Increased urinary excretion of kynurenic acid is associated with non-recovery from acute kidney injury in critically ill patients

Abstract

Background: Acute kidney injury (AKI) is often observed in critically ill patients and is associated with high morbidity and mortality. Non-recovery from AKI has a negative impact on the prognosis of affected patients and early risk stratification seems key to improve clinical outcomes. We analyzed metabolites of a conserved key inflammatory pathway (i.e. tryptophan degradation pathway) in serial urine samples of patients with AKI.

Methods: One hundred twelve ICU patients with AKI were included in a prospective observational analysis. After exclusion criteria, 92 patients were eligible for analysis. Serial urine samples were collected and tryptophan levels including key tryptophan metabolites were measured using tandem mass spectrometry.

Results: Sixty-seven patients recovered in the first 7 days of AKI (early recovery, ER) whereas n = 25 had late-/non-recovery (LNR). Urinary concentrations of tryptophan, kynurenine, 3-OH anthranillic acid, serotonine, and kynurenine/tryptophan were significantly lower in LNR patients. In contrast, creatinine normalized excretion of kynurenic acid (KynA) was substantially increased in LNR patients (7.59 ± 6.81 vs. 3.19 ± 3.44 (ER) μmol/mmol, p < 0.005). High urinary KynA excretion was associated with higher RIFLE class, longer AKI duration, increased need for RRT, and 30-day mortality. Logistic regression revealed KynA as the single most important predictor of renal recovery on days 1 and 2 of AKI.

Conclusions: Increased urinary levels of kynurenic acid, a key inflammatory metabolite of the tryprophan degradation pathway, are associated with adverse renal and clinical outcomes in critically ill patients with AKI. Urinary KynA may serve as an early risk stratificator in respective patients with AKI.

Keywords: IDO; Inflammation; Intensive care unit; Kynurenines; Renal failure; Renal recovery; Tryptophan metablism.

Fig. 1

Study design. Urine was collected on the first 3 days in 112 acute kidney injury (AKI) patients on the intensive care unit. Urinary concentrations of tryptophan and respective metabolites were assessed on the first 3 days of AKI. After 1 week, recovery status was assessed. Results are compared between patients with early recovery (ER) and late−/non-recovery (LNR)

Fig. 2

Urinary concentrations of kynurenic acid and kynurenic acid/tryptophan ratio in AKI patients with/without early recovery. Results are given on a linear scale and displayed as boxplot summaries. The middle line in the box represents the mean, and the whiskers represent the standard error of the mean. Urinary concentrations of creatinine normalized kynurenic acid (KynA) were increased in patients with late−/non-recovery (LNR) when compared to patients with early recovery (ER) (*p ≤ 0.005, **p < 0.001 and ***p < 0.0001). The urinary ratio of KynA/tryptophan was higher in LNR patients compared to ER patients. (*p = 0.01, *** < 0.0001). Corresponding serum creatinine concentrations in mg/dl are given below the graph

Fig. 3

Multivariate logistic regression model of renal recovery in AKI patients. ROC analyses for the prediction of renal recovery by urinary KynA (a-c) and the ratio of urinary KynurA/cr to tryptophan/cr (d-f), respectively; alone (full line) and in combination with the clinical parameters (SOFA score at admission and serum creatinine levels, dashed line) at days 1 (a, d), 2 (b, e) and 3 (c, f) of AKI