Metabolism of tryptophan and kynurenine in septic patient: association with the hypotension severity and prognosis

INTRODUCTION. Indoleamine 2,3 dioxygenase 1 (IDO1) metabolizes tryptophan (TRP) through the kynurenine (KYN) pathway (KP) and it is induced when systemic inflammation is present, as in sepsis. The upregulation of the KP has been identified as a hypotension culprit in in vivo models of sepsis and septic shock [1] and associated to increased mortality in critically-ill patients [2]. OBJECTIVES. We investigated the KP in septic patients to determine if it was involved in sepsis severity. We evaluated the association between IDO1 activity and the severity of sepsis-induced hypotension and we analyzed the association between the plasma concentration of KP metabolites and mortality, both at ICU discharge and at 90 days. METHODS. We performed analysis on a subgroup of patients (n=100, 50 survived and 50 deceased at ICU discharge), previously enrolled in the randomized controlled trial Albumin Italian Outcome Sepsis [3]. TRP, KYN, kynurenic acid (KYNA) and 3-hydroxyantranilic acid (3-HAA) concentration were determined through liquid chromatography mass spectrometry on ICU day 1, 2 and 7. We used KYN/TRP ratio as a surrogate of IDO1 activity. We considered the inotropic score (IS) (dopamine + adrenaline x 100 + noradrenaline x 100 [μg/kg/min]) as the expression of pressors need for keeping a mean arterial pressure above 65 mmHg. We applied univariate and multivariate models adjusted for age, sex, sepsis source, SOFA and SAPS II at ICU admission to determine associations among variables. RESULTS. TRP concentration was halved at ICU admission, while KYN, KYNA, and 3-HAA were increased by 2-10 times, compared to the physiological values. TRP decrease suggested IDO1 activation, as confirmed by the sevenfold increase of the KYN/TRP ratio. IDO1 upregulation and TRP catabolism remained unchanged during all the 7 days, as shown by constantly high KYN, KYNA, 3-HAA and KYN/TRP ratio. IS increased by 1.68 points [95%CI 1.18–2.41, P=0.006] for each twofold KYN/TRP ratio increment. KYN and its metabolites were increased in the deceased with respect to the survivors, either at ICU discharge or at 90 days (P<0.05). The univariate model showed KYN and KYNA associated to ICU discharge mortality (P<0.01), whereas KYN, KYNA and 3-HAA associated to 90-day mortality (P<0.01). The multivariate model showed KYNA associated to ICU discharge mortality (HR 1.30, [95%CI 1.10–1.54, P=0.002] for each twofold concentration increase). Moreover, KYN, KYNA and 3-HAA were independent predictors of 90-day mortality and the hazard ratios were 1.50 [95%CI 1.06–2.13, P=0.02], 1.27 [95%CI 1.08–1.49, P=0.004] and 1.23 [95%CI 1.04–1.46, P=0.02] respectively, for each twofold increase of the metabolites concentration. CONCLUSION. The KP was upregulated in septic patients. IDO1 activation was associated to the severity of sepsis-induced hypotension and KYN, KYNA and 3-HAA high concentrations were independent risk factors of mortality in septic patients.