Excessive Tryptophan Catabolism Along the Kynurenine Pathway Precedes Ongoing Sepsis in Critically Ill Patients

Abstract

It has recently been shown that an increased plasma level of the tryptophan catabolite kynurenine is an early indicator for the development of sepsis in major trauma patients. We examined the predictive value of kynurenine pathway activity for ongoing sepsis in patients being admitted to a surgical intensive care unit for different reasons. In addition, we asked whether an accumulation of kynurenines in patients' plasma depends on reduced renal clearance. We conducted a prospective observational study including 100 consecutive patients and monitored laboratory variables, physiological and adverse events, sepsis and outcome. Using tandem mass spectrometry, we quantified the five indoleamines tryptophan, serotonin (5-HT), kynurenine, quinolinic acid and kynurenic acid at baseline and twice a week during the intensive care unit stay. Among the patients enrolled, 50 did not develop sepsis in the intensive care unit (non-septic), 18 patients did not have sepsis at baseline but developed sepsis later on (preseptic) and 32 patients already fulfilled the criteria of severe sepsis and septic shock at baseline (septic). In general, non-septic critically ill patients showed activation of the kynurenine pathway, but septic shock coincided with an exacerbation of kynurenine pathway activity even in the absence of renal failure. Importantly, plasma concentrations of quinolinic acid (area under the curve 0.832 [95% confidence interval 0.710 to 0.954]) and the Quin/Trp ratio (area under the curve 0.835 [95% confidence interval; 0.719 to 0.952]) showed the best discrimination between non-septic and pre-septic patients at baseline. These findings open new avenues for further investigations on the pathophysiology of sepsis.

Plasma Kynurenic Acid Concentration in Patients Undergoing Cardiac Surgery: Effect of Anaesthesia

“…KYNA has been also suggested as a marker of distress intolerance (Chiapelli et al 2014). Noteworthy, increasing plasma KYNA concentration might predispose to sepsis and septic shock in patients after multi trauma and its level is related to sseverity of infection (Dabrowski et al 2014; Schefold et al 2009; Zeden et al 2010). All of the above-mentioned pathologies may complicate early postoperative period in cardiac surgery patients.…”

“…Raised blood KYNA has been found in septic patients (Dabrowski et al 2014; Schefold et al 2009; Zeden et al 2010), HIV-1 infection (Heyes et al 1992), chronic kidney disease (Schefold et al 2009), stroke patients (Darlington et al 2007), after severe brain injury (Mackay et al 2006) and cardiac arrest (Ristagno et al 2013). Moreover, increased salivary KYNA concentration has been observed after acute physiological stress (Chiapelli et al 2014).…”

“…Moreover, a lot of studies underline the neuroprotective properties of KYNA in animals with experimental brain injury (Darlington et al 2007; Gellért et al 2013; Sas et al 2008). KYNA production is also elevated during a bacterial or viral inflammation, an autoimmune disease and after a severe trauma (Forrest et al 2006; Hartai et al 2007; Scott et al 2009; Zeden et al 2010). Increases in plasma tryptophan metabolites have also been observed in patients undergoing elective abdominal or cardiac surgery (Forrest et al 2011; Marfella et al 1999).…”

Increased serum levels of quinolinic acid indicate enhanced severity of hepatic dysfunction in patients with liver cirrhosis

“…The neurotoxic capacity of QuinA in vivo has implicated it in a variety of neurodegenerative disorders, including Huntington's disease [23,26,27] and Alzheimer's disease [28]. Moreover, QuinA is increased in clinical conditions such as renal dysfunction [29] and sepsis [30][31][32].…”

Strong association of phenylalanine and tryptophan metabolites with activated cytomegalovirus infection in kidney transplant recipients

“…Zeden et al conducted a prospective study quantifying tryptophan and its metabolites. Their results demonstrated that plasma concentrations of quinolinic acid and the quinolinic acid/tryptophan ratio displayed the best discrimination between nonseptic and preseptic patients [15].…”