Uric acid in cardiovascular and renal disease: Marker, mediator, or therapeutic target?
TL;DR
Uric acid functions as both a biomarker and a context-dependent mediator of cardiorenal injury and the failure to translate compelling mechanistic and observational data into clinical benefit suggests any pathogenic role is likely confined to early disease stages.
Abstract
Background: Hyperuricemia is increasingly prevalent worldwide, paralleling the epidemics of metabolic syndrome and chronic kidney disease. While its causal role in gout is unequivocal, the position of uric acid in cardiovascular and renal disease remains deeply controversial, with competing interpretations as an innocent biomarker, a pathogenic mediator, or a modifiable therapeutic target. This study aimed to critically appraise the experimental, epidemiological, genetic, and clinical trial evidence concerning the role of uric acid in cardiorenal pathophysiology and the utility of urate-lowering therapy. Methods: Narrative review integrating mechanistic studies, observational cohorts, Mendelian randomization analyses, and major randomized controlled trials of xanthine oxidase inhibitors and uricosurics. Key Findings: Uric acid exerts pleiotropic, context-dependent effects: extracellular antioxidant activity contrasts with intracellular pro-oxidant signaling, endothelial dysfunction, RAAS activation, NLRP3 inflammasome stimulation, and vascular smooth muscle cell proliferation. Animal models demonstrate that hyperuricemia can directly induce hypertension and renal arteriolopathy. Large observational studies consistently associate elevated serum uric acid with incident hypertension, chronic kidney disease, and cardiovascular events, and Mendelian randomization studies partly support causality. However, landmark placebo-controlled trials—including CKD-FIX, PERL, and FEATHER—have not demonstrated slowing of kidney function decline or reduction in cardiovascular events with urate-lowering therapy in asymptomatic hyperuricemia, and febuxostat was associated with excess mortality in the CARES trial. Current guidelines therefore restrict pharmacotherapy to gout and, cautiously, to high-risk subgroups with early hypertension or mild kidney disease. Conclusion: Uric acid functions as both a biomarker and a context-dependent mediator of cardiorenal injury. The failure to translate compelling mechanistic and observational data into clinical benefit suggests that any pathogenic role is likely confined to early disease stages. Resolving the controversy will require precision-medicine trials that identify responsive phenotypes and intervene early.