Crystal clear - part I: The role of uric acid in cardiorenal disease

This review opens a two-part series by exploring the evolutionary origins, vascular implications, renal pathophysiology, and prognosis related to serum uric acid (SUA). We begin by examining the ancestral loss of uricase in hominoids, which conferred elevated SUA-initially advantageous for sodium retention and antioxidant defense, yet maladaptive in today's purine- and fructose-abundant diet. UA thus re-emerges as a biologically active molecule, exhibiting both protective antioxidant effects and harmful pro-inflammatory actions. We then delineate SUA's vascular effects: it drives oxidative stress, endothelial dysfunction, and metabolic signaling disruption, magnified in chronic kidney disease (CKD) by impaired clearance and systemic inflammation. Elevated SUA is independently linked to renal function decline, as shown in prospective cohorts across diverse populations. We also evaluate urate-lowering therapies (ULT), discussing mixed evidence of benefit on kidney outcomes and emphasizing the need for more precise risk targeting. Finally, we outline strong associations between hyperuricemia and increased all-cause and cardiovascular mortality, particularly in high-risk groups (CKD, heart failure, diabetes, gout). Taken together, this first installment highlights the importance of stratified treatment strategies in hyperuricemia, suggesting that future trials should focus on interventions tailored to specific clinical phenotypes, avoiding unnecessary UA reduction in low-risk populations.