Tryptophan metabolism is altered in immunoglobulin A nephropathy and is associated with clinical manifestations of the disease

Background: the catabolism of aromatic amino acids is closely linked to the immune response. Their metabolites act as molecular messengers, facilitating communication between the microbiome and the immune system. Selected studies suggested that the pathogenesis of immunoglobulin A nephropathy (IgAN) may be associated with alterations in tryptophan (Trp) metabolic pathways.

Aim: to test the hypothesis about probable changes in Trp metabolism in IgAN using untargeted and targeted metabolomics analyses.

Materials and methods: the cohort study included 113 patients with a clinical and morphological diagnosis of primary IgAN, comprised two subgroups: with an active/progressive process who did not receive treatment (IgAN-A, n=85); with inactive IgAN/remission (IgAN-R, n=28). Control groups included healthy volunteers without kidney disease (K1, n=31) and patients with non-inflammatory glomerulopathies (K2, n=33). Untargeted and targeted metabolomics studies of serum were performed using high-resolution high-performance liquid chromatography with mass spectrometric detection (HPLC-MS) in positive and negative ionisation mode. Intergroup differences in Trp metabolites were assessed, and their associations with clinical parameters were analysed.

Results: untargeted analysis of mass spectrometric data revealed that tryptophan synthesis and metabolism were enriched among other metabolic pathways in patients with IgAN. Significant differences were found in kynurenic acid (KynA), kynurenine (Kyn), 5-hydroxytryptophan (HTrp), 3-hydroxyanthranilic acid, tryptamine, and indole-3-lactic acid (ILA), suggesting alterations in the serotonin, kynurenine, and indole metabolic pathways. Targeted analyses showed that Trp and its metabolites’ levels differed significantly in patients with IgAN (overall group, n=113) compared to healthy controls. Compared with the IgA-R subgroup, subjects with IgAN-A had higher levels of KynA:Kyn, Kyn:Trp, KynA:Trp, and HTrp:Trp ratios, alongside decreased tryptophan and indoxyacetic acid (IAA). In the IgAN-A group, diverse associations of Trp and its metabolites with clinical parameters were revealed. Except for Trp and indole acetate, metabolites of the Trp pathway were negatively correlated with estimated glomerular filtration rate (eGFR), blood pressure, and age. Tryptophan and indole acetate had negative associations with proteinuria and positive associations with serum albumin levels. Tryptophan and IAA concentrations were inversely associated with proteinuria and directly with serum albumin levels; the associations of these clinical indicators and the ratios of HTrp, Kyn, KynA, NA and ILA to tryptophan were opposite.

Conclusions: In IgAN patients, apparent alterations in tryptophan metabolic pathways are associated with clinical parameters and may contribute to the pathogenesis of the disease.

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