Combination Of Neutrophil Gelatinase-associated Lipocalin Research Articles

#668 Combined biomarker testing for the assessment of acute kidney injury among myocardial infarction patients

Abstract Background and aims The utility of different biomarkers for the prediction of acute kidney injury following ST-elevation myocardial infarction (STEMI) has been evaluated in several studies however, very few data exist on the prognostic value of combining biomarkers. Among numerous biomarkers examined, C-reactive protein (CRP) and Neutrophil gelatinase associated Lipocalin (NGAL) stand high in their utility to assess AKI risk. The aim of this study was to assess the prognostic value of combined CRP and NGAL measurement for the assessment of the risk of AKI in reperfused STEMI patients Methods Blood samples for plasma NGAL and CRP were drawn 24 hours after admission. High NGAL and CRP were defined as values within the 4th quartile (>75percentile). Patients were stratified into 4 study groups: Low NGAL/Low CRP, LOW NGAL/high CRO, High NGAL /low CRP and high NGAL/high CRP. Patients were assessed for the occurrence of in-AKI based on the KDIGO criteria. Results A total of 311 patients were included (mean age 66 ± 14 years, 81% males). According to the 4 study groups, there was a stepwise increase in the proportion of AKI (9% vs. 21% vs. 40% vs. 68%; p 0.001; Fig. 1). In a multivariate regression model, compared to patients having low NGAL/low CRP we observed a graded, independent increase in the risk for AKI for low NGAL/high CRP, high NGAL/low CRP and high NGAL/high CRP(OR 2.89, p = 0.02 vs. OR 3.29, p < 0.001 vs. OR 17.6, p < 0.001 respectively, Table 1). Peak concentrations showed significant areas under the curves (AUCs) for the prediction of AKI for both CRP AUC (0.692, 95% CI 0.62-0.76) and NGAL (AUC 0.778, 95% CI 0.72-0.84). The combination of NGAL and CRP yielded a significant increase in AUC to 0.822 (95% CI 0.77 to 0.88) (combined biomarkers vs CRP: p < 0.001 and combined vs. NGAL: p = 0.02; Fig. 2). Conclusions In patients with reperfused STEMI, the combined assessment of NGAL and CRP provided incremental prognostic information for the prediction AKI when compared with single-biomarker measurement.

Combined biomarker testing for the assessment of cardio-renal interactions among myocardial infarction patients

Abstract Funding Acknowledgements None. Background The utility of different biomarkers for the prediction of either renal or cardiovascular outcomes following ST-elevation myocardial infarction (STEMI) has been evaluated in several studies however, very few data exist on the prognostic value of combining biomarkers. Among numerous biomarkers examined, C-reactive protein (CRP) and Neutrophil gelatinase associated Lipocalin (NGAL) stand high in their utility to assess the cardiorenal crosstalk. The aim of this study was to assess the prognostic value of combined CRP and NGAL measurement for the assessment of renal and cardiovascular outcomes in reperfused STEMI patients. Methods Blood samples for plasma NGAL and CRP were drawn 24 hours after admission. High NGAL and CRP were defined as values within the 4th quartile (>75percentile). Patients were stratified into 4 study groups: Low NGAL/Low CRP, LOW NGAL/high CRO, High NGAL /low CRP and high NGAL/high CRP. Patients were assessed for the occurrence of in-hospital adverse clinical events (MACE). These included occurrence of acute kidney injury , 30-day mortality and their combination. Results A total of 311 patients were included (mean age 66 ± 14 years, 81% males). According to the 4 study groups, there was a stepwise increase in the proportion of in hospital MACE ( 9% vs. 21% vs. 40% vs. 68% ;p,0.001,figure 1). In a multivariate regression model , compared to patients having low NGAL/low CRP we observed a graded, independent increase in the risk for MACE for low NGAL/high CRP , high NGAL/low CRP and high NGAL/high CRP levels( OR 2.89, p=0.02 vs. OR 3.29,p<0.001 vs. OR 17.6,p<0.001 respectively). Peak concentrations showed significant areas under the curves (AUCs) for the prediction of MACE for both CRP AUC (0.692,95% CI 0.62-0.76) and NGAL ( AUC 0.778,95% CI 0.72-0.84). The combination of NGAL and CRP yielded a significant increase in AUC to 0.822 (95% CI 0.77 to 0.88) (combined biomarkers vs CRP: p<0.001 and combined vs. NGAL :p=0.02,figure 2). Conclusions In patients with reperfused STEMI, the combined assessment of NGAL and CRP provided incremental prognostic information for the prediction of in hospital MACE when compared with single-biomarker measurement.Proportion of in-hospital MACEAUC CR NGAL

