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

Abstract

BackgroundAdults 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.MethodsTwenty-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.ResultsThe 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).ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0387-3) contains supplementary material, which is available to authorized users.

Protein-Bound Uremic Toxins in Hemodialysis Patients Relate to Residual Kidney Function, Are Not Influenced by Convective Transport, and Do Not Relate to Outcome

“…Plasma concentrations of the PBUTs measured in our study population were higher than in the healthy population as reported in the literature, especially for the strongly protein bound toxins (Table 6) (kynurenine: 2.0-fold [23][24][25], kynurenic acid: 75-fold [26,27], indoxyl sulfate: 72-fold [28,29], indole-3-acetic acid: 2.4-fold [29], p-cresyl sulfate: 59-fold [29], p-cresyl glucuronide: 1.6-fold [30], and hippuric acid: 11-fold higher) due to impaired tubular secretion and limited removal during HD, since only the free fraction is available for diffusion across the dialysis membrane. Kynurenic acid, indoxyl sulfate, indole-3-acetic acid, p-cresyl glucuronide and hippuric acid concentrations were inversely related to renal creatinine clearance.…”

Indole Tryptophan Metabolism and Cytokine S100B in Children with Attention-Deficit/Hyperactivity Disorder: Daily Fluctuations, Responses to Methylphenidate, and Interrelationship with Depressive Symptomatology

“…To our knowledge, no other studies have quantified IAA levels in ADHD children. Urine IAA levels were correlated with anxiety and depression scores in adults with chronic kidney disease (Karu et al 2016). Moreover, no change is detected in urinary excretion of IAA in patients with depression, with slight increase only in cerebrospinal fluid levels in patients with depression and intellectual disability (Anderson et al 1984).…”

Proteomic analysis of rat kidney under maleic acid treatment by SWATH‐MS technology

“…A previous study indicated that knocking out the Kynurenine formamidase gene, which is related to tryptophan degradation, in mice results in hardening of the glomerulus and an abnormal immune system . In addition, Karu et al reported that tryptophan metabolites may be decreased or elevated in CKD . Thus, it was speculated that the decline of these proteins would result in a lack of tryptophan, in turn causing abnormalities of the kidney.…”

“…49 In addition, Karu et al reported that tryptophan metabolites may be decreased or elevated in CKD. 50 Thus, it was speculated that the decline of these proteins would result in a lack of tryptophan, in turn causing abnormalities of the kidney.…”