Higher Neutrophil Gelatinase-associated Lipocalin Levels Research Articles

Plasma MMP and TIMP evaluation in patients with deep venous thrombosis: could they have a predictive role in the development of post-thrombotic syndrome?

Post-thrombotic syndrome (PTS) is a condition that can develop in about half of the patients with deep vein thrombosis (DVT) of lower limbs. In the present study, we evaluated the expression of inflammatory biomarkers in the early phases of DVT and their correlation with the onset of PTS. Patients were enrolled after the first episode of DVT and were followed up for 1, 4, 8, 12 and 18 months. At each visit, blood sample was collected to evaluate plasma levels of matrix metalloproteinase (MMP)-1,-2,-3,-7,-8 and -9 MMP inhibitors, TIMP-1,-2, neutrophil gelatinase-associated lipocalin (NGAL) and cytokines TNF-α and IL-6. Analysis included 201 patients [86 males (42·79%) and 115 females (57·21%); average age 56 ± 7 years]. Of the 201 patients, 47 (23·38%; 21 males, 26 females) developed PTS during the follow-up period. The control group was made up of 60 individuals without DVT (22 males and 38 females). High plasma levels of MMPs, NGAL and cytokines were recorded during the acute phase after DVT. Moreover, patients with PTS showed higher levels of MMP-1 and MMP-8 with respect to patients without PTS. There is a close relationship between DVT, the individual risk of PTS and specific biomarkers such as MMPs and other related molecules, which may help guide prevention and therapy based on the patient's individual risk profile, and has to be studied in future.

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 <0.0001) and estimated glomerular filtration rate (r = -0.68, p < 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 < 0.0001), had higher levels of NGAL (102 vs. 55 ng/ml, p < 0.0001), NT-proBNP (4043 vs. 1250 pg/ml, p < 0.0001), D-dimer (2.6 vs. 1.1 μg/ml, p < 0.0001), and high-sensitive C-reactive protein (6.0 vs.2.0 mg/l, p < 0.0001), and displayed lower values of left ventricular ejection fraction (39 vs. 50 %, p < 0.0001) and estimated glomerular filtration rate (43 vs. 65 ml/min/1.73m 2 , p < 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.

Neutrophil gelatinase-associated lipocalin as a biomarker for lupus nephritis

One of the challenges of treating patients with lupus nephritis (LN) is to accurately assess disease activity and predict its outcome. Since renal-biopsy cannot be performed routinely, new surrogate biomarkers are needed. We evaluated neutrophil gelatinase-associated lipocalin (NGAL), to predict renal outcome in LN. Serum and urinary NGAL levels, measured by the enzyme-linked immunosorbent assay, and the fractional excretion (FE) of NGAL relative to the FE of proteins (FE NGAL/FE protein ratio) were determined in a cross-sectional (n = 199) and longitudinal (n = 45) cohort of systemic lupus erythematosus (SLE) patients. Global and renal disease activity was assessed by the SLE disease activity indices, SLEDAI and rSLEDAI, respectively. Correlations between traditional biomarkers were established. Sensitivity, specificity and predictive values of NGAL for renal flare, response to therapy and progression to chronic kidney disease were calculated. The FE NGAL/FE protein ratio exhibited the best sensitivity and specificity to discriminate patients with active LN from those with non-renal flare and inactive SLE. In the prospective study, this biomarker was found to be the best candidate to predict proteinuric flares with an 87% sensitivity and 62% specificity for ratios >14.56 and complete response with a 61% sensitivity and 78% specificity for ratios >26.54 in the presence of a simultaneous worsening or improving rSLEDAIs, respectively. In both conditions, the FE NGAL/FE protein ratio outperformed the anti-dsDNA antibody titres and C3 predictive value. Progression to chronic kidney disease was best predicted by estimated glomerular filtration rate levels, but persistently high levels of serum NGAL (>444.4 ng/mL, P = 0.0001 by Kaplan-Meier) predicted a faster progression. The FE NGAL/FE protein ratio is a reliable marker of disease activity in patients with SLE and could be used as an indicator of response to therapy, although further studies are required to confirm these results.