Mortality prognosis of NGAL, NTproBNP, hsTnT, and GRACE score in patients with acute coronary syndrome

BackgroundNGAL serum concentration have predictive value for cardiovascular events and mortality in patients with acute coronary syndrome (ACS). ObjectivesAssessed the all-cause mortarlity prognosis value of serum neutrophil gelatinase-associated lipocalin (NGAL), combination with N-terminal pro B-type natriuretic peptide (NT-proBNP), and hsTnT, and GRACE score in patients with ACS. Materials and methodsWe conducted a cross-sectional analysis study used in this study in 58 patients with ACS. Serum NGAL, NT-proBNP, hs-TnT concentration and GRACE score associated with death events (after 3 months of follow-up) were assessed by receiver operating characteristic (ROC) curve. ResultsHigh performance in predicting mortality of NGAL with a cut-off value of 154.55 ng/mL (AUC, 95% CI = 0.96, 0.90 – 1.0; p = 0.001), GRACE score with 140.50 scores (AUC, 95% CI = 0.76, 0.57 – 0.96; p = 0.051). Combination of NTproBNP plus NGAL indicated with the highest value (AUC, 95% CI = 0.96, 0.91 – 1.0; Se = 80.0; Sp = 92.5; p = 0.001). The relative risk assessment indicated a high value in mortality prediction of NGAL with a cut-off value of 154.55 (OR, 95% CI = 49.0, 4.3 – 549.2; p < 0.001), and GRACE score with 140.50 scores (OR, 95% CI = 11.1, 1.1 – 108.4; p = 0.013). ConclusionNGAL can be employed as a biomarker for the early prediction of mortality events in individuals with ACS. The combination of NGAL, NT-proBNP, hsTnT, and GRACE score showed the higher outcome but not worth mentioning.

The value of plasma NGAL and NT-proBNP in the diagnosis of type 1 cardiorenal syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Background The presence of acute kidney injury in the setting of acute heart failure (AHF) is common occurrence and was termed type 1 cardiorenal syndrome (CRS1). Neutrophil gelatinase-associated lipocalin (NGAL) is one of the earliest biomarkers of acute kidney injury due to ischemia or renal toxicity. NT-proBNP has a role in the diagnosis of acute heart failure. Does the combination of NGAL and NT-proBNP increase diagnostic value of CRS1? This study was aimed to evaluate the diagnostic value of plasma NGAL and NT-proBNP in diagnosis of CRS1. Methods there were 139 patients with AHF in the department of Cardiovascular resuscitation and Interventional cardiology Ho Chi Minh City Vietnam 115 People Hospital from September 2018 to March 2019. This was a prospective cohort study. Results the optimal cut-off plasma NGAL to diagnosing CRS1 was 353.23 ng/ml, Area Under Curve (AUC) 0.732 (95% CI 0.65-0.80, p &amp;lt; 0.001), sensitivity 74.47%, specificity 68.48%, positive predictive value 54.7%, negative predictive value 84%. The optimal cut-off NT-proBNP to diagnosing CRS1 was 17681 pg/ml, AUC 0.710 (95% CI 0.627-0.784, p &amp;lt; 0.001), sensitivity 54.2%, specificity 80.2%, positive predictive value 59.1%, negative predictive value 76.8%. Combination of plasma NGAL and NT-proBNP in diagnosing CRS1 with AUC 0.756 (95% CI 0.676-0.825, p &amp;lt; 0.001), sensitivity 77.1%, specificity 69.2%, positive predictive value 56.9%, negative predictive value 85.1%. Conclusions Combination of plasma NGAL and NT-proBNP in the diagnosis of type 1 cardiorenal syndrome with higher sensivity than each biomarker.

The value of plasma NGAL and Cystatin C in the diagnosis of type 1 cardiorenal syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Background The presence of acute kidney injury in the setting of acute heart failure (AHF) is common occurrence and was termed type 1 cardiorenal syndrome (CRS1). Neutrophil gelatinase-associated lipocalin (NGAL) is one of the earliest biomarkers of acute kidney injury due to ischemia or renal toxicity. Cystatin C has a role in the diagnosis renal dysfunction. Does the combination of NGAL and Cystatin C increase diagnostic value of CRS1? This study was aimed to evaluate the diagnostic value of plasma NGAL and Cystatin C in diagnosis of CRS1. Methods there were 139 patients with AHF in the department of Cardiovascular resuscitation and Interventional cardiology Ho Chi Minh City Vietnam 115 People Hospital from September 2018 to March 2019. This was a prospective cohort study. Results the optimal cut-off plasma NGAL to diagnosing CRS1 was 353.23 ng/ml, Area Under Curve (AUC) 0.732 (95% CI 0.65-0.80, p &amp;lt; 0.001), sensitivity 74.47%, specificity 68.48%, positive predictive value 54.7%, negative predictive value 84%. The optimal cut-off Cystatin C to diagnosing CRS1 was 1.81 mg/l, AUC 0.787 (95% CI 0.71-0.852, p &amp;lt; 0.001), sensitivity 75%, specificity 83.5%, positive predictive value 70.6%, negative predictive value 86.4%. Combination of plasma NGAL and Cystatin C in diagnosing CRS1 with AUC 0.787 (95% CI 0.71-0.852, p &amp;lt; 0.001), sensitivity 72.9%, specificity 86.8%, positive predictive value 74.5%, negative predictive value 85.9%. Conclusions Combination of plasma NGAL and Cystatin C in the diagnosis of type 1 cardiorenal syndrome with higher specificity than each biomarker.

