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Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis

View Article: PubMed Central - PubMed

ABSTRACT

Inhibition of kynurenine 3-monooxygenase (KMO) protects against multiple organ dysfunction (MODS) in experimental acute pancreatitis (AP). We aimed to precisely define the kynurenine pathway activation in relation to AP and AP-MODS in humans, by carrying out a prospective observational study of all persons presenting with a potential diagnosis of AP for 90 days. We sampled peripheral venous blood at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. We measured tryptophan metabolite concentrations and analysed these in the context of clinical data and disease severity indices, cytokine profiles and C-reactive protein (CRP) concentrations. 79 individuals were recruited (median age: 59.6 years; 47 males, 59.5%). 57 met the revised Atlanta definition of AP: 25 had mild, 23 moderate, and 9 severe AP. Plasma 3-hydroxykynurenine concentrations correlated with contemporaneous APACHE II scores (R2 = 0.273; Spearman rho = 0.581; P < 0.001) and CRP (R2 = 0.132; Spearman rho = 0.455, P < 0.001). Temporal profiling showed early tryptophan depletion and contemporaneous 3-hydroxykynurenine elevation. Furthermore, plasma concentrations of 3-hydroxykynurenine paralleled systemic inflammation and AP severity. These findings support the rationale for investigating early intervention with a KMO inhibitor, with the aim of reducing the incidence and severity of AP-associated organ dysfunction.

No MeSH data available.


Plasma concentrations of tryptophan and the kynurenine pathway metabolites in tAP participants over time, grouped by AP severity according to the revised Atlanta criteria (group sizes at recruitment: mild n = 25; moderate n = 23; severe n = 9 individuals).(a) Tryptophan; (b) Kynurenine; (c) 3-hydroxykynurenine; (d) Kynurenic acid; (e) 3-hydroxyanthranilic acid; (f) 3-hydroxykynurenine to tryptophan ratio multiplied by 1000. For all panels, data points represent means and error bars represent standard errors of the mean. P-values for between-group comparisons of standardised AUC are appended. NS: not statistically significant. Dashed red lines represent healthy volunteer (n = 8) mean concentration of each metabolite.
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f5: Plasma concentrations of tryptophan and the kynurenine pathway metabolites in tAP participants over time, grouped by AP severity according to the revised Atlanta criteria (group sizes at recruitment: mild n = 25; moderate n = 23; severe n = 9 individuals).(a) Tryptophan; (b) Kynurenine; (c) 3-hydroxykynurenine; (d) Kynurenic acid; (e) 3-hydroxyanthranilic acid; (f) 3-hydroxykynurenine to tryptophan ratio multiplied by 1000. For all panels, data points represent means and error bars represent standard errors of the mean. P-values for between-group comparisons of standardised AUC are appended. NS: not statistically significant. Dashed red lines represent healthy volunteer (n = 8) mean concentration of each metabolite.

Mentions: No significant differences in peak level, mean level or standardized AUC of kynurenine, kynurenic acid, and 3-hydroxyanthranilic acid were detected among the three patient groups (Table 1). In specific, the observed difference of 3-hydroxyanthranilic acid concentration plots on Fig. 5e, although visually substantial, did not reflect a statistically significant difference, and was driven by the extreme values on two individual participants in the severe AP group.


Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis
Plasma concentrations of tryptophan and the kynurenine pathway metabolites in tAP participants over time, grouped by AP severity according to the revised Atlanta criteria (group sizes at recruitment: mild n = 25; moderate n = 23; severe n = 9 individuals).(a) Tryptophan; (b) Kynurenine; (c) 3-hydroxykynurenine; (d) Kynurenic acid; (e) 3-hydroxyanthranilic acid; (f) 3-hydroxykynurenine to tryptophan ratio multiplied by 1000. For all panels, data points represent means and error bars represent standard errors of the mean. P-values for between-group comparisons of standardised AUC are appended. NS: not statistically significant. Dashed red lines represent healthy volunteer (n = 8) mean concentration of each metabolite.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037401&req=5

f5: Plasma concentrations of tryptophan and the kynurenine pathway metabolites in tAP participants over time, grouped by AP severity according to the revised Atlanta criteria (group sizes at recruitment: mild n = 25; moderate n = 23; severe n = 9 individuals).(a) Tryptophan; (b) Kynurenine; (c) 3-hydroxykynurenine; (d) Kynurenic acid; (e) 3-hydroxyanthranilic acid; (f) 3-hydroxykynurenine to tryptophan ratio multiplied by 1000. For all panels, data points represent means and error bars represent standard errors of the mean. P-values for between-group comparisons of standardised AUC are appended. NS: not statistically significant. Dashed red lines represent healthy volunteer (n = 8) mean concentration of each metabolite.
Mentions: No significant differences in peak level, mean level or standardized AUC of kynurenine, kynurenic acid, and 3-hydroxyanthranilic acid were detected among the three patient groups (Table 1). In specific, the observed difference of 3-hydroxyanthranilic acid concentration plots on Fig. 5e, although visually substantial, did not reflect a statistically significant difference, and was driven by the extreme values on two individual participants in the severe AP group.

View Article: PubMed Central - PubMed

ABSTRACT

Inhibition of kynurenine 3-monooxygenase (KMO) protects against multiple organ dysfunction (MODS) in experimental acute pancreatitis (AP). We aimed to precisely define the kynurenine pathway activation in relation to AP and AP-MODS in humans, by carrying out a prospective observational study of all persons presenting with a potential diagnosis of AP for 90 days. We sampled peripheral venous blood at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. We measured tryptophan metabolite concentrations and analysed these in the context of clinical data and disease severity indices, cytokine profiles and C-reactive protein (CRP) concentrations. 79 individuals were recruited (median age: 59.6 years; 47 males, 59.5%). 57 met the revised Atlanta definition of AP: 25 had mild, 23 moderate, and 9 severe AP. Plasma 3-hydroxykynurenine concentrations correlated with contemporaneous APACHE II scores (R2 = 0.273; Spearman rho = 0.581; P < 0.001) and CRP (R2 = 0.132; Spearman rho = 0.455, P < 0.001). Temporal profiling showed early tryptophan depletion and contemporaneous 3-hydroxykynurenine elevation. Furthermore, plasma concentrations of 3-hydroxykynurenine paralleled systemic inflammation and AP severity. These findings support the rationale for investigating early intervention with a KMO inhibitor, with the aim of reducing the incidence and severity of AP-associated organ dysfunction.

No MeSH data available.