Tubular Damage Is Present In Patients With MGUS and Asymptomatic Multiple Myeloma Even In The Absence Of Impaired Estimated Glomerular Filtration Rate; Alterations Of Neutrophil Gelatinase-Associated Lipocalin and Cystatin-C In Myeloma Patients Post IMiD- and Bortezomib-Based Regimens

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa protein, which is produced by the injured tubule epithelium. In contrast to serum creatinine (sCr), NGAL is specifically induced in the damaged nephron and then released into blood and urine; thus it is considered as an early marker of renal tubular injury. Our group has recently shown that urinary and serum NGAL were elevated in the vast majority (90% and 70%, respectively) of newly diagnosed patients with multiple myeloma (MM), while serum cystatin-C (CysC), an accurate marker of GFR, was elevated in 70% of them. However, there is no information for the value of these markers in patients with MGUS, asymptomatic MM (AMM), as well as in symptomatic MM post treatment.Thus, we measured urinary and serum NGAL and serum CysC in 40 patients with MGUS (23M/17F, median age 72 years), 36 with AMM (16M/20F, 60 years) and 120 healthy controls. Furthermore, we measured serum NGAL and CysC in 39 newly diagnosed symptomatic MM patients (24M/15F, 70 years) before and after frontline therapy with novel agents. Serum and urinary NGAL was measured using an ELISA method (BioPorto Diagnostics A/S, Gentofte, Denmark), while CysC was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany). The estimated GFR (eGFR) was calculated using the CKD-EPI equation. Patients were divided into the 5 CKD stages of the KDIGO classification, according to eGFR (stage 1: eGFR >90 ml/min/1.73m2; stage 2: 60-89 ml/min/1.73m2; stage 3: 30-59 ml/min/1.73m2; stage 4: 15-29 ml/min/1.73m2; stage 5: <15 ml/min/1.73m2or on dialysis).Only two (5%) patients with MGUS and two (5.5%) with AMM had sCr above the upper normal limit, but none had sCr >2 mg/dl. Regarding eGFR, 34 (85%) patients with MGUS and 31 (86%) with AMM had CKD stage 1/2, while 6 (15%) MGUS and 5 (14%) AMM patients had CKD stage 3. Urinary NGAL was elevated in patients with MGUS (median: 14 ng/ml, range 0.5-31 ng/ml) and AMM (22.3 ng/ml, 0.9-78 ng/ml) compared to controls (5.3 ng/ml, 0.7-9.8 ng/ml, p<0.001 for both comparisons). Similarly, serum NGAL was elevated in patients with MGUS (106 ng/ml, 74.9-205.5 ng/ml) and AMM (94.2 ng/ml, 29.5-306.4 ng/ml) compared to controls (63ng/ml, 37-106 ng/ml; p<0.01). There was no difference between MGUS and controls or MGUS and AMM regarding CysC serum values, indicating that traditional indices of renal function could not detect early renal damage. However, 22 (55%) patients with MGUS and 24 (66%) with AMM had higher urinary NGAL values than the higher value of the controls. Similarly, 9 (22.5%) MGUS and 11 (30%) AMM patients had higher levels of serum NGAL than the higher value in the control group.Twelve (31%) patients with symptomatic MM had sCr >2 mg/dl, while 41% had CKD stages 1/2, 28% had CKD stage 3 and 31% CKD stages 4/5. As expected, patients with symptomatic MM had elevated serum NGAL and CysC (p<0.001). NGAL strongly correlated with CysC (r=0.675, p<0.001) and CKD stage (mean±SD values for stages 1/2, stage 3 and stages 4/5 were: 97±57 ng/ml, 144±79 ng/ml and 205±124 ng/ml, respectively; ANOVA p=0.014). CysC also correlated with CKD stage (0.96±0.29 mg/l, 1.54±0.32 mg/l and 2.51±1.00 mg/l respectively, ANOVA p<0.001). Seven patients received bortezomib-based regimens and 32 patients received IMiD-based regimens as frontline therapy: 9 patients achieved sCR, 13 VGPR, 12 PR, while 3 had stable disease and 2 progressed. Among patients with eGFR <50 ml/min at baseline (n=22), 4/4 who received bortezomib-based regimens and 5/18 who received IMiD-based regimens achieved at least minor renal response. After 4 cycles of therapy, serum NGAL increased in patients who received IMiD-based therapy compared to baseline (255±264 ng/ml vs. 147±104ng/ml, p=0.021), but not in patients who received bortezomib (119±68 ng/ml vs. 159±111 ng/ml p=0.520), regardless of myeloma response to treatment.We conclude that the high levels of urinary and serum NGAL in MGUS and AMM indicate the presence of subclinical renal damage in these patients early in the course of their disease, when other markers of renal function, such as sCr or even the more sensitive CysC indicate that renal function is preserved. Thus, NGAL may be useful as an early marker that predicts the development of renal damage and the progression of the disease in these patients. NGAL seems also to increase in patients with renal impairment who receive IMiD-based regimens. Disclosures:No relevant conflicts of interest to declare.