Use of Renal Near-Infrared Spectroscopy and Urinary Neutrophil Gelatinase-Associated Lipocalin Monitoring as Indicators of Acute Kidney Injury in Pediatric Cardiac Surgery.

Acute kidney injury (AKI) is a common complication following cardiac surgery under cardiopulmonary bypass (CPB) in children. A prospective study for examining urinary neutrophil gelatinase-associated lipocalin (NGAL) and renal near-infrared spectroscopy (NIRS) trends during AKI was conducted among pediatric patients undergoing cardiac surgery with CPB. Urinary NGAL showed a significant difference between intensive care unit admission (0 h) and 2 h post-admission (p < 0.001) and remained significant up to 4 h (p < 0.05). The renal NIRS in the AKI group showed a significant rate of decrease and lower values during the intraoperative period (p < 0.05). The cumulative median saturation of renal regional saturation of oxygen (rSO2) during CPB was 1637.5% min in the AKI group and 943.0% min in the non-AKI group. The median renal rSO2 scores at a reduction of 20% and 25% were significantly higher (p < 0.001) in the AKI group. Our results suggest that monitoring renal rSO2 scores and limiting their decline might be useful in preventing AKI. The combination of NGAL, renal rSO2, and renal rSO2 scores might be useful in the early diagnosis of AKI during pediatric cardiac surgery.

Enhanced Detection of Cardiac Surgery-Associated Acute Kidney Injury by a Composite Biomarker Panel in Patients with Normal Preoperative Kidney Function.

We have recently shown that minor subclinical creatinine dynamic changes enable the excellent detection of acute kidney injury (AKI) within 6–12 h after cardiac surgery. The aim of the present study was to examine a combination of neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC) and creatinine for enhanced AKI detection early after cardiac surgery. Elective patients with normal renal function undergoing cardiac surgery using cardiopulmonary bypass were enrolled. Concentrations of plasma NGAL, serum CysC and serum creatinine were determined after the induction of general anesthesia, at the termination of the cardiopulmonary bypass and 2 h thereafter. Out of 119 enrolled patients, 51 (43%) developed AKI. A model utilizing an NGAL, CysC and creatinine triple biomarker panel including sequential relative changes provides a better prediction of cardiac surgery-associated acute kidney injury than any biomarker alone already 2 h after the termination of the cardiopulmonary bypass. The area under the receiver-operator curve was 0.77, sensitivity 77% and specificity 68%.

Abstract 13213: The Prognostic Role of Serum Neutrophil Gelatinase Associated Lipocalin in Out of Hospital Cardiac Arrest Patients Who Underwent Targeted Temperature Management

This study investigated the prognostic value of serum neutrophil gelatinase-associated lipocalin (NGAL) in patients treated with targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA). The study included 85 comatose adult patients with OHCA who underwent TTM between May 2018 and December 2020. Serum NGAL and neuron-specific enolase (NSE) were measured at 24-h intervals until 72 h after return of spontaneous circulation (ROSC). The primary outcome was neurological status at 3 months after OHCA. Forty-nine patients (57.6%) had a poor neurological outcome; NGAL levels at all time points measured were significantly higher in these patients than in those with a good outcome (p&lt;0.01). NGAL showed lower maximal sensitivity (95% CI) under a false-positive rate of 0% for the primary outcome compared with NSE (18.2% [95% CI 8.2-32.7] vs. 66.7% [95% CI 50.5-80.4]). Combination of NGAL with NSE at 48 h showed the highest sensitivity (69.1% [95% CI 52.9-82.4]) and had the highest AUC (0.91 [95% CI 0.81-0.96]) for a poor outcome. The prognostic performance of NGAL alone was inadequate at all time points. However, NGAL obtained at 24 and 48 h after ROSC showed improved sensitivity when combined with NSE. NGAL should be considered as an additional biomarker to improve accuracy for prognostication in these patients.

