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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.


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Panel of comparisons between mild (n = 25), moderate (n = 23) and severe AP (n = 9) participant groups for (a) C-reactive protein; (b) Amylase; (c) Modified MODS score (as described in the revised Atlanta guidelines); (d) APACHE II score. Bar charts on the left hand side of the panel represent Tminus sample means (acute presentation – pre-recruitment), while right-hand side plots depict the time-course for each variable mean per participant group. NS: not statistically significant difference; *0.05 > P > 0.01; **P < 0.01; error bars represent standard errors of the mean.
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f4: Panel of comparisons between mild (n = 25), moderate (n = 23) and severe AP (n = 9) participant groups for (a) C-reactive protein; (b) Amylase; (c) Modified MODS score (as described in the revised Atlanta guidelines); (d) APACHE II score. Bar charts on the left hand side of the panel represent Tminus sample means (acute presentation – pre-recruitment), while right-hand side plots depict the time-course for each variable mean per participant group. NS: not statistically significant difference; *0.05 > P > 0.01; **P < 0.01; error bars represent standard errors of the mean.

Mentions: A clear rise in CRP level was evident for tAP participants (standardized AUC for CRP concentration, median (IQR): hyperamylasaemia participants: 18.9 (5.75–45.4) mg/L; tAP participants: 126.0 (49.9–201.1); P < 0.001), the magnitude of which was proportionate to AP severity (Fig. 4a) and in keeping with a substantial systemic inflammatory insult (standardized AUC for CRP concentration, median (IQR): mild: 58.9 (26.3–131.2) mg/L; moderate: 148.1 (74.5–243.9) mg/L; severe: 225.6 (174.9–260.2) mg/L; P = 0.001). The acute presentation (pre-recruitment) mean CRP concentrations were higher in severe AP, but this difference was not statistically significant (CRP concentration, median (IQR): mild: 11 (5–34) mg/L; moderate: 19 (9–39) mg/L; severe: 59 (30–65) mg/L; P = 0.166) (Fig. 4a and Supplementary Table S3). Resolution of inflammation, indicated by a fall in CRP, occurred between 48 and 72 hours for the majority of patients. Conversely, serum amylase was more than three times higher than the upper limit of the normal range upon recruitment, and normalised within 24 hours for the majority of participants. There was no association between serum amylase level upon presentation and disease severity (Fig. 4b). Furthermore, mean and minimum concentrations of albumin, as well as the corresponding mean standardized AUC for albumin were significantly lower in the severe AP group (Supplementary Table S3).


Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis
Panel of comparisons between mild (n = 25), moderate (n = 23) and severe AP (n = 9) participant groups for (a) C-reactive protein; (b) Amylase; (c) Modified MODS score (as described in the revised Atlanta guidelines); (d) APACHE II score. Bar charts on the left hand side of the panel represent Tminus sample means (acute presentation – pre-recruitment), while right-hand side plots depict the time-course for each variable mean per participant group. NS: not statistically significant difference; *0.05 > P > 0.01; **P < 0.01; error bars represent standard errors of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Panel of comparisons between mild (n = 25), moderate (n = 23) and severe AP (n = 9) participant groups for (a) C-reactive protein; (b) Amylase; (c) Modified MODS score (as described in the revised Atlanta guidelines); (d) APACHE II score. Bar charts on the left hand side of the panel represent Tminus sample means (acute presentation – pre-recruitment), while right-hand side plots depict the time-course for each variable mean per participant group. NS: not statistically significant difference; *0.05 > P > 0.01; **P < 0.01; error bars represent standard errors of the mean.
Mentions: A clear rise in CRP level was evident for tAP participants (standardized AUC for CRP concentration, median (IQR): hyperamylasaemia participants: 18.9 (5.75–45.4) mg/L; tAP participants: 126.0 (49.9–201.1); P < 0.001), the magnitude of which was proportionate to AP severity (Fig. 4a) and in keeping with a substantial systemic inflammatory insult (standardized AUC for CRP concentration, median (IQR): mild: 58.9 (26.3–131.2) mg/L; moderate: 148.1 (74.5–243.9) mg/L; severe: 225.6 (174.9–260.2) mg/L; P = 0.001). The acute presentation (pre-recruitment) mean CRP concentrations were higher in severe AP, but this difference was not statistically significant (CRP concentration, median (IQR): mild: 11 (5–34) mg/L; moderate: 19 (9–39) mg/L; severe: 59 (30–65) mg/L; P = 0.166) (Fig. 4a and Supplementary Table S3). Resolution of inflammation, indicated by a fall in CRP, occurred between 48 and 72 hours for the majority of patients. Conversely, serum amylase was more than three times higher than the upper limit of the normal range upon recruitment, and normalised within 24 hours for the majority of participants. There was no association between serum amylase level upon presentation and disease severity (Fig. 4b). Furthermore, mean and minimum concentrations of albumin, as well as the corresponding mean standardized AUC for albumin were significantly lower in the severe AP group (Supplementary Table S3).

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&thinsp;=&thinsp;0.273; Spearman rho&thinsp;=&thinsp;0.581; P&thinsp;&lt;&thinsp;0.001) and CRP (R2&thinsp;=&thinsp;0.132; Spearman rho&thinsp;=&thinsp;0.455, P&thinsp;&lt;&thinsp;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.


Related in: MedlinePlus