditary fructose intolerance, and mitochondrial disorders. 12 Transient or medication-related hyperuricemia is more common still; thiazide diuretics, valproate, phenobarbital, and calcineurin inhibitors such as cyclosporine can each elevate SUA, as can acute conditions including gastroenteritis, dehydration, haemolytic anaemia, and malignancy-associated increased cell turnover. A structured pediatric screening pathway should therefore incorporate a basic differential diagnosis step rather than treating every elevated SUA result as evidence of an underlying cardiometabolic process.Genetic determinants of urate transport further contribute to this heterogeneity and merit explicit consideration alongside metabolic and renal factors. Loss-of-function variants in ABCG2, which encodes the ATP-binding cassette transporter G2 responsible for extra-renal urate excretion, are among the best-characterized genetic contributors to hyperuricemia and gout across the age range.In a Czech cohort by Stiburkova et al. ( 2019) 13 analyzing pediatric-onset hyperuricemia and gout specifically, non-synonymous ABCG2 variants, principally the common p.Q141K (rs2231142) variant, were markedly overrepresented among children and adolescents with pediatric-onset disease; the minor allele frequency of p.Q141K was 38.7% in pediatric-onset patients compared with 21.2% in adult-onset patients (OR 2.4, p = 0.005) and 8.5% in normouricemic controls (OR 6.8, p < 0.0001), with in vitro functional studies confirming that the variant reduces ABCG2 transport capacity by approximately half. 13 Incorporating ABCG2 status, or at minimum a family history suggestive of inherited urate transport dysfunction, into the evaluation of children with persistent or unexplained hyperuricemia would help distinguish those in whom elevated SUA reflects an inherited transport defect from those in whom it reflects an acquired cardiometabolic process, and the two are not mutually exclusive.The association between elevated SUA and metabolic syndrome in children is one of the most consistently replicated observations in pediatric metabolic research. Ford et al. (2007), analyzing data from 1,370 US adolescents aged 12-17 years in the NHANES 1999-2002 survey, reported that the prevalence of metabolic syndrome rose from below 1% in the lowest SUA quartile to 21.1% in the highest (OR 14.79; 95% CI 7.78-28.11), remaining significant after adjustment for age, sex, race, and C-reactive protein. 14 A meta-analysis of 34 pediatric studies confirmed pooled correlations between SUA and fasting blood glucose (r = 0.24), fasting insulin (r = 0.26), triglycerides (r = 0.23), and an inverse correlation with high-density lipoprotein cholesterol (HDL-C) (r = -0.28). 15 These are robust associations across diverse populations, though the cross-sectional design of most contributing studies limits conclusions about temporal sequence and directionality. These associations are also consistently observed in Latin American pediatric populations, underscoring the global relevance of hyperuricemia as a cardiometabolic risk marker. In a Mexican cohort of 59 obese prepubertal children, higher SUA concentrations were positively associated with insulin resistance and hypertriglyceridemia and inversely associated with HDL-C. Moreover, each 1 mg/dL increase in SUA was associated with an approximately threefold higher likelihood of meeting the diagnostic criteria for metabolic syndrome (MetS). 16 Similarly, a large Brazilian cohort involving 1,750 children and adolescents demonstrated that serum uric acid concentrations at or above the 90th percentile were independently associated with substantially increased odds of overweight and obesity (OR 3.6). 16,17 More recently, Lorra et al. (2026) 18 further reinforced the role of SUA as an early metabolic marker among adolescents by examining 4,390 Brazilian participants aged 12-17 years. Higher SUA quartiles were consistently associated with an adverse cardiometabolic profile, including greater waist circumference, higher BMI Z-scores, elevated blood pressure, increased triglyceride levels, and higher total and low-density lipoprotein concentrations. Together, these findings indicate that the cardiometabolic implications of pediatric hyperuricemia extend beyond Asian, North American, and European populations, highlighting its relevance across diverse ethnic and geographic contexts experiencing rapid nutritional and epidemiological transitions.For cardiovascular outcomes, particularly hypertension, the evidence is comparatively stronger and includes longitudinal and interventional data. The Bogalusa Heart Study demonstrated that childhood SUA independently predicted adult blood pressure after adjustment for body mass index, age, sex, and race, with SUA trajectory over time serving as an additional predictor of adult systolic pressure. 19 The Ewha Birth and Growth Cohort Study further showed that children with SUA above the median at age three had significantly higher blood pressure at age seven, with those maintaining elevated SUA at both three and five years carrying the greatest blood pressure burden at follow-up. 20 Mechanistically, uric acid activates the renin-angiotensin-aldosterone system (RAAS), increases renal sodium reabsorption, and inhibits endothelial nitric oxide synthesis, collectively promoting vasoconstriction through pathways that may become self-sustaining once established. 21 Critically, the interventional literature provides the most direct evidence linking SUA reduction to a measurable pediatric cardiovascular outcome. In a randomized, double-blind, placebo-controlled crossover trial, Feig et al.(2008) enrolled 30 adolescents aged 11-17 years with newly diagnosed stage 1 essential hypertension and SUA >/= 6 mg/dL, and demonstrated that allopurinol 200 mg twice daily reduced mean systolic blood pressure by 6.9 mmHg versus 2.0 mmHg with placebo (p = 0.009), with blood pressure normalizing in 20 of 30 adolescents during active treatment compared with 1 during placebo. 22 A subsequent trial in 60 obese pre-hypertensive adolescents confirmed that urate-lowering therapy reduced systolic blood pressure by approximately 10 mmHg, significantly exceeding the placebo response. 23 These trials support a causal role for uric acid in blood pressure elevation in a that is further by the biological of the proposed CKD and the evidence remains predominantly observational, and causality should be characterized as and rather than independently associated with increased by in children and with the in part through insulin resistance and blood pressure. 