Combination of neutrophil gelatinase-associated lipocalin and matrix metalloproteinase-9 are biomarkers for the detection of colon tubular adenocarcinoma.

BACKGROUNDTubular adenocarcinoma of the colon, which originates from the epithelium of the glands, is a major health concern worldwide. However, it is difficult to detect at an early stage. The lack of biomarkers is a main barrier to the diagnosis and treatment of tubular adenocarcinoma. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted protein that induces the expression of matrix metalloproteinase-9 (MMP-9) and is involved in various tumors. NGAL and MMP-9 have been reported to be associated with tumorigenesis and development. They may have potential as biomarkers for diagnosis of tubular adenocarcinoma of the colon.AIMTo determine whether NGAL and MMP-9 can be used as potential biomarkers to indicate the progression of tubular adenocarcinoma of the colon.METHODSSamples were collected from surgically excised tissue from various patients. The content of pro-gastrin-releasing peptide (pro-GRP) in the serum was measured by an electrochemiluminescence immunoassay. The expression patterns of NGAL and MMP-9 and the relationship between NGAL and MMP-9 were examined by quantitative real-time PCR, Western blotting and immunohistochemical analysis.RESULTSIn this study, we found that NGAL and MMP-9 can be used as biomarkers for the detection of tubular adenocarcinoma of the colon and that their combination improved diagnostic accuracy. By analyzing the expression of NGAL in tubular adenocarcinoma at different levels, we found that NGAL expression was significantly upregulated in primary tubular adenocarcinoma tissues compared with normal tissues. The upregulation of NGAL expression was strongly correlated with both the degree of differentiation and the disease stage (I–III), indicating that NGAL could serve as a diagnostic biomarker for tubular adenocarcinoma. When using NGAL as a biomarker for diagnosis, the accuracy was similar to that achieved with the widely used biomarker pro-GRP, suggesting that NGAL is reliable. Moreover, the expression of MMP-9 was also strongly correlated with the differentiation stage, demonstrating that MMP-9 could be used as a biomarker to indicate the progression of tubular adenocarcinoma of the colon. More importantly, the combination of NGAL and MMP-9 produced a more accurate diagnosis of tubular adenocarcinoma, and these results were further confirmed by immunohistochemical analysis of tissue sections.CONCLUSIONOur study demonstrated that both NGAL and MMP-9 can be used as biomarkers for the diagnosis of colon tubular adenocarcinoma and that the results could be further improved by combining them.

Prognostic role of serum neutrophil gelatinase-associated lipocalin in cardiac arrest patients: A prospective observational study.

Accurate neurological prognostication is of the utmost importance to avoid futile treatments in patients treated with targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA). This study aimed to investigate the prognostic value of serum neutrophil gelatinase-associated lipocalin (NGAL) by comparing with neuron-specific enolase (NSE), which is currently recommended by international guidelines in patients treated with TTM after OHCA.The study included 85 comatose adult patients with OHCA who underwent TTM between May 2018 and December 2020. Serum NGAL and NSE were measured at 24-hour intervals until 72 hours after return of spontaneous circulation (ROSC). The primary outcome was their prognostic performance for poor neurological outcome at 3 months after OHCA.Forty-nine patients (57.6%) had a poor neurological outcome; NGAL levels at all time points measured were significantly higher in these patients than in those with a good outcome (P < .01). NGAL showed lower maximal sensitivity (95% confidence interval [CI]) under a false-positive rate of 0% for the primary outcome compared with NSE (18.2% [95% CI 8.2–32.7] vs 66.7% [95% CI 50.5–80.4]). The combination of NGAL with NSE at 48 h showed the highest sensitivity (69.1% [95% CI 52.9–82.4]) and had the highest area under the curve (0.91 [95% CI 0.81–0.96]) for a poor outcome. The prognostic performance of NGAL alone was inadequate at all time points. However, NGAL combined with NSE at 24 and 28 hours after ROSC showed improved sensitivity compared to NGAL alone.NGAL should be considered a supplementary biomarker in combination with NSE for prognostication in patients with OHCA treated with TTM.

Enhancing Military Burn- and Trauma-Related Acute Kidney Injury Prediction Through an Automated Machine Learning Platform and Point-of-Care Testing.

