ORIGINAL ARTICLE
Urinary Neutrophil Gelatinase–Associated Lipocalin as an Early Predictor of Disease Severity and Mortality in Acute Pancreatitis Michal Lipinski, MD, PhD,* Alicja Rydzewska-Rosolowska, MD, PhD,† Andrzej Rydzewski, MD, PhD,‡§ and Grazyna Rydzewska, MD, PhD*§ Objectives: In reference to our earlier publication, laboratory tests that reflect severe intravascular volume depletion can be used for predicting the severity of acute pancreatitis (AP). The aim of the study was to assess whether urinary level of neutrophil gelatinase–associated lipocalin (NGAL) could represent a useful marker of AP severity. Methods: We observed a cohort of 104 prospectively enrolled patients. The patients were classified into 3 groups: mild AP, moderately severe AP, and severe AP. Urine samples were collected on admission (NGAL-as) and during the first 24 hours (NGAL-first day) for examination of urinary level of NGAL concentrations from the first day. Results: Acute pancreatitis was considered severe in 16 (15%) patients, moderately severe in 25 (24%) patients, and mild in 63 (61%) patients. There were statistically significant trends for an increase in severity (P = 0.04, P = 0.003) and mortality (P < 0.031, P = 0.01) with raising NGAL-as and NGAL-first day concentrations, respectively. The areas under the curve for severity predicted by NGAL-as and NGAL-first day were 0.75 and 0.93, respectively. The areas under the curve for mortality prediction by NGAL-as and NGAL-first day were 0.980 and 0.92, respectively. Conclusions: The urinary level of NGAL is a promising new diagnostic and prognostic factor for severe AP in an early stage of the disease. Key Words: acute pancreatitis, prediction, NGAL, mortality (Pancreas 2015;44: 448–452)
A
cute pancreatitis (AP) is a common, usually self-limiting disease; although in some cases, it may affect surrounding tissues and distant organs. Patients with early signs of organ failure are at particularly high risk of death due to AP.1–4 Improvement of outcome in severe AP (SAP) depends on early identification of patients with poor prognosis, treatment under intensive care unit (ICU) conditions, early administration of enteral nutrition,5 as well as considering endoscopic retrograde cholangiopancreatography in patients with gallstone-induced disease. Many factors [ie, C-reactive protein (CRP), procalcitonin, interleukin, D-dimer, estimated glomerular filtration rate (eGFR)] have been evaluated with respect to their value for prediction of AP severity.6 C-reactive protein, one of the most recognized and frequently assessed parameters, is nonspecific for AP and its elevation is observed after 48 hours from the onset of symptoms, whereas the first 2 days of the disease are critical for implementation of appropriate fluid therapy and endoscopy. Therefore, it From the *Department of Gastroenterology, Central Clinical Hospital of the Ministry of Interior, Warsaw; †Department of Nephrology and Transplantation, Medical University of Bialystok, Bialystok; ‡Department of Internal Medicine and Nephrology, Central Clinical Hospital of the Ministry of Interior, Warsaw; and §Faculty of Health Sciences, Uniwersytet Jana Kochanowskiego w Kielcach, Kielce, Poland. Received for publication March 29, 2014; accepted September 24, 2014. Reprints: Michal Lipinski, MD, PhD, Department of Gastroenterology, Central Clinical Hospital of the Ministry of Interior, 137 Woloska Str, 02-507 Warsaw, Poland (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
448
www.pancreasjournal.com