Serum neutrophil gelatinase-associated lipocalin as a predictor of the development of bronchopulmonary dysplasia in preterm infants

BackgroundBronchopulmonary dysplasia (BPD) is a chronic lung disease mostly occurring in preterm infants. The pathogenesis of BPD involves early inflammation and remodeling of the premature lung. AimTo search for the novel predictive marker of BPD development, we studied serum levels of neutrophil gelatinase-associated lipocalin (NGAL), an innate immune mediator, in preterm infants. MethodsSerum NGAL concentrations at birth were measured by enzyme-linked immunosorbent assay. The reference levels were determined in 52 infants having no anomalies or inherited diseases. The levels and clinical variables were assessed in association with BPD. ResultsGeometric means (95%CI) of serum NGAL levels at birth of infants having no underlying diseases were 32.4 (22.1–47.5), 58.6 (47.9–71.8), and 126.2 (99.0–168.7) ng/mL for <31, 31–36 and >36 gestational weeks (GW), respectively (p<0.001). These levels positively correlated with neutrophil (p<0.0001) or monocyte counts (p<0.0001). The median NGAL levels (307.8ng/mL) and neutrophil counts (4141/μL) at birth of 16 preterm infants (<31GW) who developed BPD were higher than those (42.9ng/mL and 1357/μL) of 20 infants (<31GW) who did not (p<0.0001 and p=0.012), respectively. In multivariable analysis for 36 infants born less than 31GW, higher NGAL levels (≥82ng/mL) but not neutrophil counts at birth had a significant association with developing BPD (gestational-age adjusted odds ratio [OR]=37.45 [3.08–455.49], p<0.01). ConclusionsHigh serum levels of NGAL at birth could be an early sensitive marker for BPD in preterm infants, because their levels were physiologically low.

Serum level of neutrophii gelatinase-associated lipocalin in preeclampsia with gestational diabetes mellitus

