Elevated Neutrophil Gelatinase-associated Lipocalin Research Articles

#996 Validation of peritoneal NGAL as a biomarker for peritonitis: a comparison between laboratory-base method and rapid stick test

Abstract Background and Aims Neutrophil gelatinase-associated lipocalin (NGAL) is a protein involved in iron homeostasis, inflammation, and fibrosis. Initially discovered in human granulocytes, NGAL is found in various tissues. In renal contexts, NGAL's small size (23-25 kDa) and positive charge aid glomerular filtration and absorption in the proximal tubule. Notably, elevated NGAL levels were identified in peritoneal fluids during peritonitis in 2009, establishing it as a biomarker for early Peritoneal Dialysis (PD)-associated peritonitis diagnosis for values more than 100 μg/L. While our medical centre currently relies on the lab-based NGAL assay (NGALlab), advancements introduce the NGAL dipstick test (NGALds), offering a rapid and semi-quantitative colorimetric assessment. This study compares NGALds with NGALlab in clinical practice, assessing NGALds's potential for early peritonitis detection in PD patients' peritoneal fluid. Method This study involves a validation of diagnostic accuracy conducted through a retrospective analysis of parallel samples obtained from peritoneal effluents. Samples were collected from both healthy patients during routine analysis and from cases with suspected or confirmed peritonitis. Both NGALlab and NGALds analyses were conducted on each sample. The analysis aimed to evaluate the performance of the new NGALds by comparing it with the established NGALlab. Peritoneal NGALlab quantification employed the standard BioPorto test (BioPorto Diagnostics, Hellerup, Denmark), utilizing a particle-enhanced turbidimetric immunoassay. The novel NGALds is a rapid semi-quantitative assay that measures NGAL levels in biological fluids through colourimetric test strips, utilizing an antibody sandwich lateral flow dipstick test. NGAL values were categorized into colour-coded levels: 25 μg/L, 50 μg/L, 100 μg/L, 150 μg/L, 300 μg/L, and 600 μg/L. Statistical analyses were performed using SPSS Statistics 26.0 software. Spearman rank correlation coefficients (Rs) assessed categorical groups of NGAL values for peritoneal NGALds and NGALlab tests. A graphic comparison of these two tests was presented through a Bland-Altman plot Results Out of 301 peritoneal effluent samples, 156 were diagnosed with suspected peritonitis by ISPD Criteria. As Table 1 showed, NGALds showed a strong correlation with NGALlab categories (Rs = 0.876, P = 10−96), successfully diagnosing 96% (150 out of 156) peritonitis cases. Discrepancies between NGALlab and NGALds, visualized in the Bland-Altman plot (Fig. 1), were most notable when NGAL values exceeded the 600 μg/L threshold. However, this difference doesn't impact clinical significance, as high NGAL values remain diagnostically for peritonitis with both methods. Conclusion In conclusion, our study underscores a significant correlation between NGAL values measured by the laboratory method (NGALlab) and the NGAL dipstick test (NGALds). Importantly, NGALds exhibited a strong capability, correctly identifying 96% of peritonitis cases determined by NGALlab. Beyond statistical correlation, the NGAL dipstick emerges as a valid alternative for swift evaluation in patients presenting symptoms suggestive of peritonitis. Its ease of use, rapidity, and semi-quantitative colorimetric assessment make NGALds a patient-friendly tool. This user-friendly characteristic holds immense potential for streamlined clinical workflows, allowing for prompt and efficient peritonitis diagnosis.

#758 NGAL dipstick for peritonitis: bridging the gap between rapid assessment and clinical efficiency in peritoneal dialysis

