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



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.



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).



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.
ACROSS, School of Physical Sciences, University of Tasmania, Hobart, Tasmania, Australia. Naama.Karu@utas.edu.au.|Present address: The Metabolomics Innovation Centre (TMIC), Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada. Naama.Karu@utas.edu.au.
Naama
N
Karu
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Charlotte
C
McKercher
Central Science Laboratory, University of Tasmania, Hobart, Tasmania, Australia.
David S
DS
Nichols
Central Science Laboratory, University of Tasmania, Hobart, Tasmania, Australia.
Noel
N
Davies
ACROSS, School of Physical Sciences, University of Tasmania, Hobart, Tasmania, Australia.|Present address: Trajan Scientific and Medical, 7 Argent Place, Ringwood, Victoria, 3134, Australia.
Robert A
RA
Shellie
ACROSS, School of Physical Sciences, University of Tasmania, Hobart, Tasmania, Australia.|Present address: Future Industries Institute, University of South Australia, Mawson Lakes Campus, GPO Box 2471, Adelaide, South Australia, 5001, Australia.
Emily F
EF
Hilder
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.|Renal unit, Royal Hobart Hospital, Hobart, Tasmania, Australia.
Matthew D
MD
Jose
D000368:Aged; D000369:Aged, 80 and over; D001007:Anxiety / Q000097:blood; D015415:Biomarkers / Q000097:blood; D003071:Cognition; D003430:Cross-Sectional Studies; D003863:Depression / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007200:Indican / Q000097:blood; D007210:Indoleacetic Acids / Q000097:blood; D007249:Inflammation / Q000097:blood*; D007736:Kynurenic Acid / Q000097:blood; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000097:blood; D018384:Oxidative Stress; D010865:Pilot Projects; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000523:psychology*; D011795:Surveys and Questionnaires; D013648:Tasmania; D014364:Tryptophan / Q000097:blood / Q000378:metabolism*
D015415:Biomarkers; D007210:Indoleacetic Acids; D019798:Neopterin; C030737:indoleacetic acid; D014364:Tryptophan; D007736:Kynurenic Acid; D007200:Indican; D006854:Hydrocortisone
Anxiety; Chronic kidney disease; Cognition; Cortisol; Depression; Inflammation; Kynurenine; Neopterin; Tryptophan