Impact of Uric Acid Levels on Kidney Disease Progression

Abstract

Background: Hyperuricemia is associated with the progression of chronic kidney disease (CKD), but it is not known whether the relationship is causal. We examined the association of hyperuricemia and uric acid lowering therapy (UALT) with progression of CKD in patients with CKD 3 and 4 in the Cleveland Clinic CKD registry. Methods: We included 1,676 patients with CKD stages 3 and 4 from Ohio, who had measured their uric acid (UA) levels a year prior to the recording of the second eGFR <60 mL/min/1.73 m², and follow-up eGFR, between 2005 and 2009. Our primary composite outcome included a 50% drop in eGFR or progression to ESRD. Secondary outcomes included the rate of decline in eGFR, all-cause mortality, progression to ESRD, and a composite measure of progression to ESRD or death. We assessed the association between UA, UALT, and outcomes using Cox models and competing risks regression models. Results: In multivariable models, higher UA was associated with the composite endpoint, but it reached statistical significance only in the 4th quartile (≥8.9 mg/dL). Receipt of UALT was significantly associated with increased risk of the composite outcome. Neither UA nor UALT (considered a time-dependent covariate) was significantly associated with mortality. The inference was similar for UA as high vs. low, quartiles, or continuous. Similarly, neither high UA nor UALT were significantly associated with ESRD, the composite of ESRD and mortality, or eGFR decline. Conclusions: Hyperuricemia is associated with increased risk of progression to ESRD in patients with CKD stages 3 and 4, but UALT does not ameliorate the risk, suggesting that the relationship is not causal.

Genetically Elevated Serum Uric Acid and Renal Function in an Apparently Healthy Population

“…Meanwhile, consistent with previous studies [4][5][6][7][8][9][10][11][12], we found that uric acid levels were negatively correlated with eGFR in all subjects. In the regression analysis, various potential confounders were added in sequential order, but the results revealed only a modest reduction effect (the regression coefficient changed from -0.20 to -0.22 after adjusting for a range of confounders), strengthening the notion of a relationship between uric acid and eGFR.…”

“…The association between uric acid and kidney disease has been previously investigated. Numerous studies reported a positive association between the levels of circulating uric acid and the risk of CKD progression [4][5][6][7][8][9][10][11][12], but this was negated in other studies [13][14][15]. Observational studies experience residual problems of poorly measured or unmeasured confounding factors and reverse causality when the disease process has a long latency period.…”

Changeover Trial of Febuxostat and Topiroxostat for Hyperuricemia with Cardiovascular Disease: Sub-Analysis for Chronic Kidney Disease (TROFEO CKD Trial)

“…Hyperuricemia is associated with increased risk of new-onset kidney disease and progression to chronic kidney disease (CKD). 1 – 3 ) Xanthine oxidase reductase inhibitors (XOR-I) are used for the treatment of hyperuricemia worldwide. Recently, the effectiveness of novel XOR-I, febuxostat and topiroxostat, was reported.…”

Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

“…Multiple factors such as hypertension, diabetes, and proteinuria promote onset and progression of CKD to end stage of renal disease (ESRD) [4,5]. Recent human and animal studies have uncovered that hyperuricemia is also an independent risk factor of CKD and is prevalent in patients with this disease [6]. Thus, understanding the mechanism by which uric acid induces pathological changes in the kidney will aid to develop novel therapeutic approaches for alleviating the progression of CKD.…”