Abstract Background and Aims Neutrophil gelatinase-associated lipocalin (NGAL) is a versatile protein known for its multifunctional roles, extending beyond its conventional use as a biomarker. It actively participates in crucial biological processes such as inflammation, proliferation, and migration. This study seeks to evaluate NGALds, a recently developed dipstick test, in comparison to the established laboratory method (NGALlab) for the early detection of peritonitis related to peritoneal dialysis (PD). The focus of the investigation lies in analyzing peritoneal fluid to develop a rapid and effective diagnostic tool, aiming to enhance the management of peritonitis. Method A retrospective analysis was undertaken to validate diagnostic accuracy, utilizing parallel samples obtained from peritoneal effluents. Samples were obtained from both PD stable patients undergoing routine analysis and from PD patients with suspected or confirmed peritonitis. The assessment of NGALds involved a direct comparison with the established NGALlab. Peritoneal NGALlab quantification was conducted using the BioPorto test, employing a particle-enhanced turbidimetric immunoassay. The NGALds, a rapid semi-quantitative assay, utilized colorimetric test strips and an antibody sandwich lateral flow dipstick test. The greatest value of NGAL detected by dipstick is 600 μg/L. Statistical analyses, including Spearman rank correlation coefficients (Rs), were performed with SPSS Statistics 26.0 software. Additionally, ROC analysis was carried out using white cell count and percentage of Neutrophils in peritoneal fluids as the gold standard. Results Among the 301 peritoneal effluent samples analyzed, 156 were diagnosed with suspected peritonitis using NGALlab and ISPD criteria. Each sample underwent analyses with both NGALlab and NGALds. As depicted in Fig. 1, NGALds exhibited a robust correlation with NGALlab categories (Rs = 0.876, P < 0.001), accurately identifying 96% (150 out of 156) of peritonitis cases. Discrepancies between NGALlab and NGALds were most evident when NGAL values exceeded the 600 μg/L threshold. Nevertheless, these variations did not impact clinical significance, as both methods consistently diagnosed elevated NGAL values indicative of peritonitis. After ROC analysis, which yielded an AUC of 0.82 (p < 0.001) (Fig. 2), the Youden Index was employed to identify a threshold value of 100 μg/L for the diagnosis of suspected peritonitis. Importantly, the application of this threshold to NGALds demonstrated a positive predictive value of 0.64 and a negative predictive value of 0.87. Conclusion In conclusion, our study reinforces the significant correlation between NGAL values obtained through the laboratory standard (NGALlab) and the novel NGAL dipstick test (NGALds). Notably, NGALds exhibited high efficacy, accurately identifying 96% of peritonitis cases diagnosed by NGALlab. This robust performance positions the NGAL dipstick as a valuable and accessible alternative for rapid assessment in patients exhibiting symptoms indicative of peritonitis. The user-friendly attributes of NGALds not only make it a practical diagnostic tool but also a patient-centric one. Furthermore, the high negative predictive value provides confidence in considering NGALds as a frontline diagnostic tool for suspected peritonitis. The ease of use and prompt results open a promising avenue for improving clinical workflows, offering an opportunity for expedited and efficient peritonitis diagnosis. For instance, NGALds could find utility in centres where NGAL is unavailable in the laboratory or at the patient's home.

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study.

Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

Neutrophil-Enriched Biomarkers and Long-Term Prognosis in Acute Coronary Syndrome: a Systematic Review and Meta-analysis.

Activated neutrophils release a range of inflammatory products that represent potential biomarkers, and there is interest in the prognostic value of these in acute coronary syndrome (ACS) patients. We conducted a systematic review to examine neutrophil-enriched biomarkers and the occurrence of major adverse cardiovascular events (MACE) in patients with ACS. We identified twenty-seven studies including 17,831 patients with ACS. The most studied biomarkers were neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase (MPO). Meta-analyses showed that elevated NGAL was associated with higher MACE rates (unadjusted risk ratio (RR) 1.52, 95% CI 1.12-2.06, p = 0.006) as were elevated MPO levels (unadjusted RR 1.61, 95% CI 1.22-2.13, p = 0.01). There was limited data suggesting that increased levels of calprotectin, proteinase-3 and double-stranded DNA were also associated with MACE. These results suggest that higher levels of neutrophil-enriched biomarkers may be predictive of MACE in patients with ACS, although higher-quality studies are needed to confirm these observations.

Predictive value of elevated neutrophil gelatinase-associated lipocalin levels for assessment of in-hospital adverse outcomes among myocardial infarction patients.

