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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.


(a) Cumulative number of enrolled participants per calendar day of the recruitment phase of the study. Solid line: overall study participants; dashed line; tAP participants. (b) Box & whiskers plot of the time interval from patient presentation to hospital to study recruitment, in minutes. Blue box: overall study participants; red box tAP participants. Boxes: 1st and 3rd quartile; horizontal lines: median values; error bars:1st and 9th deciles; dots: outlying values beyond 1st and 9th decile.
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f3: (a) Cumulative number of enrolled participants per calendar day of the recruitment phase of the study. Solid line: overall study participants; dashed line; tAP participants. (b) Box & whiskers plot of the time interval from patient presentation to hospital to study recruitment, in minutes. Blue box: overall study participants; red box tAP participants. Boxes: 1st and 3rd quartile; horizontal lines: median values; error bars:1st and 9th deciles; dots: outlying values beyond 1st and 9th decile.

Mentions: A total of 79 patients were recruited, 57 patients (72.2%) of whom were diagnosed with AP in accordance with the revised Atlanta guidelines (“true AP” – tAP). Of the 57 tAP patients, 10 had an amylase level below 300 upon presentation, and either a subsequent amylase rise or a confirmation of AP by imaging. The demographic characteristics of the study participants are summarized in Supplementary Table S1, and a CONSORT diagram is shown in Fig. 2. There was no effect of day of the week (P = 0.317) or time of day (P = 0.397) on recruitment. Moreover, time of day for recruitment (T0) followed a random distribution. The cumulative frequency of participant enrolment by calendar day of the recruitment phase and the relative frequency of enrolment by weekday are shown in Fig. 3a and Supplementary Table S2, respectively. No systematic bias was present for the twenty-nine potentially eligible patients that were not recruited. Thirty patients declined to participate, of whom 12 had AP and 3 required admission to critical care. One male participant formally withdrew from the study within 12 hours from recruitment.


Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis
(a) Cumulative number of enrolled participants per calendar day of the recruitment phase of the study. Solid line: overall study participants; dashed line; tAP participants. (b) Box & whiskers plot of the time interval from patient presentation to hospital to study recruitment, in minutes. Blue box: overall study participants; red box tAP participants. Boxes: 1st and 3rd quartile; horizontal lines: median values; error bars:1st and 9th deciles; dots: outlying values beyond 1st and 9th decile.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: (a) Cumulative number of enrolled participants per calendar day of the recruitment phase of the study. Solid line: overall study participants; dashed line; tAP participants. (b) Box & whiskers plot of the time interval from patient presentation to hospital to study recruitment, in minutes. Blue box: overall study participants; red box tAP participants. Boxes: 1st and 3rd quartile; horizontal lines: median values; error bars:1st and 9th deciles; dots: outlying values beyond 1st and 9th decile.
Mentions: A total of 79 patients were recruited, 57 patients (72.2%) of whom were diagnosed with AP in accordance with the revised Atlanta guidelines (“true AP” – tAP). Of the 57 tAP patients, 10 had an amylase level below 300 upon presentation, and either a subsequent amylase rise or a confirmation of AP by imaging. The demographic characteristics of the study participants are summarized in Supplementary Table S1, and a CONSORT diagram is shown in Fig. 2. There was no effect of day of the week (P = 0.317) or time of day (P = 0.397) on recruitment. Moreover, time of day for recruitment (T0) followed a random distribution. The cumulative frequency of participant enrolment by calendar day of the recruitment phase and the relative frequency of enrolment by weekday are shown in Fig. 3a and Supplementary Table S2, respectively. No systematic bias was present for the twenty-nine potentially eligible patients that were not recruited. Thirty patients declined to participate, of whom 12 had AP and 3 required admission to critical care. One male participant formally withdrew from the study within 12 hours from recruitment.

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.