Delayed recognition of acute kidney injury (AKI) results in poor outcomes in military and civilian burn-trauma care. Poor predictive ability of urine output (UOP) and creatinine contribute to the delayed recognition of AKI. To determine the impact of point-of-care (POC) AKI biomarker enhanced by machine learning (ML) algorithms in burn-injured and trauma patients. We conducted a 2-phased study to develop and validate a novel POC device for measuring neutrophil gelatinase-associated lipocalin (NGAL) and creatinine from blood samples. In phase I, 40 remnant plasma samples were used to evaluate the analytic performance of the POC device. Next, phase II enrolled 125 adults with either burns that were 20% or greater of total body surface area or nonburn trauma with suspicion of AKI for clinical validation. We applied an automated ML approach to develop models predicting AKI, using a combination of NGAL, creatinine, and/or UOP as features. Point-of-care NGAL (mean [SD] bias: 9.8 [38.5] ng/mL, P = .10) and creatinine results (mean [SD] bias: 0.28 [0.30] mg/dL, P = .18) were comparable to the reference method. NGAL was an independent predictor of AKI (odds ratio, 1.6; 95% CI, 0.08-5.20; P = .01). The optimal ML model achieved an accuracy, sensitivity, and specificity of 96%, 92.3%, and 97.7%, respectively, with NGAL, creatinine, and UOP as features. Area under the receiver operator curve was 0.96. Point-of-care NGAL testing is feasible and produces results comparable to reference methods. Machine learning enhanced the predictive performance of AKI biomarkers including NGAL and was superior to the current techniques.

Diagnostic and prognostic significance of aberrant miR-652-3p levels in patients with acute decompensated heart failure and acute kidney injury.

ObjectiveThis study aimed to examine a novel microRNA (miR-652-3p) biomarker to improve early diagnosis of acute kidney injury (AKI) in patients with acute decompensated heart failure (ADHF) and to evaluate the survival predictive value of miR-652-3p.MethodsWe retrospectively analyzed the data of 196 patients with ADHF, including 65 who developed AKI during hospitalization. Neutrophil gelatinase-associated lipocalin (NGAL) levels were measured in serum and urine samples. Real-time quantitative PCR was applied to evaluate miR-652-3p mRNA expression. The diagnostic performance of miR-652-3p was examined using receiver operating characteristic curve analysis. The prognostic value of miR-652-3p was also analyzed.ResultsSerum and urinary NGAL and miR-652-3p levels were elevated in patients with ADHF and AKI. Serum and urinary miR-652-3p expression had diagnostic value in predicting AKI onset in patients with ADHF, and it had improved diagnostic performance when used with NGAL. Patients with AKI and high miR-652-3p levels had a high failure rate of renal recovery and poor 180-day survival.ConclusionSerum and urinary miR-652-3p may be a candidate biomarker for early diagnosis of AKI in patients with ADHF and for predicting the prognosis of AKI. The combination of NGAL and miR-652-3p may accurately predict AKI onset in ADHF.

Value of serum level of microRNA-494 in predicting prognosis of acute renal injury after cardiac surgery in children

To explore the value of serum microRNA-494 (miR-494) expression in predicting the prognosis of acute renal injury (AKI) after cardiac surgery in children. 116 children with AKI after cardiopulmonary bypass for congenital heart disease admitted to Sanya People's Hospital from January 2016 to March 2019 were enrolled. The expression of miR-494 in serum was detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), and the levels of serum neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) were detected by enzyme linked immunosorbent assay (ELISA) of all the children. The children were divided into survival group and death group according to 28-day survival. Serum levels of miR-494, NGAL and KIM-1 were measured in two groups. Multivariate Logistic regression was used to analyze the risk factors of death in children with AKI after cardiac surgery. The receiver operating characteristic (ROC) curve analysis of serum levels of miR-494, NGAL and KIM-1 in predicting prognosis of children with AKI after cardiac surgery was performed. Pearson correlation analysis was used to analyze the correlation between serum levels of miR-494 and NGAL, KIM-1. After cardiopulmonary bypass in 116 children with AKI, 27 cases died and 89 cases survived during the 28-day observation. Compared with the survival group, the proportion of cyanosis in the death group was significantly increased, the proportion of blood perfusion was significantly decreased, the time of cardiopulmonary bypass and postoperative mechanical ventilation were significantly prolonged, and the blood glucose level was significantly increased after operation. There was no significant difference in other general data. The serum levels of miR-494, NGAL and KIM-1 in the death group were significantly higher than those in the survival group [miR-494 (2-ΔΔCt): 3.75±1.28 vs. 1.48±0.71, NGAL (mg/L): 583.60±52.72 vs. 320.52±31.84, KIM-1 (g/L): 30.53±6.38 vs. 17.40±3.72, all P < 0.01]. Multivariate Logistic regression analysis showed cyanosis [odds ratio (OR) = 1.716, 95% confidence interval (95%CI) was 1.184-2.982, P = 0.039], postoperative blood glucose (OR = 1.925, 95%CI was 1.262-3.387, P = 0.005), serum miR-494 (OR = 2.527, 95%CI was 1.706-5.148, P < 0.001), NGAL (OR = 2.473, 95%CI was 1.620-4.935, P < 0.001) and KIM-1 (OR = 1.805, 95%CI was 1.213-3.106, P < 0.001) were independent risk factors for death in children with AKI after cardiac surgery. ROC curve analysis showed the area under the curve (AUC) to predict the death of children with postoperative AKI was 0.868, 0.857 and 0.819 respectively, AUC of serum miR-494, NGAL and KIM-1 levels combination to predict the death of children with postoperative AKI was the largest (0.964, 95%CI was 0.908-0.997), with a high sensitivity and specificity of 97.0% and 91.8%. The correlation analysis showed the expression level of serum miR-494 was positively correlated with NGAL and KIM-1 in the death group (r1 = 0.902, r2 = 0.873, both P < 0.01). Serum levels of miR-494 increased significantly in children with AKI after cardiac surgery, which is an independent risk factor for death in children with AKI after cardiac surgery, and the combination of NGAL and KIM-1 levels had a high value in predicting the prognosis of children with AKI after cardiac surgery.