Objective To investigate the relationship of serum neutrophil gelatinase associatedlipocalin (NGAL) levels among preeclamptic women with or without gestational diabetes mellitus (GDM),GDM and healthy pregnant controls. Methods This study included 263 singleton pregnant women who visited the antenatal chinics in Guangdong Women and Children's Hospital and Health Instutite Affiliated to Guangzhou Medical College from December 2009 to November 2010,77 healthy pregnant women,77 women with preeclampsia,77 women with GDM and 32 women complicated with both preeclampsia and GDM.Blood pressure,height and body weight of all subjects were measured.Peripheral blood samples were collected to detect serum NGAL,parameters of glycolipid metabolism,24-hour urine protein content,uric acid,creatinine and lactate dehydrogenase.Maternal levels of serum NGAL were quantified by enzyme-linked immunosorbent assay.Meanwhile,body mass index (BMI) and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. Data under normal distribution were analyzed with one-way ANOVA and Student's t test,and those under abnormal distribution were compared with Kruskal-Wallis H or Mann-Whitney U test. Results The preeclampsia with GDM group had higher serum NGAL level [(70.82±20.02) ng/ml] as compared with preeclampsia group [(56.17 ±18.22) ng/ml],GDM group [(43.99 ± 14.82) ng/ml] and healthy pregnant control group [(17.80±5.78) ng/ml],t=3.65,5.97,14.76,P＜0.01,respectively.The NGAL levels in preeclampsia group without GDM were higher than in GDM group (t=5.90,P＜0.01).In both the preeclampsia with and without GDM groups,NGAL levels in patients with severe preeclampsia were higher than in the mild ones [(76.44±28.06) ng/ml or(60.15±25.86) ng/ml,t=2.82,P＜0.05; (61.61±37.14) ng/ml or (46.30±13.97) ng/ml,t=4.74,P＜0.01].After adjusted by gesrational weeks and maternal age,NGAL level was positively correlated with BMI before pregnancy (r=0.335,P＜0.01),BMI after pregnancy (r=0.427,P＜0.01),systolic blood pressure (r=0.648,P＜0.01),diastolic blood pressure (r=0.664,P＜0.01),fasting blood glucose (r=0.320,P＜0.01),fasting insulin level (r=0.381,P＜0.01),HOMA-IR (r=0.399,P＜0.01),triglyceride level (r=0.405,P＜0.01),total cholesterol (r=0.145,P＜0.05),free fatty acids (r=0.335,P＜0.01),uric acid (r =0.292,P＜0.01),creatinine (r =0.226,P ＜ 0.01),and 24-hour urine protein content (r =0.436,P＜0.01),and negatively correlated with high density lipoprotein-cholesterol (r=-0.189,P =0.008).Stepwise regression analysis showed that systolic blood pressure (β =0.251,P ＜ 0.01),diastolic blood pressure (β=0.351,P＜0.01),HOMA-IR (β=0.265,P＜0.01) and 24-hour urine protein content (β=0.140,P=0.011) were independent factors of NGAL. Conclusions Serum NGAL levels increase significantly in patients with preeclampsia or GDM,and are correlated with parameters of glycolipid metabolism end endothelial dysfunction,which might play a role in the pathogenesis of preeclampsia and GDM. Key words: Pre-eclampsia; Diabetes, gestational; Acute-phase proteins; Proto-oncogene proteins; Lipocalins

Hydrocarbons and Kidney Damage: Potential Use of Neutrophil Gelatinase-Associated Lipocalin and Sister Chromatide Exchange

Background: Millions of workers are exposed to polycyclic aromatic hydrocarbons (PAHs) and it is known that the kidney is a target for toxic chemicals. We have evaluated neutrophil gelatinase-associated lipocalin (NGAL) as a potential marker of tubular damage and have used it, with sister chromatid exchange (SCE) analysis, to evaluate carcinogenic risk in a group of workers from an oil refinery. Methods: NGAL and SCE analysis were evaluated in 160 subjects. Exposed subjects were divided into three groups, according to levels of exposure to PAHs: 40 highly exposed workmen (WM), 40 less exposed office workers (OW), and 40 subjects (GE) living in Gela. The control group included 40 healthy subjects (HS). Results: WM, OW and GE showed higher NGAL levels than HS. WM had higher levels of NGAL than the OW and GE groups; in ROC analysis, serum NGAL showed a good diagnostic profile (sensitivity 87.5%; specificity 100.0%), as did urinary NGAL (sensitivity 90.0%; specificity 92.5%). Moreover, regarding SCE analysis, WM showed higher values than HS. A direct correlation between SCE and serum NGAL was found in WM, the group most exposed to PAHs. Conclusion: The high values of NGAL are an expression of damage to the renal tubule determined by exposure to PAHs. Compared to the other groups studied, chromosomal aberrations – expressed as SCE – were increased in WM, the group most exposed to PAHs, indicating genotoxic damage. NGAL may also play a role in the process of carcinogenesis having a direct correlation with the number of SCEs.