would be advantageous to identify a rapid marker that could effectively predict severity of the disease in its early stage. The need for a new marker for predicting the course of pancreatitis is even greater since the revision of Atlanta classification of AP in 2012,7 which introduced new criteria, puts greater emphasis on prognostic factors. Prediction of organ failure persisting more than 48 hours has become very important, as it determines the diagnosis of SAP. Neutrophil gelatinase–associated lipocalin (NGAL) is a 24-kd glycoprotein released from activated neutrophils in inflamed tissue. Neutrophil gelatinase–associated lipocalin expression is markedly induced in injured epithelia, including those of proximal collecting tubule. Previous studies showed that NGAL is a sensitive marker of ischemic damage to renal tubular epithelium and thereby indicate NGAL as an early predictor of acute kidney injury (AKI).8,9 Acute renal failure is present in 14% to 16% cases of AP10,11 and is associated with poor prognosis, particularly in older patients and those with multiorgan failure (MOF) or local pancreatic complications. Mortality rate in AP accompanied by acute renal failure is as high as 81%.12,13 It is worth emphasizing that, in the assessment of AP prognosis, there is a tendency to take into consideration factors reflecting intravascular volume depletion (serum urea nitrogen, serum creatinine, eGFR, and hematocrit), which often accompanies the first hours of AP. Parameters assessing hypovolemia can be used either as isolated prognostic factors or be included in multifactorial prognostic scales. High serum creatinine and eGFR reduction are already known as unfavorable prognostic factors in AP.6,14 However, urine level of NGAL (uNGAL), a parameter reflecting renal dysfunction more accurately and at earlier stage of the disease, has never been evaluated as a predictor of AP severity in humans. The aim of the study was to assess whether uNGAL could represent a useful marker of AP severity.
MATERIALS AND METHODS We performed an observational cohort study of 104 prospectively enrolled patients (68 men and 36 women; median age, 51 years; range, 20–92 years). Informed consent was obtained from all patients before enrollment into the study. All patients admitted to the Department of Gastroenterology of the Central Clinical Hospital of the Ministry of Interior (Poland) with a diagnosis of AP and disease onset within the last 48 hours were recruited within 24 hours from the time of admission (n = 104). The following exclusion criteria were applied: chronic kidney disease and time from appearance of first symptoms to admission exceeding 48 hours. The diagnosis was established based on the presence of 2 of the following 3 features: (1) abdominal pain typical of AP; (2) serum lipase and/or amylase 3 or more times the upper normal limit; and (3) ultrasonography, computed tomography, or magnetic resonance imaging findings suggesting AP. On the basis of the presence of persistent organ failure (more than 48 hours) as a criterion for the diagnosis of SAP, and local complications Pancreas • Volume 44, Number 3, April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 3, April 2015
uNGAL in Prediction of AP Severity
[diagnosis of moderately severe AP (MSAP)], patients were classified into 3 groups as follows: mild AP (MAP), MSAP, and SAP. Organ failure was identified using Modified Marshall Scoring System. If failure involved more than 1 organ, the case was classified as MOF. Urine samples obtained on admission (NGAL-as) and from 24-hour urine collections (NGAL-first day) were gathered for determination of uNGAL concentrations from the first day. The uNGAL assays were performed using a standardized clinical platform (ARCHITECT analyzer). The ARCHITECT assay was characterized by functional sensitivity less than 2 ng/ml [20% coefficient of variation, 95% confidence interval (CI)].15 BISAP score was determined in all patients within the first 24 hours from admission. Value of uNGAL and BISAP score for prediction of clinical outcome was evaluated by receiver operating characteristic (ROC) curve analysis. The risk score was developed using a logistic regression model. P < 0.05 was considered statistically significant. The study was approved by the Ethics Committee of the Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland (reference code: 39/2011).