Urinary biomarkers of cell cycle arrest are delayed predictors of acute kidney injury after pediatric cardiopulmonary bypass.

Several novel biomarkers that predict acute kidney injury (AKI) have recently been proposed. We have evaluated the sequential patterns of biomarker elevation after pediatric cardiopulmonary bypass (CPB) and determined their diagnostic accuracy. We measured the ability of neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), liver type fatty-acid binding protein (L-FABP), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-2 (TIMP-2), and insulin-like growth factor binding protein 7 (IGFBP7), to predict AKI (≥50% increase in serum creatinine from baseline). Areas under the receiver-operator characteristic curves (AUCs) were calculated for each biomarker and for various biomarker combinations at multiple time points after CPB. Of 150 patients examined, AKI had developed in 50 patients by 24h after CPB, with an elevated NGAL concentration first noted at 2h post-CPB, increases in IL-18, L-FABP, and the product of TIMP-2 and IGFBP7 first noted at 6h, and an elevated KIM-1 level noted at 12h. At each time point, urine NGAL remained the marker with the highest predictive ability (AUC > 0.9). The addition of any other biomarker did not increase the predictive accuracy of NGAL alone at 2 and 6h. At 12h, when compared to NGAL alone, the combination of NGAL, IL-18, and TIMP2 improved the AUC for AKI prediction (from 0.938 to 0.973). While urine NGAL remains a superior stand-alone test at the 2 and 6h time points after pediatric CPB, a panel of carefully selected biomarkers may prove optimal at later time points.

Abstract 14905: Combined Assessment of Serum Neutrophil Gelatinase-Associated Lipocalin and N-Terminal Pro-B-Type Natriuretic Peptide Levels on Admission Improves the Prediction of Mortality in Patients Hospitalized to Coronary Care Units

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is best known clinically as a novel and early marker of acute kidney injury. Renal dysfunction portends significant risk in patients admitted to coronary care units (CCUs). Thus, a sensitive marker of renal injury might also help to risk stratify patients hospitalized to CCUs. We prospectively investigated the prognostic value of a combination of serum NGAL and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels on admission for mortality in patients hospitalized to CCUs. Methods: We measured serum NGAL and NT-proBNP levels on admission in 974 consecutive patients hospitalized to CCUs. Among these patients, heart failure was present in 55%, and acute coronary syndrome in 40%. Results: Serum NGAL levels significantly correlated with NT-proBNP levels (r = 0.37, p &lt;0.0001) and estimated glomerular filtration rate (r = -0.68, p &lt; 0.0001). During a mean follow-up period of 829 days after admission, there were 178 (18%) all-cause deaths including 145 cardiovascular deaths. Comparably, patients who died were older (median, 78 vs. 72 yrs, p &lt; 0.0001), had higher levels of NGAL (102 vs. 55 ng/ml, p &lt; 0.0001), NT-proBNP (4043 vs. 1250 pg/ml, p &lt; 0.0001), D-dimer (2.6 vs. 1.1 μg/ml, p &lt; 0.0001), and high-sensitive C-reactive protein (6.0 vs.2.0 mg/l, p &lt; 0.0001), and displayed lower values of left ventricular ejection fraction (39 vs. 50 %, p &lt; 0.0001) and estimated glomerular filtration rate (43 vs. 65 ml/min/1.73m 2 , p &lt; 0.0001) than those who did not. In multivariate Cox regression analysis including 11 clinical and biochemical variables, tertiles of NGAL (p = 0.02) and NT-proBNP (p = 0.02) was independently associated with all-cause deaths. The combination of NGAL and NT-proBNP tertiles were associated with increased all-cause mortality rates ( Figure ). Conclusion: The combined assessment of NGAL and NT-proBNP levels on admission may be useful for evaluating the risk of mortality in patients admitted to CCUs.

