Linking tryptophan metabolites to cognitive dysfunction in chronic kidney disease

Introduction

:Cognitive impairment (CI) is a common and serious complication in patients with chronic kidney disease (CKD). Its development and progression are influenced by a complex interplay of factors, including the accumulation of uremic toxins (UTs), imbalances in electrolytes and acid–base status, anaemia, vascular injury, neuroinflammation, metabolic abnormalities, and coexisting comorbidities such as diabetes and hypertension [1]. UTs are defined as compounds retained due to impaired renal excretion that show deleterious biological effects. These toxins are mainly derived from amino acid metabolism, particularly tryptophan, and disrupt biological or biochemical functions. Tryptophan is a precursor of several bioactive compounds through the kynurenine, indole and serotonin pathways. CKD leads to the accumulation of 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 CI, whereas less is known about the other tryptophan metabolites. We aimed to evaluate the link between these tryptophan-metabolism-related toxins and CI in patients with CKD.

Methods

3033 patients with CKD stages 2 to 5 enrolled in the CKD–Renal Epidemiology and Information Network (CKD-REIN) prospective cohort study in France. UT concentrations were measured in serum using a validated liquid chromatography–tandem mass spectrometry method. Patients with both UT measurements and cognitive function screening (using the 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 the2389 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 (age, sex, education level), cardiovascular risk factors (systolic blood pressure per 10 mmHg increase, diabetes mellitus, dyslipidemia, obesity, current smoking), cerebrovascular disease, current depression, eGFR, urinary albumin-to-creatinine ratio, and UTs known to be associated with CI (pCS: p-cresyl sulfate, TMAO: trimethylamine-N-oxide and PAG: phenylacetylglutamine), 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]).

Conclusions

We examined different branches of the same metabolic pathway, which led to the production of various UTs. Among the studied metabolites derived from tryptophan, IS showed an independent association with CI in patients with CKD, whereas no such relation was observed for KYN or IAA. These results highlight the potential value of strategies aimed at lowering excess IS production or enhancing its clearance to help prevent or manage CKD-induced CI. Although these UTs share a common origin and receptor, they follow distinct metabolic pathways and exert different effects, underscoring the need for further research into the tryptophan pathway and its role in CI in CKD. Identifying the biological risk factors for neurological complications will help optimize therapeutic management and develop novel therapeutic approaches.

References

1. Bolignano D, Simeoni M, Hafez G, Pepin M, Gallo A, Altieri M, Liabeuf S, Giannakou K, De A, Capasso G; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) collaborators, 2024. Cognitive impairment in CKD patients: a guidance document by the CONNECT network. Clin Kidney J. Sep 30;18(2):sfae294. doi: 10.1093/ckj/sfae294.