RESULTS A total of 104 patients with AP (68 men and 36 women; median age, 51 years; range, 20–92 years) were included in the study. Acute pancreatitis was considered severe in 16 (15%) patients, MSAP was found in 25 (24%) patients, and MAP in 63 (61%) patients, according to the criteria outlined in the methodology section. The etiology of AP was biliary in 42 (40%) patients, alcoholic in 42 (40%) patients, and other cause (post– endoscopic retrograde cholangiopancreatography, idiopathic, hereditary, etc) in 14 (14%) patients (Table 1). In multivariate analysis, odds ratio (OR) for SAP significantly increased with raising concentrations (per 100-U increase) of both NGAL-as (OR, 2.34; 95% CI, 1.04–5.29; P = 0.04) and NGAL-first day (OR, 1.74; 95% CI, 1.2–2.53; P = 0.003). Eight of 104 patients developed MOF. A multivariate analysis of MOF predictors identified increase (per 100 U) in NGAL-as (OR, 4.78; 95% CI, 1.33–17.3; P = 0.016) and NGAL-first day (OR, 1.78; 95% CI, 1.15–2.75; P = 0.009) as significant predictors. In our study, 8 (7.7%) patients with AP died in the course of the disease. Rise in concentration of NGAL by 100 U was associated with nearly 4-fold increase in risk of fatal AP when measured in a urine sample at the time of admission to hospital (OR, 3.96; 95% CI, 1.13–13.8; P = 0.031) and nearly 2-fold increase in risk
FIGURE 1. NGAL-as level in prediction of SAP. AUC, 0.75; the cutoff value is 68.9 ng/mL.
of fatal AP if measurements were carried out in urine samples collected during 24 hours on the first day of hospitalization (OR, 1.59; 95% CI, 1.11–2.26; P = 0.01). The optimal cutoff point for urine NGAL concentration that distinguished SAP from MSAP and MAP was determined by constructing a ROC curve. In ROC analysis, AUCs for NGAL-as and NGAL-first day were 0.75 (95% CI, 0.622–0.890) and 0.93 (95% CI, 0.882–0.988), respectively (Figs. 1 and 2). BISAP score of 3 or greater for detection of SAP had sensitivity and specificity of 68.5% and 95.4%, respectively. The AUC for severity predicted by BISAP amounted to 0.95 (95% CI, 0.915–0.987). The optimal cutoff point for discriminating between SAP and MSAP/MAP using NGAL-as concentration was 68.9 ng/mL with sensitivity of 81.2% and specificity of 71.5%. Moreover, for NGAL-first day, the optimal cutoff point was 73 ng/mL with 87.5% sensitivity and 85.2% specificity. For a cutoff value of greater than 51.5 ng/mL, NGAL-as had 78% sensitivity and 62% specificity for predicting MSAP (AUC, 0.713; 95% CI, 0.611–0.816). NGAL-first day of 30.6 ng/mL was chosen as an optimal cutoff point to distinguish MSAP from MAP, and the sensitivity and specificity were 95% and 92%, respectively (AUC, 0.9714; 95% CI, 0.937–1.000). Using the area under ROC curve, we determined the ability of urine NGAL levels to predict MOF. We identified the optimal
TABLE 1. Characteristics of Patients With AP Included in the Study Variable
All Patients, n = 104
Age (median age; range), y Sex (male/female) BMI (SD) SAP, n (%) MSAP, n (%) MAP, n (%) Etiology (% of total) Gallstones Alcohol Other causes (post-ERCP, idiopathic, hereditary, etc)
51; 20–92 68/36 26.8 (5) 16 (15) 25 (24) 63 (61) 42 (40) 42 (40) 14 (14)
BMI indicates body mass index; ERCP, endoscopic retrograde cholangiopancreatography.
© 2014 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 2. NGAL-first day level in prediction of SAP. AUC, 0.93; the cutoff value is 73 ng/mL. www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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TABLE 2. Results of ROC Analysis of NGAL-as, NGAL-First Day, and BISAP Score and Optimal Cutoff Levels (ng/mL) for Discrimination Between MSAP, SAP, and Fatal AP
MSAP SAP Fatal AP
FIGURE 3. NGAL-as in prediction of fatal AP. AUC, 0.80; the cutoff value is 86.5 ng/mL.