Identification of Factors Causing Sudden Coagulation in Patients with Acute Myocardial Infarction

Background: Coronary artery disease (CAD) evolving to acute myocardial infarction (AMI) is due to the thrombotic occlusion of coronary vessels in the presence of destabilized atheroma, rich in inflammatory cells secreting proteolytic enzymes that induce the development of thrombosis. The aim of this study was to analyse the plasma of AMI patients for the detection of proteases or factors that may cause fast coagulation. Methods: The patients were analysed for the presence in plasma of cardiac troponin T (c-TnT) or proteases as neutrophil gelatinase-associated lipocalin (NGAL) using ELISA method and matrix metalloproteinase-9 (MMP-9) utilising flow cytometry technique and interleukin-8 (IL-8) using flow cytometry methodology. Results: The presence of AMI was demonstrated by high levels of c-TnT; in comparison with controls the AMI patients displayed a significant increase in the values of MMP-9 and low levels of antithrombin III: these markers were negatively correlated: MMP-9 appeared to cause the coagulation activity documented by the consumption of antithrombin III. The same patients also showed high levels of NGAL, which is known to modulate MMP-9 activity and to be involved in coagulation process: patients also exhibited an increased amount of IL-8 which appears to be associated with high levels of NGAL: this cytokine seems to affect the values of NGAL which is linked to coagulation process. Conclusion: The high levels of MMP-9, NGAL and IL-8 in AMI patients seemed to be interrelated and connected with the process leading to rapid coagulation. These markers may be measured in absence of AMI, particularly in CAD patients, as their detection may reveal a risk of sudden coronary coagulation.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin-C Are Sensitive Markers of Renal Injury in Patients with Multiple Myeloma,