Comparative proteomic analysis of neutrophils from patients with microscopic polyangiitis and granulomatosis with polyangiitis

Both microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) belong to ANCA-associated vasculitis (AAV), in which neutrophils play a key role in their pathology. In this study, in order to discriminate between MPA and GPA, protein profiles of peripheral blood polymorphonuclear cells (PMNs) of 11 MPA patients and 9 GPA patients and 10 healthy controls (HC) were analyzed by 2D-DIGE. In all the 864 spots detected, intensity of 55 spots was significantly different (p<0.05) among the three groups by ANOVA. 31 out of the 55 spots were identified by mass spectrometry. Orthogonal partial-least-squares-discriminate analysis revealed that the abundance profile of the protein spots discriminated the AAV group from the HC group, and the MPA group from the GPA group completely. 13 protein spots were considered as biomarker candidates to distinguish between MPA and GPA. In those, spots whose intensity was higher in MPA than in GPA included actin with various pI values, while a considerable part of spots whose intensity was higher in GPA were proteins related with the activity of neutrophils. Among the candidate proteins, ROC analysis showed that a combination of neutrophil gelatinase-associated lipocalin and a-kinase anchor protein 7 isoforms beta had a high diagnostic potential. In this study, protein profiles of polymorphonuclear cells (PMNs) of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) patients and healthy controls (HC) were investigated by 2D-DIGE, and MS analysis. As a result, we found that the protein profiles of PMNs were useful for distinguishing between patients (MPA and GPA) and HC, and between patients with MPA and patients with GPA. Especially, we found that the 13 protein spots that consisted of 10 proteins considerably contributed to the discrimination between MPA and GPA. This is the first to demonstrate that protein profiles of PMNs are different among MPA, GPA and healthy control. The 10 proteins we identified in this study would be new biomarkers for the diagnosis of the diseases, and may be reflect the pathology difference between MPA and GPA.

AB0153 Comparative proteomic analysis of neutrophils from patients with microscopic polyangiitis and granulomatosis with polyangiitis

BackgroundBoth microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) belong to ANCA-associated vasculitis (AAV), in which neutrophils are thought to be involved in their pathology. Clinically, it is often difficult...

Neutrophil gelatinase-Associated lipocalin predicts acute kidney injury in patients undergoing liver transplantation

Postoperative acute kidney injury (AKI) increases morbidity and mortality after liver transplantation (LT). Novel methods of assessing AKI including cystatin C (CyC) and neutrophil gelatinase-associated lipocalin (NGAL) have been identified as potential markers of AKI. We compare the ability of standard renal markers (serum creatinine [sCr], estimated glomerular filtration rate [eGFR] and intensive therapy unit organ failure scores with CyC and NGAL to predict AKI within the first 48 hours after LT. 95 patients (median age 50 [interquartile range = 41-59], 60% male) underwent LT (25% with acute liver failure). AKI was defined according to the Acute Kidney Injury Network criteria. Severe AKI was classified as ≥stage 2. NGAL (urine [u] and plasma [p]) and CyC concentrations taken immediately after transplantation on admission to the Liver Intensive Care Unit were compared with standard markers of renal function. Predictive ability was assessed using the area under the curve generated by receiver operator characteristic analysis (AUROC) and logistic regression. Day 0 sCr, uNGAL, pNGAL, CyC, and eGFR predicted AKI as did SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. APACHE II and pNGAL were the most powerful predictors of severe AKI (APACHE II AUROC = 0.87 [0.77-0.97], P < 0.001; pNGAL AUROC = 0.87 [0.77-0.92], P < 0.001). Using multivariate logistic regression, APACHE II (odds ratio 1.64/point [95% confidence interval = 1.22-2.21, P = 0.001] and pNGAL [odds ratio = 1.01/ng/mL [95% confidence interval = 1.00-1.02], P = 0.002) retained independent significance. A "renal risk score" using APACHE II > 13 and pNGAL > 258 ng/mL was calculated with a score of ≥1 having a 100% sensitivity and 76% specificity for severe AKI. In conclusion, a combination of NGAL and APACHE II predicts AKI with high sensitivity and specificity after LT.