cutoff point for NGAL urine concentration at the time of admission at 86.5 ng/mL (AUC, 0.87; 95% CI, 0.779–0.964) with sensitivity and specificity of 75% and 76%, respectively. Calculated cutoff level of NGAL-first day with optimal sensitivity and specificity (87.5% and 95.8%, respectively) was 176 ng/mL (AUC, 0.967; 95% CI, 0.932–1.000). The ROC curve analysis showed also that AUC for NGAL-as with regard to prediction of death among patients with AP was 0.80 (95% CI, 0.632–0.968). The optimal cutoff point was established at 86.5 ng/mL with sensitivity of 75% and specificity of 74%, respectively (Fig. 3). Furthermore, ROC analysis recognized the optimal NGAL-first day level identifying patients with fatal AP at 93.8 ng/mL (AUC, 0.927; 95% CI, 0.839–1.000). Sensitivity and specificity were 87.5% and 87.5%, respectively (Fig. 4). Accuracy of death prediction in AP patients based on BISAP score 3 or greater was 0.927 (95% CI, 0.869–0.984), with sensitivity and specificity of 75% and 90.6%, respectively (Table 2).
DISCUSSION Early identification of SAP is essential for improving treatment outcomes in this disease. One of the studies demonstrated that patients with a 24-hour delay in admission to the ICU presented with a 4-fold increase in the risk of death.16 Prediction of
FIGURE 4. NGAL-first day in prediction of fatal AP. AUC, 0.92; the cutoff value is 93.8 ng/mL.
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NGAL-as
NGAL-First Day
BISAP ≥ 3
0.71 (51.5) 0.75 (68.9) 0.80 (86.5)
0.97 (30.6) 0.93 (73) 0.92 (93.8)
0.95 0.92
prognosis in AP, especially during the first 24 hours, is still difficult and constitutes a challenge for clinicians. Accurate, early determination of AP course ensures a timely and appropriate therapeutic intervention. Therefore, there is an urgent need to find a simple parameter or scale, which would indeed predict the outcome at an early phase of the disease. Unfortunately, such an ideal marker of AP course is not yet accessible.17 Many studies have confirmed the possibility of using some interleukins,18,19 coagulation abnormalities,20 and procalcitonin21 in predicting the severity of AP. In most hospitals, the high cost and lack of access to analytical methods significantly reduce the common use of proinflammatory cytokines as markers of AP. For these reasons, CRP is still regarded as one of the most accurate single prognostic parameters in AP. Synthesis of CRP by hepatocytes is induced by the release of interleukin-1 and -6, and therefore the peak of serum CRP is usually observed at 48 hours after the onset of pain. These characteristics call into question the term “early prognostic marker” used to describe CRP. Acute kidney injury is one of the most common complications of AP. Hypoperfusion plays a major role in the pathogenesis not only of AKI but also of MOF,22,23 which are the main causes of death in SAP. Therefore, pathophysiological role of hypovolemia in determination of AP severity is crucial. It is worth emphasizing that indicators of hypoperfusion and hypovolemia (serum creatinine, eGFR, serum urea nitrogen, and hematocrit) constitute valuable prognostic factors as early as on the first day of the disease.6,14,24,25 Acute kidney injury is induced by ischemia and reperfusion injury, in which neutrophil infiltration is considered to be an important and decisive early event. Neutrophil gelatinase–associated lipocalin was previously recognized as a marker of kidney disease—AKI in particular,26 as well as cardiac27 and oncological diseases.28 To date, studies have focused on assessing the accuracy of NGAL in predicting AP course depending on serum concentrations in humans29 or were carried out on animals.30 The results of those studies confirm the potential for using NGAL to predict AP. Urinary NGAL concentration has never been evaluated as a predictor in AP. Intention to test these studies is interesting, as some studies have shown that in certain diseases, concentration of NGAL in urine is several times higher than in serum.31 Low concentration of NGAL in serum is typical under physiological conditions, because the glomeruli filter and proximal tubes reabsorb circulating NGAL. Normal urinary level of NGAL is very low (
