Abstract
Blood metabolites of the tryptophan pathway were found to be associated with kidney function and disease in observational studies. In order to evaluate causal relationship and direction, we designed a study using a bidirectional Mendelian randomization approach. The analyses were based on published summary statistics with study sizes ranging from 1,960 to 133,413. After correction for multiple testing, results provided no evidence of an effect of metabolites of the tryptophan pathway on estimated glomerular filtration rate (eGFR). Conversely, lower eGFR was related to higher levels of four metabolites: C-glycosyltryptophan (effect estimate = - 0.16, 95% confidence interval [CI] (- 0.22; - 0.1); p = 9.2e-08), kynurenine (effect estimate = - 0.18, 95% CI (- 0.25; - 0.11); p = 1.1e-06), 3-indoxyl sulfate (effect estimate = - 0.25, 95% CI (- 0.4; - 0.11); p = 6.3e-04) and indole-3-lactate (effect estimate = - 0.26, 95% CI (- 0.38; - 0.13); p = 5.4e-05). Our study supports that lower eGFR causes higher blood metabolite levels of the tryptophan pathway including kynurenine, C-glycosyltryptophan, 3-indoxyl sulfate, and indole-3-lactate. These findings aid the notion that metabolites of the tryptophan pathway are a consequence rather than a cause of reduced eGFR. Further research is needed to specifically examine relationships with respect to chronic kidney disease (CKD) progression among patients with existing CKD.