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

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

Influence of core body temperature on Tryptophan metabolism, kynurenines, and estimated IDO activity in critically ill patients receiving target temperature management following cardiac arrest.

BACKGROUND/AIMS Temperature control improves neurological prognosis in comatose cardiac arrest (CA) survivors. Previous reports demonstrate that most affected patients show signs of significant systemic inflammation. In an effort to better characterize potential temperature-related effects on key inflammatory pathways, we investigate the course of Tryptophan (Trp) levels, Tryptophan catabolites (including kynurenines) and indoleamine-2,3-dioxygenase (IDO)-activity in post CA patients. MATERIAL/METHODS In an observational blinded endpoint analysis, a total of n=270 serial samples from 20 post CA patients (63.1±16.6 yrs., 45% shockable rhythm, mean time to return of spontaneous circulation (ROSC) 26.6±16.0min) treated with target temperature management (TTM) were analyzed. Core body temperatures, course of Trp, Trp catabolites (incl. kynurenines), and estimated IDO-activity were followed up for a maximum of 7 days after ROSC. Patients were followed up until hospital discharge or death and functional outcome was recorded. RESULTS Over the 7-day observational interval, marked changes in Trp serum levels and IDO-activity were noted. In general, Trp serum levels but not IDO-activity seemed to parallel with the course of core body temperature. In explorative analyses, a correlation of Trp (rho=0.271 (95%-CI: 0.16-0.38, p<0.0001) and IDO-activity (rho=-0.155, 95%-CI: -0.27 to -0.037, p=0.01) with core body temperature was observed. Linear mixed effect models revealed a positive significant association of core body temperature with Trp serum levels (Likelihood ratio test χ(2)=6.35, p=0.012). In patients with good (vs. unfavorable) outcome, a tendency toward higher Trp serum levels, lower IDO-activity, and lower Kynurenic acid levels was noted. CONCLUSIONS We observed significant changes in Trp catabolism and IDO-activity that appeared temperature associated in post CA patients. Under hypothermia, decreased serum levels of Trp and increased IDO-activity were noted. We speculate from our data that IDO-induction during hypothermia contributes to the previously described increased susceptibility to infection or sepsis under reduced temperatures