Abstract LB-212: Elevated plasma NGAL and MIC-1 are novel biomarkers for the diagnosis of pancreatic adenocarcinoma

Abstract Pancreatic cancer (PC) is a highly lethal malignancy (5-year survival &amp;lt;5%). The secretory glycoproteins neutrophil gelatinase associated lipocalin (NGAL) and macrophage inhibitory cytokine-1 (MIC-1) have both been shown to be involved in the pathogenesis of PC. We hypothesized that plasma NGAL and MIC-1 levels are elevated in patients with PC and could be useful in the diagnosis of PC either alone or in combination with CA19-9. To investigate this hypothesis, we analyzed NGAL, MIC-1 and CA19-9 levels in plasma samples from patients with PC (n=145, 66 pre-operative and 79 postoperative samples) and compared it with that in healthy individuals (n=27). NGAL and MIC-1 levels were measured using ELISA while CA19-9 levels were analyzed by radioimmunoassay. The mean plasma NGAL, MIC-1 and CA19-9 levels in pre-operative PC patients were 141 ± 17.5 ng/nl, 59±32.4 ng/ml and 988±449.5 U/ml which was higher than their corresponding levels in the healthy controls (74.5±3 ng/ml (p=0.0004), 7±2.7 ng/ml (p=0.11) and 35±2.7 U/ml (p&amp;lt;0.00001) for NGAL, MIC-1 and CA19-9, respectively). At a cut-off of &amp;gt;90ng/ml, NGAL was 67% sensitive (95% C.I. 60%-80%) and 93% specific (95% C.I. 76%-99%) in distinguishing PC from controls. In comparison, CA19-9 at a cut-off of &amp;gt;37U/ml was 82% sensitive (95% C.I. 73%-89%) and 67% specific (95% C.I. 46%-83%) while MIC-1 at a level &amp;gt;1.85 ng/ml had a sensitivity of 82% (95% C.I. 73%-89%) and specificity of 63% (95% C.I. 42%-80%). Neither NGAL nor MIC-1 levels differed significantly between PC patients with resectable vs unresectable tumors (p=0.54 and 0.37), male vs. female (p=0.92 and 0.11), by histological grade (p=0.26 and 0.29), location of tumor (p=0.58 and 0.96) or among those with or without a concomitant diagnosis of type 2 diabetes (p=0.46 and 0.50 respectively). However, NGAL (but not MIC-1) levels were significantly higher in PC patients above 65 yrs of age (177.1±30 ng/ml compared to 97±8.6 ng/ml in those ≤ 65 yrs old, p=0.017) and lower in post-operative compared to pre-operative PC patients (106±7 ng/ml vs. 138±15 ng/ml respectively, p=0.057). Applying a criterion of positivity of at least one of the three markers improved the sensitivity of diagnosing PC to 98.5%, while positivity for any two markers (NGAL or CA19-9, MIC-1 or CA19-9 and NGAL or MIC-1) was less sensitive in diagnosing PC (92%, 97% and 91% sensitive respectively). The highest specificity was obtained when both NGAL and CA19-9 were above their cut-offs (96%). Adding MIC-1 to this did not improve specificity. Twelve pre-operative PC patients had CA19-9&amp;lt;37U/ml. 58% (n=7) of these patients had NGAL levels above the cut-off compared to 83% (n=10) for MIC-1. Using a criterion of either NGAL or MIC-1 positivity in these patients correctly identified 92% (n=11) PC patients who were negative for CA19-9. In summary, we have identified NGAL as a highly specific marker of PC compared to CA19-9. Further, a combination of NGAL, MIC-1 and CA19-9 was more sensitive than either marker alone in diagnosing PC, while a combination of CA19-9 and NGAL gave the highest specificity. A combination of NGAL and MIC-1 was useful to identify PC patients who were negative for CA19-9. Our results suggest a potential role for NGAL and MIC-1 in the diagnosis of PC, especially in patients who do not express CA19-9. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-212.

Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery

Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers for AKI has impaired our ability to intervene in a timely manner. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is recently demonstrated as an early biomarker of AKI after CPB, increasing 25-fold within 2 h and declining 6 h after surgery. In the present study, we tested whether interleukin-18 (IL-18) is a predictive biomarker for AKI in the same group of patients following CPB. Exclusion criteria included pre-existing renal insufficiency and nephrotoxin use. Serial urine samples were analyzed by enzyme-linked immunosorbent assay for IL-18 in 20 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 35 controls (age, race, and gender-matched patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected only 48-72 h after CPB. In contrast, urine IL-18 increased at 4-6 h after CPB, peaked at over 25-fold at 12 h, and remained markedly elevated up to 48 h after CPB. The performance of IL-18 as demonstrated by area under the receiver operating characteristics curve for diagnosis of AKI at 4, 12, and 24 h after CPB was 61, 75, and 73% respectively. Also, on multivariate analysis, both IL-18 and NGAL were independently associated with number of days in AKI among cases. Our results indicate that IL-18 is an early, predictive biomarker of AKI after CPB, and that NGAL and IL-18 are increased in tandem after CPB. The combination of these two biomarkers may allow for the reliable early diagnosis and prognosis of AKI at all times after CPB, much before the rise in serum creatinine.