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 m ²; 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.

Author summary

Why was this study done?

• Epidemiological studies have shown strong correlations between serum urate (SU) levels and chronic kidney disease (CKD) risk.

• Elevated SU levels are often found in patients with CKD, but it is not clear whether high serum urate is a cause of kidney disease or just a common co-occurrence.

• Previous studies examining whether SU levels had a causal effect on CKD were limited due to not having large enough samples to detect a true causal relationship if it existed and/or had limitations related to the methodology.

• Several clinical trials have been started that aim to use urate-lowering medication to prevent CKD.

What did the authors do and find?

• To determine whether SU level has a causal effect on CKD, we used a methodology known as Mendelian randomization to test whether genetic variants known to increase SU level also increased the risk of CKD.

• We used multiple datasets to perform Mendelian randomization analyses, which included meta-analyses performed across multiple population-based cohorts, 4 individual population-based cohorts, and the large electronic-medical-record-linked UK Biobank.

• Across all datasets, we found no significant causal connection between SU level and risk of CKD.

What do these findings mean?

• Our findings do not support a causal role of SU level in CKD.

• Lower SU levels would be unlikely to translate into reduced risk of CKD.