Kynurenines in polycystic kidney disease

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder, characterized by kidney cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. Due to its role in inflammation and oxidative stress, tryptophan metabolism and related kynurenines may have relevance in ADPKD.

Methods: Data were collected from a well-characterized longitudinal cohort of pediatric and adult patients with ADPKD and compared to age-matched healthy subjects. To evaluate the role of kynurenines in ADPKD severity and progression, we investigated their association with height-corrected total kidney volume (HtTKV) and kidney function (estimated glomerular filtration rate (eGFR)). Key tryptophan metabolites were measured in plasma using a validated liquid chromatography-mass spectrometry assay.

Results: There was a significant accumulation of kynurenine and kynurenic acid (KYNA) in children and adults with ADPKD as compared to healthy subjects. Downstream kynurenines continued to accumulate in adults with ADPKD concurrent with the increase of inflammatory markers IL-6 and MCP-1. Both markers remained unchanged in ADPKD as compared to healthy children, suggesting alternate pathways responsible for the observed rise in kynurenine and KYNA. KYNA and kynurenine/tryptophan positively associated with disease severity (HtTKV or eGFR) in patients with ADPKD. After Bonferroni adjustment, baseline kynurenines did not associate with disease progression (yearly %change in HtTKV or yearly change in eGFR) in this limited number of patients with ADPKD.

Conclusion: Kynurenine metabolism seems dysregulated in ADPKD as compared to healthy subjects. Inhibition of kynurenine production by inhibition of main pathway enzymes could present a novel way to reduce the progression of ADPKD.

Keywords: ADPKD; Kynurenines; Tryptophan.

Fig. 1

Changes in plasma concentrations of kynurenine pathway intermediates (A–D) across the investigated study groups: healthy children, children with ADPKD (normal eGFR), healthy adults and adults with ADPKD (eGFR above or below 60 mL/min/1.73m², respectively). All concentrations are presented as ng/mL, except for tryptophan (calculated in μg/mL) and MCP-1 (calculated in pg/mL). Significance levels (after Bonferroni adjustment): healthy subjects versus ADPKD patients (children and adults, respectively): *p < 0.0056, ***p < 0.0001 and children versus adults with ADPKD: ^#p < 0.0056, ^###p < 0.0001

Fig. 2

Tryptophan/kynurenine pathway and changes in plasma concentrations of kynurenines in ADPKD patients versus healthy subjects. Dark blue arrows (up or down for concentration increase or decrease as compared to healthy age-matched subjects) represent changes observed in children and adults with ADPKD; light blue arrows represent change only seen in adults and light grey only in children; other colors such as for the increase of IDO1 (indoleamine 2,3-dioxygenase) expression and the decline of nicotinamide indicate hypothetical changes. Abbreviations: 3HAO 3-hydroxyanthranilate dioxygenase; IDO indoleamine 2,3-dioxygenase; KAT kynurenine transaminase; KFO kynurenine formylase; KMO kynurenine monooxygenase; KYNU kynureninase; NAD⁺ nicotinamide adenine dinucleotide; QPRT quinolinate phosphoribosyl transferase; TDO tryptophan 2,3-dioxygenase