Inflammatory biomarkers are known to rise and have predictive value for adverse outcomes in patients with acute coronary ischemia. One of those biomarkers is neutrophil gelatinase-associated lipocalin (NGAL). To date, only very few studies have assessed the prognostic value of NGAL in this setting. We investigated the prognostic utility of elevated NGAL levels on clinical outcomes among ST-elevation myocardial infarction patients. High NGAL was defined as values within the 4th quartile. Patients were assessed for major in-hospital adverse clinical events (MACE). Multivariable logistic regression and area under the receiver operating characteristic curve (AUC) were used to further evaluate NGAL association for MACE and discrimination ability. A total of 273 patients were included. patients with high NGAL were at increased risk for MACE (62% vs. 19%; odds ratio 6.88, 95% confidence interval, 3.77-12.54, P < 0.001). After propensity score matching, the incidence of MACE was significantly higher in patients with high vs. low NGAL levels (69% vs. 6%, P = 0.002). In multivariable regression, high NGAL level was independently associated with MACE. The discrimination ability of NGAL to identify MACE (AUC 0.823), is significantly better than that of other inflammatory markers. Among ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention, high NGAL levels are associated with adverse outcomes, independent of traditional inflammatory markers.

Predictive value of elevated neutrophil gelatinase-associated lipocalin (NGAL) levels for assessment of in hospital adverse outcomes among myocardial infarction patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Inflammatory biomarkers are known to rise and have significant predictive value for adverse outcomes in patients with acute coronary ischemia .Neutrophil gelatinase-associated lipocalin (NGAL), a glycoprotein stored in mature neutrophil granules, is significantly increased in patients with myocardial infarction compared with patients with stable coronary artery disease and healthy subjects. To date, very few studies have assessed the prognostic value of NGAL in this setting. Purpose We investigated the prognostic utility of elevated NGAL levels on clinical outcomes among ST elevation myocardial infarction patients (STEMI) treated with primary coronary intervention (PCI). Methods Blood samples for plasma NGAL were drawn immediately after admission. High NGAL was defined as values within the 4th quartile (&amp;gt;75percentile). Patients were assessed for major in-hospital adverse clinical events (MACE). These included reduced left ventricular ejection fraction, clinical heart failure findings and 30-day mortality. Multivariable logistic regression was used to evaluate the association between NGAL group and MACE. Receiver operating characteristic curve (AUC) was used to evaluate the discrimination ability of NGAL compared with other inflammatory biomarkers including white blood cell count(WBC), peak troponin level, peak C-reactive protein(CRP) and neutrophil/lymphocyte ratio(NLR) for the prediction of MACE. Results A total of 273 patients were included (mean age 66 ± 14 years, 81% males). Patients with high NGAL were at increased risk for MACE (62% vs. 19%; OR 6.88, 95%CI 3.77-12.54, p&amp;lt;0.001, Figure 1). After propensity score matching, 55 pairs of comparable patients were identified. Following matching, the incidence of MACE was significantly higher in patients with high vs. low NGAL levels (69% vs. 6%, p=0.002; figure 1). In the multivariable logistic regression high NGAL level was independently associated with MACE (OR 9.25, 95%CI 4.33-19.76, P&amp;lt;0.001). The discrimination ability of NGAL to identify MACE (AUC 0.823) was significantly better (figure 2; p&amp;lt;0.001) than that of CRP (AUC 0.627), troponin (AUC 0.588), WBC (AUC 0.583) and NLR (AUC 0.601). Conclusions Among STEMI patients undergoing primary PCI, high NGAL levels are associated with adverse outcomes, independent of traditional inflammatory markers.

Chronic circadian disruption impairs cardiovascular rhythms and leads to kidney disease in mice

