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

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 <i>via</i> an in-depth analysis of the causal relationship between blood metabolites and renal function. 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 <i>via</i> 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. 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. 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.