Urinary Neutrophil Gelatinase–Associated Lipocalin as an Early Predictor of Disease Severity and Mortality in Acute Pancreatitis Michal Lipinski, MD, PhD,* Alicja Rydzewska-Rosolowska, MD, PhD,† Andrzej Rydzewski, MD, PhD,‡§ and Grazyna Rydzewska, MD, PhD*§ Objectives: In reference to our earlier publication, laboratory tests that reflect severe intravascular volume depletion can be used for predicting the severity of acute pancreatitis (AP). The aim of the study was to assess whether urinary level of neutrophil gelatinase–associated lipocalin (NGAL) could represent a useful marker of AP severity. Methods: We observed a cohort of 104 prospectively enrolled patients. The patients were classified into 3 groups: mild AP, moderately severe AP, and severe AP. Urine samples were collected on admission (NGAL-as) and during the first 24 hours (NGAL-first day) for examination of urinary level of NGAL concentrations from the first day. Results: Acute pancreatitis was considered severe in 16 (15%) patients, moderately severe in 25 (24%) patients, and mild in 63 (61%) patients. There were statistically significant trends for an increase in severity (P = 0.04, P = 0.003) and mortality (P < 0.031, P = 0.01) with raising NGAL-as and NGAL-first day concentrations, respectively. The areas under the curve for severity predicted by NGAL-as and NGAL-first day were 0.75 and 0.93, respectively. The areas under the curve for mortality prediction by NGAL-as and NGAL-first day were 0.980 and 0.92, respectively. Conclusions: The urinary level of NGAL is a promising new diagnostic and prognostic factor for severe AP in an early stage of the disease. Key Words: acute pancreatitis, prediction, NGAL, mortality (Pancreas 2015;44: 448–452)
A
cute pancreatitis (AP) is a common, usually self-limiting disease; although in some cases, it may affect surrounding tissues and distant organs. Patients with early signs of organ failure are at particularly high risk of death due to AP.1–4 Improvement of outcome in severe AP (SAP) depends on early identification of patients with poor prognosis, treatment under intensive care unit (ICU) conditions, early administration of enteral nutrition,5 as well as considering endoscopic retrograde cholangiopancreatography in patients with gallstone-induced disease. Many factors [ie, C-reactive protein (CRP), procalcitonin, interleukin, D-dimer, estimated glomerular filtration rate (eGFR)] have been evaluated with respect to their value for prediction of AP severity.6 C-reactive protein, one of the most recognized and frequently assessed parameters, is nonspecific for AP and its elevation is observed after 48 hours from the onset of symptoms, whereas the first 2 days of the disease are critical for implementation of appropriate fluid therapy and endoscopy. Therefore, it From the *Department of Gastroenterology, Central Clinical Hospital of the Ministry of Interior, Warsaw; †Department of Nephrology and Transplantation, Medical University of Bialystok, Bialystok; ‡Department of Internal Medicine and Nephrology, Central Clinical Hospital of the Ministry of Interior, Warsaw; and §Faculty of Health Sciences, Uniwersytet Jana Kochanowskiego w Kielcach, Kielce, Poland. Received for publication March 29, 2014; accepted September 24, 2014. Reprints: Michal Lipinski, MD, PhD, Department of Gastroenterology, Central Clinical Hospital of the Ministry of Interior, 137 Woloska Str, 02-507 Warsaw, Poland (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
448
www.pancreasjournal.com
