Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study

Abstract

Background: Adults with chronic kidney disease (CKD) exhibit alterations in tryptophan metabolism, mainly via the kynurenine pathway, due to higher enzymatic activity induced mainly by inflammation. Indoles produced by gut-microflora are another group of tryptophan metabolites related to inflammation and conditions accompanying CKD. Disruptions in tryptophan metabolism have been associated with various neurological and psychological disorders. A high proportion of CKD patients self-report symptoms of depression and/or anxiety and decline in cognitive functioning. This pilot study examines tryptophan metabolism in CKD and explores associations with psychological and cognitive functioning.

Methods: Twenty-seven adults with CKD were part of 49 patients recruited to participate in a prospective pilot study, initially with an eGFR of 15-29 mL/min/1.73 m². Only participants with viable blood samples and complete psychological/cognitive data at a 2-year follow-up were included in the reported cross-sectional study. Serum samples were analysed by Liquid Chromatography coupled to Mass Spectrometry, for tryptophan, ten of its metabolites, the inflammation marker neopterin and the hypothalamic-pituitary-adrenal (HPA) axis marker cortisol.

Results: The tryptophan breakdown index (kynurenine / tryptophan) correlated with neopterin (Pearson R = 0.51 P = 0.006) but not with cortisol. Neopterin levels also correlated with indoxyl sulfate (R = 0.68, P < 0.0001) and 5 metabolites of tryptophan (R range 0.5-0.7, all P ≤ 0.01), which were all negatively related to eGFR (P < 0.05). Higher levels of kynurenic acid were associated with lower cognitive functioning (Spearman R = -0.39, P < 0.05), while indole-3 acetic acid (IAA) was correlated with anxiety and depression (R = 0.52 and P = 0.005, R = 0.39 and P < 0.05, respectively).

Conclusions: The results of this preliminary study suggest the involvement of inflammation in tryptophan breakdown via the kynurenine pathway, yet without sparing tryptophan metabolism through the 5-HT (serotonin) pathway in CKD patients. The multiple moderate associations between indole-3 acetic acid and psychological measures were a novel finding. The presented pilot data necessitate further exploration of these associations within a large prospective cohort to assess the broader significance of these findings.

Keywords: Anxiety; Chronic kidney disease; Cognition; Cortisol; Depression; Inflammation; Kynurenine; Neopterin; Tryptophan.

Fig. 1

A schematic diagram of Tryptophan metabolism, including box plots of quantified metabolites. Metabolites are in squares, enzymes in circles (yellow affected by cytokines, pink by cortisol), double-tip arrow indicates multi-step metabolism, Green arrow and metabolite are produced only by gut microflora. Box plots depict mean levels ± s.d (μM) grouped by kidney function, from left to right: blue, 15 ≤ eGFR ≤ 36 (CKD stage 3b-4, n = 13); red, eGFR < 15 (CKD stage 5, non-dialysis); grey, Haemodialysis patients (CKD stage 5). For each metabolite, a horizontal line under a pair of box plots indicates a non-significant difference in mean values (Welsh’s one-way ANOVA with Games-Howell post-hoc test, P > 0.05). Abbreviations: ACSAD, 2-amino-3-carboxymuconate semialdehyde; ALDH, aldehyde dehydrogenase; Anth A, anthranilic acid; CKD, chronic kidney disease; DDC, aromatic amino acid decarboxylase; eGFR, estimated glomerular filtration rate; IAA, indole-3-acetic acid; IDO, indoleamine-(2,3)-dioxygenase; IFNγ, interferon-γ; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYN, kynurenine; KYNA, kynurenic acid; KYNU, Kynureninase ; MAO, monoamine oxidase ; NAD+, Nicotinamide adenine dinucleotide; N-F, N-formyl; PicoA, picolinic acid; QuinaA, quinaldic acid; QuinoA, quinolinic acid; SULT, sulfotransferase; TDO, tryptophan 2,3-dioxygenase; TPH, tryptophan hydroxylase; UGT, UDP glucuronosyltransferase; XanthA, xanthurenic acid

Fig. 2

Scatter plots depicting relationships between serum metabolites. a tryptophan breakdown index (KYN/TRP) vs. eGFR; b kynurenine vs. neopterin; c neopterin vs. indoxyl sulfate. Marker colours indicate kidney function, and not used for separate calculations: red, CKD stage 5 (empty, HD; full, non-HD); blue, CKD stage ≤ 4. Pearson correlation tests (n = 27) were conducted on log-transformed data as required, then back-transformed for presentation in this figure. Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HD, haemodialysis; KYN, kynurenine; TRP, tryptophan