No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study

Abstract

Background: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).

Methods and findings: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.

Conclusions: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.

Fig 1. Study design overview.

Overview of the study design. ARIC, Atherosclerosis Risk in Communities; CARDIA, Coronary Artery Risk Development in Young Adults; CHS, Cardiovascular Health Study; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FHS, Framingham Heart Study; GRS, genetic risk score; MR, Mendelian randomization; SNV, single nucleotide variant; SU, serum urate.

Fig 2. MR analysis of the effect of SU on eGFR and CKD.

Estimates of causal effects of serum urate on eGFR (A) and CKD (B) by 7 MR analyses. Effects are shown per 1-mg/dl increase of serum urate. The effect sizes/odds ratios and P values were calculated using all single nucleotide variants (SNVs), except for the outlier-corrected MR, where pleiotropic SNVs (detected by MR-PRESSO) were excluded. In the outlier-corrected analysis, 11 outliers were removed for eGFR and 4 outliers were removed for CKD (see S2 Table). CKD, chronic kidney disease; MR, Mendelian randomization; SNV, single nucleotide variant; SU, serum urate.

Fig 3. Effects of individual SNVs on SU, eGFR, and CKD.

Effects of individual SNVs on SU (x-axis, both panels), eGFR (y-axis, A), and CKD (y-axis, B), as estimated by the respective genome-wide association meta-analyses. Error bars indicate 95% confidence intervals. SNVs identified as outliers by the MR-PRESSO outlier test are highlighted in red. CKD, chronic kidney disease; MR, Mendelian randomization; SNV, single nucleotide variant; SU, serum urate.