Association of Tryptophan Metabolites with Cognitive Impairment in Chronic Kidney Disease

Abstract Background CKD leads to the accumulation of uremic toxins (UTs), including tryptophan-derived metabolites such as kynurenine (KYN), indoxyl sulfate (IS), and indole-3-acetic acid (IAA). IS has been identified as a potential contributor to cognitive impairment (CI), whereas less is known about the other tryptophan metabolites. We aimed to evaluate the association between these toxins related to tryptophan metabolism and CI in patients with CKD. Methods 3033 patients with CKD stages 2 to 5 enrolled in CKD–Renal Epidemiology and Information Network (CKD-REIN) cohort. Patients with both UT measurement and cognitive function screening (with mini-mental state examination (MMSE)) were included. CI was defined as an MMSE score ≤ 26/30. Logistic regression was used to assess the association between the studied UTs and MMSE. Results Of the 2389 included patients (mean (SD) age: 66.5 (12.8) years, 66% males, mean (SD) estimated glomerular filtration rate (eGFR) 34.8 (13.4) ml/min/1.73m2), 858 patients (35.9%) had an MMSE score ≤ 26/30. After adjustment for sociodemographic factors, cardiovascular risk factors, cerebrovascular disease, current depression, eGFR, urinary albumin-to-creatinine ratio, and UTs known to be associated with CI, no significant association was found between KYN or IAA and MMSE ≤ 26/30, whereas IS was significantly associated (Odds Ratio [OR], 95% confidence interval: 1.11 [1.00-1.21]). Conclusion Among tryptophan-derived metabolites studied, IS was associated with CI in patients with CKD, in contrast to KYN and IAA. Despite sharing a common origin, the UTs studied follow distinct metabolic pathways with different effects, highlighting the need for further investigation of the tryptophan pathway on CI in CKD.