Abstract 3918Renal impairment (RI) is a common complication of patients with multiple myeloma (MM). The evaluation of RI is based mainly on the estimation of glomerular filtration rate (GFR) using the MDRD equation. However, MDRD formula has greater value in patients with stabilized serum creatinine, while the majority of MM patients have acute renal damage. Thus, it is of great importance to evaluate novel markers of kidney injury in MM setting. Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 KDa protein which is overproduced by proximal tubular cells in response to injury. NGAL is upregulated within 2 hours of injury, well before functional changes are observed in both preclinical and clinical studies. NGAL has never been evaluated in MM. Cystatin-C (Cys-C) is a cysteine protease inhibitor which provides a better reflection of GFR (renal tubular function) than serum creatinine. The aim of the study was to evaluate NGAL and Cys-C in MM and explore possible correlations with patients' RI.We studied: i) 64 patients with newly diagnosed myeloma: 16 with asymptomatic disease (7M/9F; median age 59 years, range 37–82 years) and 48 with symptomatic myeloma (30M/18F; median age 70 years, range 45–89 years; ii) 8 patients with MGUS (4M/4F; median age 72 years, range 39–84 years); and iii) in 20 healthy, gender and age-matched controls. Serum Cys-C was measured on the Behring Nephelometer-II analyser using a latex particle-enhanced nephelometric immunoassay (Dade Behring, Liederbach, Germany). Serum NGAL was measured using an ELISA methodology (Quantikine, R&D Systems, Minneapolis, MN, USA). eGFR was evaluated using the MDRD formula.Twenty-six (54%) patients with symptomatic MM had eGFR >60 ml/min, while 12 (25%) had eGFR 30–60 ml/min and 10 (21%) eGFR <30 ml/min. All patients with asymptomatic MM and MGUS had an eGFR >60 ml/min. However, NGAL serum levels were elevated in patients with both asymptomatic (median: 91.7 μg/l, range: 29.5–206.4 μg/l) and symptomatic MM (115.4 μg/l, 15.4–417.3 μg/l) compared to controls (52.5 μg/l, 26.5–72.6 μg/l; p<0.001 for both comparisons). Even MGUS patients had elevated NGAL values compared to controls (116.5 μg/l, 74.9–205.5 μg/l; p<0.01). Only patients with symptomatic MM had increased levels of Cys-C compared to controls (1.37 mg/L, 0.7–4.0 mg/l vs. 0.7 mg/l, 0.6–1.0 mg/l; p<0.01). NGAL strongly correlated with Cys-C (r=0.506, p<0.001) and eGFR (r=-0.457, p<0.01), while Cys-C showed also strong correlation with eGFR (r=-0.804, p<0.001) as well as with ISS (ISS-3 had higher values of Cys-C compared to ISS-2 and ISS-1, p-ANOVA<0.001), beta2-microglobulin (r=0.434, p=0.002), high sensitivity CRP (r=0.364, p=0.012), serum interleukin-6 (r=0.349, p=0.016) and age (r=0.339, p=0.019). Regarding eGFR, the median levels (range) of NGAL were 97.8 μg/l (17.5–244.2 μg/l), 151.2 μg/l (15.4–232.3 μg/l) and 233.4 μg/l (101.7–417.3 μg/l) for patients with eGFR >60 ml/min, 30–60 ml/min and <30 ml/min, respectively (p-ANOVA<0.001). The respective median values for Cys-C were: 0.9 mg/l (0.7–2.0 mg/l), 1.5 mg/l (1.1–3.2 mg/l) and 2.9 (1.7–3.9 mg/l) for patients with eGFR >60 ml/min, 30–60 ml/min and <30 ml/min (p-ANOVA<0.001). The ROC analysis showed that NGAL values of >50.5 μg/l have a 80.8% sensitivity and 86.4% specificity for eGFR <60 ml/min (AUC=0.764). Similarly, Cys-C values of >1.15 mg/l have a 73.1% sensitivity and 100% specificity for eGFR <60 ml/min (AUC=0.941). Median levels of Cys-C were higher in patients with BJ proteinuria ≥200 mg/day (1.6 mg/l, 0.7–3.9 mg/l) compared to all others (1.1 mg/l, 0.7–1.9 mg/l; p=0.003). The respective values of NGAL for patients with BJ proteinuria ≥200 mg/day vs. <200 mg/day were: 169.7 μg/l (15.4–417.3 μg/l) vs. 105.5 μg/l (35–212.7; p=0.099). The ROC analysis showed that NGAL values of >61.7 μg/l have a 76.9% sensitivity and 81% specificity for BJ proteinuria ≥200 mg/day (AUC=0.641), while Cys-C values of >1.5 mg/l have a 92.3% sensitivity and 76.2% specificity for BJ proteinuria ≥200 mg/day (AUC=0.941).Our data suggest that both NGAL and Cys-C are very sensitive markers that reflect RI in newly-diagnosed patients with multiple myeloma. The high levels of NGAL in asymptomatic MM patients and in MGUS patients may indicate the presence of subclinical renal damage in these patients early in the course of their disease and may reveal NGAL as an early marker that predicts the development of RI in MM. Disclosures:No relevant conflicts of interest to declare.

Prognostic utility of plasma neutrophil gelatinase‐associated lipocalin in patients with acute heart failure: The NGAL EvaLuation Along with B‐type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial

AimsNeutrophil gelatinase-associated lipocalin (NGAL) is a measure of acute kidney injury. Renal dysfunction portends significant risk after discharge from acute heart failure (AHF). Thus, a sensitive marker of renal injury might also help to risk stratify HF patients.Methods and resultsGALLANT [NGAL EvaLuation Along with B-type NaTriuretic Peptide (BNP) in acutely Decompensated Heart Failure] was a multicentre, prospective study to assess the utility of plasma NGAL, alone and in combination with BNP, as an early risk marker of adverse outcomes. We studied 186 patients (61% male). There were 29 events (AHF readmissions and all-cause mortality) at 30 days (16%). Patients with events had higher levels of NGAL than those without (134 vs. 84 ng/mL, P < 0.001). The area under the receiver operating characteristic curve was higher for NGAL (0.72) than BNP (0.65), serum creatinine (0.57), or estimated glomerular filtration rate (eGFR; 0.55). In multivariable analyses, NGAL predicted events (P= 0.001), BNP approached significance (P= 0.052 and 0.070 without creatinine and GFR, respectively) while neither serum creatinine nor eGFR were significant. The addition of discharge NGAL over BNP alone improved classification by a net 10.3% in those with events and 19.5% in those without events, for a net reclassification improvement of 29.8% (P= 0.010). Subjects with both BNP and NGAL elevated were at significant risk [hazard ratio (HR) = 16.85, P= 0.006], as were subjects with low BNP and high NGAL (HR = 9.95, P= 0.036).ConclusionsPlasma NGAL is a measure of kidney injury that at the time of discharge is a strong prognostic indicator of 30 days outcomes in patients admitted for AHF.Clinical trial registration number: NCT 00693745