would be advantageous to identify a rapid marker that could effectively predict severity of the disease in its early stage. The need for a new marker for predicting the course of pancreatitis is even greater since the revision of Atlanta classification of AP in 2012,7 which introduced new criteria, puts greater emphasis on prognostic factors. Prediction of organ failure persisting more than 48 hours has become very important, as it determines the diagnosis of SAP. Neutrophil gelatinase–associated lipocalin (NGAL) is a 24-kd glycoprotein released from activated neutrophils in inflamed tissue. Neutrophil gelatinase–associated lipocalin expression is markedly induced in injured epithelia, including those of proximal collecting tubule. Previous studies showed that NGAL is a sensitive marker of ischemic damage to renal tubular epithelium and thereby indicate NGAL as an early predictor of acute kidney injury (AKI).8,9 Acute renal failure is present in 14% to 16% cases of AP10,11 and is associated with poor prognosis, particularly in older patients and those with multiorgan failure (MOF) or local pancreatic complications. Mortality rate in AP accompanied by acute renal failure is as high as 81%.12,13 It is worth emphasizing that, in the assessment of AP prognosis, there is a tendency to take into consideration factors reflecting intravascular volume depletion (serum urea nitrogen, serum creatinine, eGFR, and hematocrit), which often accompanies the first hours of AP. Parameters assessing hypovolemia can be used either as isolated prognostic factors or be included in multifactorial prognostic scales. High serum creatinine and eGFR reduction are already known as unfavorable prognostic factors in AP.6,14 However, urine level of NGAL (uNGAL), a parameter reflecting renal dysfunction more accurately and at earlier stage of the disease, has never been evaluated as a predictor of AP severity in humans. The aim of the study was to assess whether uNGAL could represent a useful marker of AP severity.
MATERIALS AND METHODS We performed an observational cohort study of 104 prospectively enrolled patients (68 men and 36 women; median age, 51 years; range, 20–92 years). Informed consent was obtained from all patients before enrollment into the study. All patients admitted to the Department of Gastroenterology of the Central Clinical Hospital of the Ministry of Interior (Poland) with a diagnosis of AP and disease onset within the last 48 hours were recruited within 24 hours from the time of admission (n = 104). The following exclusion criteria were applied: chronic kidney disease and time from appearance of first symptoms to admission exceeding 48 hours. The diagnosis was established based on the presence of 2 of the following 3 features: (1) abdominal pain typical of AP; (2) serum lipase and/or amylase 3 or more times the upper normal limit; and (3) ultrasonography, computed tomography, or magnetic resonance imaging findings suggesting AP. On the basis of the presence of persistent organ failure (more than 48 hours) as a criterion for the diagnosis of SAP, and local complications Pancreas • Volume 44, Number 3, April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 3, April 2015
uNGAL in Prediction of AP Severity
[diagnosis of moderately severe AP (MSAP)], patients were classified into 3 groups as follows: mild AP (MAP), MSAP, and SAP. Organ failure was identified using Modified Marshall Scoring System. If failure involved more than 1 organ, the case was classified as MOF. Urine samples obtained on admission (NGAL-as) and from 24-hour urine collections (NGAL-first day) were gathered for determination of uNGAL concentrations from the first day. The uNGAL assays were performed using a standardized clinical platform (ARCHITECT analyzer). The ARCHITECT assay was characterized by functional sensitivity less than 2 ng/ml [20% coefficient of variation, 95% confidence interval (CI)].15 BISAP score was determined in all patients within the first 24 hours from admission. Value of uNGAL and BISAP score for prediction of clinical outcome was evaluated by receiver operating characteristic (ROC) curve analysis. The risk score was developed using a logistic regression model. P < 0.05 was considered statistically significant. The study was approved by the Ethics Committee of the Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland (reference code: 39/2011).