Shift workers have an increased risk of developing hypertension and reduced kidney function. Disruption of behavioral or environmental circadian rhythms increases cardiometabolic disease risk in humans and animals. We hypothesized that chronic circadian disruption (CCD) impairs cardiovascular rhythms and increases renal injury markers. Male C57BL/6J mice starting at 8-week of age were maintained under a normal light/dark cycle (12-h light, 12-h dark, control) or a CCD protocol (10-h light, 10-h dark, T20) with ad libitum food and water for 10 weeks. T20 mice gained significantly more body weight compared to control mice. Control mice showed a diurnal variation in food intake, while T20 mice had similar food intake during both light and dark phases with more food consumed in the light phase compared to control mice. Mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured by telemetry after 10 weeks of CCD. MAP between the light and dark periods was significantly different in control mice (12:12 LD), while T20 mice (10:10 LD) lacked diurnal variation (control 119±3 vs.101±2 mm Hg, dark vs. light, respectively, p&lt;0.001; T20 114±13 vs.113±12 mm Hg, dark vs. light, respectively, p=0.86; n=3-4). Control mice showed a diurnal variation in HR, whereas T20 mice did not show a light-dark difference (Control- 584±11 vs. 511±4 bpm, dark vs. light, respectively, p=0.001; T20- 537±14 vs. 526±5 bpm, dark vs. light, respectively, p=0.48; n=3-4). Dark phase HR was significantly decreased in T20 mice (p=0.01, control vs. T20). Control mice had a light-dark difference in activity, while T20 mice lacked diurnal variation in activity with significantly higher activity during the light phase (p=0.04, control vs. T20). Mice were placed in metabolic cages for urine collection during the light (control: ZT0-12; T20: ZT0-10) and dark (control: ZT12-0; T20: ZT10-0) phases. Urinary excretion of renal tubular injury markers albumin, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were measured (ELISA). Control mice had significantly higher albumin and NGAL excretion in dark vs. light phases, while T20 mice lacked a significant diurnal pattern with significantly elevated albumin and NGAL during the light phase compared to control mice (albumin: control 1.00±0.23 vs. 0.09±0.05 ug/hr dark vs. light, p=0.04, control light vs. T20 light, p=0.04; NGAL: control 1410±223 vs. 89±58 pg/hr dark vs. light, p=0.02, control light vs.T20 light, p=0.04, n=4-6). CCD also blunted the diurnal rhythm of KIM-1 excretion (light cycle, p=0.04, n=3-6). The diurnal variation in sodium and potassium excretion was also lost in T20 mice. These results indicate that CCD impairs cardiovascular rhythms as well as diurnal excretion of electrolytes and renal injury markers, which may increase risk for kidney disease. P01HL136267, AHA 856877 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

THE DIAGNOSTIC VALUE OF URINE GELATINASE-ASSOCIATED LIPOCALIN AS A BIOMARKER FOR ACUTE KIDNEY INJURY IN PRETERM INFANTS WITH HEMODYNAMICALLY SIGNIFICANT PATENT DUCTUS ARTERIOSUS

THE DIAGNOSTIC VALUE OF URINE GELATINASE-ASSOCIATED LIPOCALIN AS A BIOMARKER FOR ACUTE KIDNEY INJURY IN PRETERM INFANTS WITH HEMODYNAMICALLY SIGNIFICANT PATENT DUCTUS ARTERIOSUS

Serum procalcitonin, C-reactive protein, and neutrophil gelatinase-associated lipocalin in early diagnosis of acute kidney injury after upper urinary tract calculi.

To investigate the value of serum procalcitonin(PCT), C-reactive protein(CRP), and neutrophil gelatinase-associated lipocalin(NGAL) in the early diagnosis of acute kidney injury(AKI) after upper urinary tract calculi(UUTC). The clinical data of 86 patients who underwent UUTC surgery in our hospital from March 2020 to April 2021 were analyzed retrospectively(Approval number: 20211205L, Date: 2021-12-21). Patients were divided into an AKI group (AKI≥7 days after the operation) and a Non-AKI group. PCT, CRP, and NGAL concentrations were compared before and two hours after the operation. Multivariate logistic regression analysis was used to identify risk factors affecting the early occurrence of AKI post-operation. The receiver operating characteristic curve evaluated PCT, CRP, and NGAL in the early AKI diagnosis. A total of 86 patients (30 with AKI and 56 with Non-AKI) were included. Kidney injury molecule-1(KIM-1) and urinary microalbumin(mAlb) concentrations were significantly higher in the AKI group (P<0.05). PCT, CRP, and NGAL concentrations were significantly higher two hours after the operation than before the operation (P<0.05). KIM-1 levels and elevated PCT, CRP and NGAL concentrations affected the establishment of AKI after UUTC. The sensitivity of PCT, CRP, and NGAL in evaluating AKI after UUTC were 81.17%, 84.42%, and 79.02%; the specificity was 62.31%, 71.48%, and 73.32%; and the AUC was 0.812, 0.885 and 0.804 respectively. PCT, CRP, and NGAL concentrations in patients with AKI after UUTC were significantly increased two hours after the operation, which can be used for the early diagnosis of AKI after UUTC operation.

Association of neutrophil gelatinase associated lipocalin, ischemia modified albumin with uric acid in the etiopathogenesis of preeclampsia.