Neutrophil Gelatinase-Associated Lipocalin: A Biomarker in COPD

<h3>Background</h3> Neutrophil gelatinase-associated lipocalin (NGAL) is an antimicrobial peptide that could be involved in the pathogenesis of COPD. This study aimed to measure the plasma levels of NGAL in a large cohort of patients with COPD and control subjects and examine the levels of NGAL by COPD characteristics. <h3>Methods</h3> The study included 402 patients with COPD and 229 control subjects aged 40 to 76 years from the Bergen COPD Cohort Study. All patients with COPD had an FEV₁/FVC ratio of < 0.7, an FEV₁ < 80% predicted, and a smoking history of ≥ 10 pack-years. Plasma levels of NGAL were determined by enzyme immunoassay. Linear regression models were fitted with NGAL as the outcome variable. Confounders examined were sex, age, smoking, Charlson comorbidity score, use of inhaled steroids, neutrophil cell count, plasma creatinine and ferritin, and C-reactive protein. <h3>Results</h3> Mean ± SD plasma concentrations of NGAL were 75.1 ± 31.8 ng/mL in patients with COPD and 56.5 ± 22.0 ng/mL in control subjects (<i>P</i> < .01). NGAL levels were bivariately associated with age, smoking, body composition, Charlson comorbidity score, neutrophil blood count, creatinine, and C-reactive protein but were significantly elevated in patients with COPD, even after adjustment for confounders. Frequent exacerbations and hypoxemia was associated with higher levels of NGAL, whereas increasing Global Initiative for Chronic Obstructive Lung Disease stage was associated with lower levels of NGAL among patients with COPD. <h3>Conclusions</h3> Plasma levels of NGAL were significantly higher in patients with COPD compared with control subjects. NGAL was related to important COPD characteristics.

Elevated Serum Neutrophil Gelatinase-Associated Lipocalin Is an Early Predictor of Severity and Outcome in Acute Pancreatitis

About 210,000 new cases of acute pancreatitis (AP) involving reversible inflammation of the pancreas are reported in the United States every year. About one-fourth of all patients with AP go on to develop severe acute pancreatitis (SAP), which, unlike uncomplicated or mild acute pancreatitis (MAP, usually a self-limiting disease), constitutes a life-threatening condition with systemic complications, chiefly multiorgan dysfunction. An early prediction of the severity and outcome of patients with acute pancreatitis (AP) can lead to better treatment regimens for patients with SAP. There is currently no established biomarker for the early diagnosis of SAP. In this study, we investigated the potential of serum neutrophil gelatinase-associated lipocalin (NGAL) as an early marker to distinguish severe (SAP) from MAP and examine its ability to predict the prognosis of patients with SAP. To check the time kinetics of rise in NGAL during AP, we quantified NGAL levels in sera from mice with MAP or SAP at various time points (6, 12, 24 and 48 h) using sandwich enzyme-linked immunosorbent assay. NGAL levels were also quantified in serum from 28 MAP and 16 SAP cases and compared with 28 chronic pancreatitis and 30 healthy control samples. Samples collected within 5 days from onset of symptoms were included. The relationship of NGAL levels with survival and multiorgan failure (MOF) in SAP was also examined. Although NGAL levels were significantly higher in mice with both MAP and SAP 6 h after induction (compared to control animals), only mice with SAP exhibited a significant increase in NGAL levels at 24 h (P=0.003). NGAL levels declined at 48 h after induction in animals with both MAP and SAP but did not reach baseline levels. Among patients, mean (+/-s.e.) serum NGAL level was significantly higher in SAP (634+/-139 ng/ml) compared to MAP (84.7+/-7 ng/ml, P=0.0001). On subanalysis, the difference between MAP and SAP cases was significant in the first 48 h but not at 72, 96, or 120 h. NGAL was 100%, 96%, 97%, and 84% specific and 100%, 87.5%, 92%, and 94% sensitive in distinguishing SAP from MAP at 48, 72, 96, and 120 h, respectively, after the onset of symptoms. NGAL levels were significantly higher in SAP cases complicated by MOF (P=0.004), and high NGAL levels in SAP appeared to correlate with a fatal outcome. Our data provide the first evidence for the potential of serum NGAL as an early marker to distinguish MAP from SAP. Further, high NGAL levels predict MOF and fatal outcome in patients with SAP. This study provides sufficient evidence for multi-institutional randomized trials for estimating the potential of NGAL as early biomarker for SAP.