RESULTS A total of 104 patients with AP (68 men and 36 women; median age, 51 years; range, 20–92 years) were included in the study. Acute pancreatitis was considered severe in 16 (15%) patients, MSAP was found in 25 (24%) patients, and MAP in 63 (61%) patients, according to the criteria outlined in the methodology section. The etiology of AP was biliary in 42 (40%) patients, alcoholic in 42 (40%) patients, and other cause (post– endoscopic retrograde cholangiopancreatography, idiopathic, hereditary, etc) in 14 (14%) patients (Table 1). In multivariate analysis, odds ratio (OR) for SAP significantly increased with raising concentrations (per 100-U increase) of both NGAL-as (OR, 2.34; 95% CI, 1.04–5.29; P = 0.04) and NGAL-first day (OR, 1.74; 95% CI, 1.2–2.53; P = 0.003). Eight of 104 patients developed MOF. A multivariate analysis of MOF predictors identified increase (per 100 U) in NGAL-as (OR, 4.78; 95% CI, 1.33–17.3; P = 0.016) and NGAL-first day (OR, 1.78; 95% CI, 1.15–2.75; P = 0.009) as significant predictors. In our study, 8 (7.7%) patients with AP died in the course of the disease. Rise in concentration of NGAL by 100 U was associated with nearly 4-fold increase in risk of fatal AP when measured in a urine sample at the time of admission to hospital (OR, 3.96; 95% CI, 1.13–13.8; P = 0.031) and nearly 2-fold increase in risk
FIGURE 1. NGAL-as level in prediction of SAP. AUC, 0.75; the cutoff value is 68.9 ng/mL.
of fatal AP if measurements were carried out in urine samples collected during 24 hours on the first day of hospitalization (OR, 1.59; 95% CI, 1.11–2.26; P = 0.01). The optimal cutoff point for urine NGAL concentration that distinguished SAP from MSAP and MAP was determined by constructing a ROC curve. In ROC analysis, AUCs for NGAL-as and NGAL-first day were 0.75 (95% CI, 0.622–0.890) and 0.93 (95% CI, 0.882–0.988), respectively (Figs. 1 and 2). BISAP score of 3 or greater for detection of SAP had sensitivity and specificity of 68.5% and 95.4%, respectively. The AUC for severity predicted by BISAP amounted to 0.95 (95% CI, 0.915–0.987). The optimal cutoff point for discriminating between SAP and MSAP/MAP using NGAL-as concentration was 68.9 ng/mL with sensitivity of 81.2% and specificity of 71.5%. Moreover, for NGAL-first day, the optimal cutoff point was 73 ng/mL with 87.5% sensitivity and 85.2% specificity. For a cutoff value of greater than 51.5 ng/mL, NGAL-as had 78% sensitivity and 62% specificity for predicting MSAP (AUC, 0.713; 95% CI, 0.611–0.816). NGAL-first day of 30.6 ng/mL was chosen as an optimal cutoff point to distinguish MSAP from MAP, and the sensitivity and specificity were 95% and 92%, respectively (AUC, 0.9714; 95% CI, 0.937–1.000). Using the area under ROC curve, we determined the ability of urine NGAL levels to predict MOF. We identified the optimal
TABLE 1. Characteristics of Patients With AP Included in the Study Variable
All Patients, n = 104
Age (median age; range), y Sex (male/female) BMI (SD) SAP, n (%) MSAP, n (%) MAP, n (%) Etiology (% of total) Gallstones Alcohol Other causes (post-ERCP, idiopathic, hereditary, etc)
51; 20–92 68/36 26.8 (5) 16 (15) 25 (24) 63 (61) 42 (40) 42 (40) 14 (14)
BMI indicates body mass index; ERCP, endoscopic retrograde cholangiopancreatography.
© 2014 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 2. NGAL-first day level in prediction of SAP. AUC, 0.93; the cutoff value is 73 ng/mL. www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Lipinski et al
TABLE 2. Results of ROC Analysis of NGAL-as, NGAL-First Day, and BISAP Score and Optimal Cutoff Levels (ng/mL) for Discrimination Between MSAP, SAP, and Fatal AP
MSAP SAP Fatal AP
FIGURE 3. NGAL-as in prediction of fatal AP. AUC, 0.80; the cutoff value is 86.5 ng/mL.
