Causal associations between circulating metabolites and chronic kidney disease: a Mendelian randomization study.

BACKGROUND

Circulating metabolites have been associated with cross-sectional renal function in population-based research. Nevertheless, there is currently little proof to support the idea that metabolites either cause or prevent renal function. New treatment targets and ways to screen individuals with impaired renal function will be made possible an in-depth analysis of the causal relationship between blood metabolites and renal function.

METHODS

We assessed the causal relationship between 452 serum metabolites and six renal phenotypes (CKD, rapid progression to CKD [CKDi25], rapid eGFR decline [CKD rapid3], dialysis, estimated glomerular filtration rate, and blood urea nitrogen) using univariate Mendelian randomization, primarily employing the inverse variance weighted method with robust sensitivity analyses. Heterogeneity and pleiotropy were examined Cochrane's Q test and MR-Egger regression, and statistical significance was adjusted using Bonferroni correction. To assess potential adverse effects of metabolite modulation, we conducted a phenome-wide Mendelian randomization analysis, followed by multivariate Mendelian randomization to adjust for confounders.

RESULTS

We identified glycine and N-acetylornithine as potential causal mediators of CKD and renal dysfunction. Notably, lowering glycine levels may increase the risk of cholelithiasis and cholecystitis, while reducing N-acetylornithine could have unintended effects on tinnitus.

CONCLUSION

Glycine and N-acetylornithine represent promising therapeutic targets for CKD and renal function preservation, but their modulation requires careful risk-benefit assessment to avoid adverse effects.