Preeclampsia is a multisystem illness that manifests in the third trimester of pregnancy after 20weeks of gestation and is marked by proteinuria and hypertension (PE). Changes in lifestyle, such as eating a high-calorie dietand delaying delivery, have raised the likelihood of developing PE. Eclampsia, abrupt renal failure, thromboembolic episodes leading to cardiac and brain problems, pulmonary embolism, and coagulopathy associated with HELLP syndrome are a few of the complications that might follow preeclampsia in pregnant moms. The objects of this study is to estimate and correlate the levels of NGAL (neutrophil gelatinase associated lipocalin), IMA (ischemia modified albumin) and Uric acid in prreclampsia. 40 diagnosed cases of preeclampsia and 40 healthy age and gestational age matched healthy controls were included in the study. Blood samples were collected from them and serum NGAL, IMA and Uric acid levels were estimated. Estimation of NGAL (neutrophil gelatinase associated lipocalin), IMA (ischemia modified albumin) was done by commercially available ELISA kits standard spectrophotometry methods in autoanalyzer Mind ray BS300 using commercially available kits. The parameters of NGAL and IMA were significantly increased in patients with PE (p<0.001) when compared with the healthy control subjects. γ-glutamyl transferases and OPN were found in patients with ALD (p<0.001) when compared with the control subjects. OPN showed significant positive correlations with AST (r=0.76, p<0.001), ALT (r=0.64 p<0.001), ALP (r=0.68, p<0.001), and GGT (r=0.61, p<0.001). The current study focuses on the roles of NGAL and IMA, two sensitive markers of kidney injury thatare particularly useful in identifying widespread endothelial dysfunction. As a result, the pattern of elevated NGAL and IMA levels can be useful for diagnosis.

Prospects for the Use of NGAL and KIM-1 for the Diagnosis of Acute Kidney Injury in Patients Receiving Antibacterial Therapy

The developers of Clinical Practice Guidelines for Acute Kidney Injury titled The Initiative to Improve Global Kidney Disease Outcomes (KDIGO) point at the need of new biomarkers for diagnosis acute kidney injury (AKI).The objective: to study and evaluate the diagnostic significance of the levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in patients with AKI in the early postoperative period when antibiotic therapy is used.Subjects and Methods. AKI frequency was assessed in 276 patients during the early postoperative period after the antibacterial drugs had been prescribed. Serum levels of KIM-1 and NGAL, glomerular filtration rate (GFR), creatinine, protein in urine were tested before the start of antibiotic therapy, in 24–48 hours, and in patients with AKI – additionally in 72–96 hours. The normal initial renal excretory function was registered only in 36 patients (13.04%). The majority of patients (242 patients, 86.96%) were diagnosed with chronic kidney disease of various stages.Results. NGAL and KIM-1 levels were higher in the group of patients with AKI before start of antibiotic therapy versus the group of patients with preserved renal function. However, a statistically significant increase in the level of KIM-1 and NGAL was found only in the group of patients with stages 3A and 3B of CKD versus the groups of patients with stages 1 and 2 of CKD. The second important observation is that a comorbid pathology in patients led to a high AKI incidence when antibiotic therapy was used – 35.86% (30–42%; 95%CI).Conclusion. The relationship of NGAL and KIM-1 levels with glomerular filtration rate (GFR) and KIM-1 level with the presence of proteinuria as indicators of impaired renal filtration function suggests that NGAL and KIM-1 levels reflect the state of renal filtration function. Based on this observation, it should be accepted that NGAL and KIM-1 levels can be used as markers for the diagnosis of AKI in patients receiving antibiotic therapy. The prescription of antibiotic therapy in the postoperative period in patients with surgical pathology and renal dysfunction leads to a high AKI incidence. Elevated KIM-1 and NGAL levels in AKI during the antibiotic therapy suggests their involvement in the reparation process.

Urinary Neutrophil Gelatinase-Associated Lipocalin Can Predict the Efficacy of Volume Expansion Therapy in Patients With Hepatitis B Cirrhosis and AKI.

