Hyperuricemia in chronic kidney disease: Emerging pathophysiology and a novel therapeutic strategy Original paper

What was reviewed?

Hyperuricemia in chronic kidney disease was reviewed as an emerging pathophysiological process shaped by the interplay of glomerular filtration and tubular urate handling. This review emphasized how the hyperuricemia in chronic kidney disease phenotype reflects not only reduced filtration but also excessive tubular reabsorption, a distinction with major implications for interpreting serum uric acid levels and targeting therapy. The authors synthesized mechanistic, epidemiologic, and therapeutic evidence, presenting a cohesive framework in which urate acts as both a marker and a mediator of progressive kidney injury. They highlighted two key mechanisms—monosodium urate crystal formation and soluble uric acid–driven inflammation, both contributing to oxidative stress, endothelial dysfunction, and altered intrarenal hemodynamics.

Who was reviewed?

The review summarized mechanistic and clinical evidence from both human and experimental studies. It examined patients with CKD across stages, individuals with diabetes, hypertensive cohorts, and general population groups included in longitudinal studies and meta-analyses. Therapeutic summaries incorporated randomized controlled trials of xanthine oxidase inhibitors and uricosuric agents (including URAT1 inhibitors), as well as retrospective real-world CKD cohorts. Visual elements such as the phenotype-guided treatment algorithm on page 11 demonstrated how these patient groups may be stratified for future targeted interventions.

Most important findings

A central finding is that serum uric acid inadequately reflects true urate burden or pathogenic potential in CKD. The review distinguished glomerular under-filtration from tubular over-reabsorption, noting that the latter may drive early and potentially causal urate-mediated injury. The diagrams in the paper showed how soluble urate and monosodium urate crystals activate the NLRP3 inflammasome, generating IL-1β, IL-18, mitochondrial reactive oxygen species, epithelial injury, and fibrosis. Endothelial dysfunction—mediated by reduced eNOS activity, oxidative stress, and HIF-1α stabilization—disrupts glomerular autoregulation, producing either hyperfiltration or hypoperfusion patterns. Epidemiologic evidence consistently links higher serum uric acid to CKD progression, though recent work shows urinary urate excretion markers (FEUA, UUCR) better correlate with kidney injury. Therapeutic findings indicated that xanthine oxidase inhibitors lower serum urate but inconsistently improve renal outcomes, whereas URAT1 inhibitors (dotinurad, verinurad) enhance urinary uric acid excretion and may better address tubular reabsorption phenotypes, though evidence remains preliminary.

Key implications

This review reframes hyperuricemia in CKD as a heterogeneous, phenotype-driven disorder requiring more precise tools than serum urate alone. Urinary urate excretion indices and uric acid–creatinine ratios may better identify patients at risk for progressive kidney injury. The mechanistic evidence suggests that intrarenal urate—not merely circulating urate—drives inflammasome activation, oxidative stress, and endothelial dysfunction. Therapies enhancing urate excretion through URAT1 inhibition may provide clinical benefit, particularly in tubular over-reabsorption phenotypes. Future trials must incorporate phenotype stratification to determine which patients respond best to specific urate-lowering strategies.

Citation

Takata T, Mae Y, Hoi S, Iyama T, Isomoto H. Hyperuricemia in chronic kidney disease: Emerging pathophysiology and a novel therapeutic strategy.International Journal of Molecular Sciences. 2025;26:9000. doi:10.3390/ijms26189000