Uncovering the Link Between Kynurenic Acid Pathway and Kidney Failure

Abstract

Introduction: Recent studies have focused on some uremic toxins, particularly those derived from tryptophan, as potential modifiable risk factors of chronic kidney disease (CKD) progression. The kynurenine pathway is the major enzymatic pathway for sequentially catabolizing tryptophan, resulting in key metabolites including kynurenine and kynurenic acid (KA) by the aminoadipate aminotransferase. We aimed at evaluating the association of serum KA levels and KA-to-kynurenine ratio (as indicators of aminoadipate aminotransferase activity) with kidney failure.

Methods: The Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) study is a prospective cohort of patients with CKD having an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m². Baseline samples of uremic toxins were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for our outcome. The kidney gene expression of the kynurenine pathway was evaluated in 5 or 6 nephrectomy CKD mice and adenine-diet CKD mice under nephroprotective low protein diet (5% w/w).

Results: Over a median follow-up period of 5 years, 608 out of the 2406 patients progressed to kidney failure. A 2-fold increase in serum KA levels and KA-to-kynurenine ratio were respectively associated with a 22% and 20%-increase in the hazard of kidney failure after multiple adjustments. In the mouse model, positive correlation was found between aminoadipate aminotransferase expression and fibrosis-related genes and kidney fibrosis. A low-protein diet was associated with a decrease in aminoadipate aminotransferase expression in the kidney as well as in inflammatory and fibrosis markers.

Conclusion: Our findings suggest that the kynurenine pathway is associated with kidney failure, and that the inhibition of aminoadipate aminotransferase and the subsequent reduction of KA accumulation is a promising target to mitigate kidney disease progression.

Keywords: chronic kidney disease; kidney failure; kynurenic acid pathway; kynurenine; tryptophan.

Graphical abstract

Figure 1

Flowchart of the study.

Figure 2

Kidney fibrosis is associated with upregulation of aminoadipate aminotransferase. (a) Tryptophan pathway. (b) Chronogram of the experiment. (c) Concentrations of KA, kynurenine, tryptophan, and KA-to-kynurenine ratio in the plasma expressed as fold change from the control group. (d) Relative mRNA expression for Col1a1, IL-6; TNF alfa, Ccl2, Nqo1, Sod2, Gp9, Gpx4, Cat, and AADAT in the kidney (n = 5–17). (e) Heatmap showing the Pearson correlation coefficients between the concentration of KA, kynurenine, and KA-to-kynurenine ratio, and kidney function parameters (n = 3–10). (f) Chronogram of the experiment. (g) Concentrations of KA, kynurenine, tryptophan, and the KA-to-kynurenine ratio in the plasma expressed as fold change from the control group. (h) Relative mRNA expression for Col1a1, IL-6; TGF beta, and AADAT in the kidney (n = 5). ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001 correspond to significant differences between groups by unpaired t test. AADAT, aminoadipate aminotransferase; IDO, indoleamine 2,3-dioxygenase; KA, kynurenic acid; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; TDO,tryptophan 2,3-dioxygenase.