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

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