cutoff point for NGAL urine concentration at the time of admission at 86.5 ng/mL (AUC, 0.87; 95% CI, 0.779–0.964) with sensitivity and specificity of 75% and 76%, respectively. Calculated cutoff level of NGAL-first day with optimal sensitivity and specificity (87.5% and 95.8%, respectively) was 176 ng/mL (AUC, 0.967; 95% CI, 0.932–1.000). The ROC curve analysis showed also that AUC for NGAL-as with regard to prediction of death among patients with AP was 0.80 (95% CI, 0.632–0.968). The optimal cutoff point was established at 86.5 ng/mL with sensitivity of 75% and specificity of 74%, respectively (Fig. 3). Furthermore, ROC analysis recognized the optimal NGAL-first day level identifying patients with fatal AP at 93.8 ng/mL (AUC, 0.927; 95% CI, 0.839–1.000). Sensitivity and specificity were 87.5% and 87.5%, respectively (Fig. 4). Accuracy of death prediction in AP patients based on BISAP score 3 or greater was 0.927 (95% CI, 0.869–0.984), with sensitivity and specificity of 75% and 90.6%, respectively (Table 2).
DISCUSSION Early identification of SAP is essential for improving treatment outcomes in this disease. One of the studies demonstrated that patients with a 24-hour delay in admission to the ICU presented with a 4-fold increase in the risk of death.16 Prediction of
FIGURE 4. NGAL-first day in prediction of fatal AP. AUC, 0.92; the cutoff value is 93.8 ng/mL.
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NGAL-as
NGAL-First Day
BISAP ≥ 3
0.71 (51.5) 0.75 (68.9) 0.80 (86.5)
0.97 (30.6) 0.93 (73) 0.92 (93.8)
0.95 0.92
prognosis in AP, especially during the first 24 hours, is still difficult and constitutes a challenge for clinicians. Accurate, early determination of AP course ensures a timely and appropriate therapeutic intervention. Therefore, there is an urgent need to find a simple parameter or scale, which would indeed predict the outcome at an early phase of the disease. Unfortunately, such an ideal marker of AP course is not yet accessible.17 Many studies have confirmed the possibility of using some interleukins,18,19 coagulation abnormalities,20 and procalcitonin21 in predicting the severity of AP. In most hospitals, the high cost and lack of access to analytical methods significantly reduce the common use of proinflammatory cytokines as markers of AP. For these reasons, CRP is still regarded as one of the most accurate single prognostic parameters in AP. Synthesis of CRP by hepatocytes is induced by the release of interleukin-1 and -6, and therefore the peak of serum CRP is usually observed at 48 hours after the onset of pain. These characteristics call into question the term “early prognostic marker” used to describe CRP. Acute kidney injury is one of the most common complications of AP. Hypoperfusion plays a major role in the pathogenesis not only of AKI but also of MOF,22,23 which are the main causes of death in SAP. Therefore, pathophysiological role of hypovolemia in determination of AP severity is crucial. It is worth emphasizing that indicators of hypoperfusion and hypovolemia (serum creatinine, eGFR, serum urea nitrogen, and hematocrit) constitute valuable prognostic factors as early as on the first day of the disease.6,14,24,25 Acute kidney injury is induced by ischemia and reperfusion injury, in which neutrophil infiltration is considered to be an important and decisive early event. Neutrophil gelatinase–associated lipocalin was previously recognized as a marker of kidney disease—AKI in particular,26 as well as cardiac27 and oncological diseases.28 To date, studies have focused on assessing the accuracy of NGAL in predicting AP course depending on serum concentrations in humans29 or were carried out on animals.30 The results of those studies confirm the potential for using NGAL to predict AP. Urinary NGAL concentration has never been evaluated as a predictor in AP. Intention to test these studies is interesting, as some studies have shown that in certain diseases, concentration of NGAL in urine is several times higher than in serum.31 Low concentration of NGAL in serum is typical under physiological conditions, because the glomeruli filter and proximal tubes reabsorb circulating NGAL. Normal urinary level of NGAL is very low (
