Pediatric hyperuricemia: genetic basis, metabolic mechanisms, and clinical implications.
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Hyperuricemia (HUA) is a heterogeneous group of metabolic disorders caused by long-term disturbances in purine metabolism. In recent years, although adult HUA and gout have been extensively studied, the understanding of HUA and gout in children and adolescents remains insufficient. Diagnostic criteria for adult HUA are well-established, but no consensus has yet been reached regarding its definition in children and adolescents. This review summarizes the current understanding of pediatric HUA, emphasizing its genetic basis, metabolic mechanisms, and clinical associations. ATP-binding cassette subfamily G member 2 (ABCG2) dysfunction, gene-defined forms of autosomal dominant tubulointerstitial kidney disease (ADTKD), particularly ADTKD-UMOD and ADTKD-REN, and selected purine metabolism disorders contribute to early-onset HUA, gout, nephrolithiasis, and renal involvement. Obesity-related insulin resistance (IR) may promote urate accumulation through pathways linked to oxidative stress, endothelial dysfunction, and inflammasome activation. Persistent elevation of uric acid (UA) has been associated with chronic kidney disease (CKD) progression, elevated blood pressure (BP), and subclinical cardiovascular remodeling. However, many of these mechanistic associations are supported primarily by adult and experimental studies and require further validation in children. We also review non-pharmacological management and indication-based pharmacological treatment strategies for pediatric HUA. These indications include asymptomatic hyperuricemia (AH), pediatric gout, UA nephrolithiasis, inherited purine metabolism disorders, CKD-associated HUA, and tumor lysis syndrome (TLS)-associated acute HUA, with emphasis on pediatric evidence, regulatory approval, off-label use, dosing, monitoring, and safety. In children, asymptomatic serum urate elevation is often the first recognized presentation, whereas nephrolithiasis, gout, renal dysfunction, or acute HUA should prompt evaluation for genetic, metabolic, renal, or treatment-related causes. These findings underscore the need for early identification and personalized intervention in children with HUA to prevent long-term renal and metabolic complications.