Background/Purpose: Hyperuricemia is the central risk factor for gout. In observational studies hyperuricemia also predicts the development and progression of chronic kidney disease independent of other measured risk factors. The use of xanthine oxidase inhibitors coincides with improved renal function – whether this is due to reduced serum urate or some other physiological mechanism remains unresolved. We applied Mendelian randomization to the question – is increased serum urate, determined by genetic modulation of renal excretion, detrimental to renal function?

Methods: Data from the Atherosclerosis Risk in Communities (n=5237) and Framingham Heart (n=3033) studies were used. Mendelian randomization uses genetic variants known to be causal of a modifiable exposure (serum urate in this study) to test for association of that exposure with an outcome (renal function in this study). Mendelian randomization by the two stage least squares method was conducted with serum urate as the exposure, a genetic risk score (based on variants from 5 urate transporters; SLC2A9, ABCG2, SLC17A1, SLC22A11, SLC22A12) as the instrumental variable and serum creatinine (SCr) or estimated glomerular filtration rate (eGFR) as the outcome. All analysis was done using STATA 8.0 and analyses adjusted for possible confounding variables.

Results: Increased serum urate genetic risk score associated with improved renal function in men (SCr P=0.023, eGFR P=0.045) but not women (SCr P=0.73, eGFR P=0.42) (Table). Analysis of individual genetic variants revealed that the effect size associated with serum urate did not correlate with the effect size associated with renal function in the Mendelian randomization model.

Conclusion: Contrary to the established relationship of increased serum urate with reduced renal function, increase in serum urate caused by genetic variation in uric acid transporters results in improved renal function. The single variant analysis suggests that the renal protection could be mediated by the activity of renal transporters in increasing serum urate levels. These results justify further research into the mechanism of renal function protection mediated by xanthine oxidase inhibitors.

Table Mendelian randomization analysis of SU against eGFR/SCr.

Ordinary least square regression: Beta is the change in SCr/eGFR attributed to a unit change in serum urate (left).

Two stage least square: Beta is the change in SCr/eGFR caused by a unit change in serum urate attributed to the genetic risk score (right).