Serum Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Predicting Worsening Renal Function in Acute Decompensated Heart Failure

Background The development of worsening renal function (WRF, defined as creatinine rise ≥0.3 mg/dL) occurs frequently in the setting of acute decompensated heart failure (ADHF) and strongly predicts adverse clinical outcomes. Neutrophil gelatinase–associated lipocalin (NGAL) is produced by the nephron in response to tubular epithelial damage and serves as an early marker for acute renal tubular injury. We sought to determine the relationship between admission serum NGAL levels and WRF in the setting of ADHF. Methods and Results We measured serum NGAL levels in 91 patients admitted to the hospital with ADHF. Patients were adjudicated by independent physician into those that did or did not develop WRF over the ensuing 5 days of in-hospital treatment. In our study cohort (68% male, mean age 61 ± 15 years, mean left ventricular ejection fraction 31 ± 14%), median admission serum NGAL level was 165 ng/mL (interquartile range [IQR] 108–235 ng/mL). Thirty-five patients (38%) developed WRF within the 5-day follow-up. Patients who developed WRF versus those without WRF had significantly higher median admission serum NGAL levels (194 [IQR 150–292] ng/mL vs. 128 [IQR 97–214] ng/mL, P = .001). High serum NGAL levels at admission were associated with greater likelihood of developing WRF (odds ratio: 1.92, 95% confidence interval 1.23–3.12, P = .004). In particular, admission NGAL ≥140 ng/mL had a 7.4-fold increase in risk of developing WRF, with a sensitivity and specificity of 86% and 54%, respectively. Conclusions The presence of elevated admission serum NGAL levels is associated with heightened risk of subsequent development of WRF in patients admitted with ADHF.

Neutrophil gelatinase-associated lipocalin in normal and neoplastic human tissues. Cell type-specific pattern of expression.

Neutrophil gelatinase-associated lipocalin (NGAL) has recently been identified in myeloperoxidase-negative neutrophil granules. Members of the lipocalin family are thought to bind and transport small lipophilic molecules such as retinoids and roles in cell regulation have been proposed. Recently, NGAL has also been demonstrated in the colonic mucosa in certain pathologic conditions. The aim of this study was to examine the distribution of NGAL in normal and neoplastic tissues by immunohistochemistry. Interestingly, NGAL was found in a variety of normal and pathological human tissues. A cell type-specific pattern of expression was seen in bronchus, stomach, small intestine, pancreas, kidney, prostate gland, and thymus. The comparative analysis of the putative rat homologue neu-related lipocalin showed a very similar pattern of expression with the exception of pancreas and kidney. Neoplastic human tissues showed a very heterogeneous expression of NGAL protein. High NGAL levels were found in adenocarcinomas of lung, colon and pancreas. In contrast, renal cell carcinomas of various subtypes and prostate cancers contained low NGAL levels. Lymphomas and thymic tumours were negative for NGAL immuno-labeling. Knowledge about the location of NGAL in normal cells and in disease states provides the first clues towards understanding its biological function.