21 These data collectively support SUA as a clinically cardiometabolic marker in children, with the cardiovascular providing the and most actionable evidence for clinical kidney is a principal of urate excretion and a proposed of demonstrate that urate elevation tubular and in renal through changes that are by xanthine oxidase in these mechanisms to CKD in and in children remains an important and most clinical evidence from the CKD in cohort which enrolled children with CKD across North American Hyperuricemia was independently associated with a renal of a greater than in or of renal after adjustment for blood pressure, CKD and body mass index, with the in children with SUA above mg/dL. These are important but the design causal trial has yet urate-lowering therapy CKD in children, and this remains a critical evidence pediatric CKD cohort further a between SUA and hypertension and with the lowest risk at SUA between 5.5 and mg/dL. This that both of SUA are associated with adverse outcomes in children with and argues for a defined range rather than In practical it also that SUA independent beyond and in pediatric a that supports its routine measurement in this in the absence of causal children with syndrome, and disease, SUA are more and the renal more yet longitudinal SUA is not part of in most of these groups. 9 This represents a in pediatric that not on causal before most frequently obstacle to incorporating SUA into routine pediatric metabolic screening is the absence of validated, age-and sex-specific diagnostic thresholds for children. The adult cut-offs of 416 μmol/L for males and 357 μmol/L for females are in adult data and reflect the urate are not derived from children, do not account for the trajectory of SUA across childhood, and do not reflect the sex divergence that emerges only with the of rather than at a fixed Dai et some of the most age-and sex-stratified SUA reference data currently 7 5,439 healthy children aged 5-14 years in Southeast China with stringent exclusion criteria, data three clinically SUA increases with age in both sexes throughout no significant sex before age divergence emerges from ages with SUA substantially with the of and the of the 97.5th percentile SUA in healthy children is below adult approximately μmol/L in boys and μmol/L in 7 in the Dai et al. cohort sex-specific SUA incorporating both BMI and in mean SUA = in years in girls, mean SUA = 7 The stronger BMI in boys and the stronger age in girls the differential of and to urate across the two reference data from the and additional Chinese cohorts that the 97.5th percentile SUA in healthy boys or exceeds μmol/L across diverse populations, substantially above the 416 μmol/L adult confirming that applying fixed adult cut-offs to adolescent males clinically significant in this 7,8 from the on The most pediatric reference currently in was through more than a of prospective data from over healthy children across using The by et al. explicitly SUA as one of the the most with concentrations substantially in the pediatric compared to the adult population, a the as a direct that the use of adult reference intervals a measurable risk of children as when results in elevated relative to or SUA reference intervals used in clinical further the of this divergence from adult for children aged 1 to 12 years, the reference range is mg/dL in both sexes, to mg/dL in males and mg/dL in females aged 12 to 19 years. these pediatric data converge with the Chinese cohort findings of Dai et al. across independent populations, and 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where CKD and hypertension in children are often disease, an biomarker that cardiometabolic and renal risk than have The SUA is no beyond clinical and is in most and across and for adult gout and in data from and European children may not be to or pediatric populations, in whom in body dietary purine intake, and renal are published pediatric SUA reference from was in this a that before screening thresholds can be proposed with In the in should age-and sex-stratified reference data from the most available while this for pediatric SUA reference intervals in this editorial is therefore not only a scientific but a of global pediatric populations, including those existing child cohort studies in and Latin should be and with this in Hyperuricemia and explicitly routine treatment of hyperuricemia in adolescents on A screening would therefore clinical pathways when an elevated result when review is and when should be pathways that currently only in and on the evidence with these we propose the minimum clinical SUA measurement should be in the routine fasting metabolic panel of all children with overweight or obesity >/= for age and at and at metabolic the and association between elevated SUA and metabolic syndrome in this and the low of SUA should part of the evaluation of any child presenting with hypertension, of obesity status, where the interventional trial data the available for measurement and SUA should be alongside serum and in children with CKD of any where the cohort data support its use as an independent biomarker , while that the case for urate-lowering therapy to CKD pediatric interventional trial In children with or confirmed SUA should be as part of metabolic that the association is and but not yet as causal in pediatric should be interpreted using age-and sex-specific reference data rather than adult validated pediatric reference intervals are the published age-and sex-stratified data of Dai et al. 7 and cohort studies the most available reference framework for clinical elevated SUA is the should reduction of fructose-rich and sugar-sweetened beverages, and of with urate-lowering therapy for children with clinical and only after of the pediatric evidence with Serum uric acid is an marker whose associations with hypertension, insulin resistance, metabolic syndrome, and in children are by a substantial and diverse body of cardiovascular outcomes and hypertension specifically, interventional data blood pressure reduction urate-lowering therapy in adolescents support a causal CKD and the evidence remains predominantly observational, and causality should be rather than The to clinical are the absence of age-and sex-specific diagnostic thresholds for children, the lack of reference and the absence of screening trials that hyperuricemia in children are The data to reference intervals across diverse in and international trials in high-risk pediatric groups are and trials in pediatric CKD and hypertension the most In the should SUA in children at cardiometabolic and renal results age-and reference and both the of adult thresholds and the of in A biomarker of this and low a defined and role in pediatric metabolic and the evidence now available is to that