Backgrounds: Kidney biomarkers in urine appear to be useful in differential diagnosis between acute tubular necrosis and other types of acute kidney injury (AKI) in cirrhosis. In clinical practice, prerenal azotemia (PRA) is often distinguished from other types of AKI by volume expansion therapy. The aim of the current study was to investigate the accuracy of urinary biomarkers in the differential diagnosis between PRA and other types of AKI. Methods: A total of 65 patients with hepatitis B cirrhosis were prospectively included and divided into AKI and non-AKI groups. Patients with hepatitis B cirrhosis and AKI discontinue diuretics, vasodilators, and nephrotoxic drugs and give volume expansion therapy. The efficacy was judged after 48 h of treatment. Urinary biomarkers were measured at the time of diagnosis of AKI and 48 h after volume expansion therapy. Univariate and multivariate analyses were used to identify independent risk factors for nonresponse to volume expansion therapy. Results: Of the 65 patients, 49 patients with newly diagnosed AKI were screened in the study, and 16 hospitalized patients with hepatitis B cirrhosis without AKI at the same period were screened as the control group. In patients with cirrhosis and AKI, 29 (59.18%) patients were in the response group and 20 (40.81%) patients were in the nonresponse group. The mortality rate in the nonresponse group was significantly higher than that in the response group (75% vs. 13.8% p < 0.001). After logistic regression analysis, urinary neutrophil gelatinase-associated lipocalin (NGAL) and serum creatinine (SCr) at diagnosis of AKI showed significant association with nonresponse to volume expansion therapy. The cutoff values for SCr and urinary NGAL were 128.50 µmol/L and 90.75 ng/ml, respectively. The area under the receiver operating curve (AUC) for SCr and urinary NGAL was 0.815 and 0.831. Conclusion: Elevated urinary NGAL can reflect the degree of kidney injury and is an independent risk factor for nonresponse to volume expansion therapy in patients with hepatitis B cirrhosis and AKI.

Relationship between Neutrophil Gelatinase-Associated Lipocalin, Eosinophil Cationic Protein, Cytokines, and Atopic Sensitization in Patients with Allergic Diseases.

The effect of neutrophil gelatinase-associated lipocalin (NGAL) on eosinophil activation, atopic sensitization, and systemic inflammation in allergic diseases has rarely been investigated. This study aimed to investigate the relationship between NGAL, eosinophil cationic protein (ECP), cytokines, and allergen-specific immunoglobulin E (sIgE) in allergic diseases. A total of 136 patients with allergies and 58 healthy individuals were evaluated. The concentrations of NGAL, ECP, tumor necrosis factor-α (TNF-α), interleukin-5 (IL-5), sIgE, total IgE (tIgE), and high-sensitivity C-reactive protein (hsCRP) were measured. The transforming growth factor-β1 (TGF-β1) level was measured as a profibrotic marker of bronchial asthma. Allergic patients had significantly higher NGAL, ECP, and hsCRP levels than healthy individuals. However, there was no significant difference in NGAL levels between patients with positive and negative ECP tests and those with high and low sIgE scores. Asthmatic patients with elevated NGAL exhibited a significantly higher TGF-β1 level than those without elevated NGAL. However, no significant difference was observed in the ECP, IL-5, and sIgE levels between the two groups. Among the patients with a positive ECP test, subjects with elevated hsCRP had two times higher NGAL levels than those without elevated hsCRP. NGAL was positively correlated with TNF-α, TGF-β1, and hsCRP, but not with ECP, IL-5, tIgE, and sIgE. An elevated NGAL level led to a 1.3-fold increase in the prevalence of high TGF-β1 (odds ratio: 1.31; 95% CI: 1.04–2.58; P < 0.001). In conclusion, NGAL elevation may be more closely linked to allergic inflammation and a possible fibrotic change in the airways than to the severity of eosinophil activation and atopic sensitization.

Predictive Value of Elevated Neutrophil Gelatinase-Associated Lipocalin (NGAL) Levels for Assessment of Cardio-Renal Interactions among ST-Segment Elevation Myocardial Infarction Patients.

Background: Elevated serum neutrophil gelatinase-associated lipocalin (NGAL) levels reflect both inflammatory reactions and renal tubular injury. Recently, associations with endothelial dysfunction and plaque instability were also proposed. We investigated the prognostic utility of elevated NGAL levels for renal and clinical outcomes among ST-segment elevation myocardial infarction (STEMI) patients treated with primary coronary intervention (PCI). Methods: We performed a prospective, observational, open-label trial. High NGAL was defined as values within the third tertile (>66 percentile). Results: A total of 267 patients were included (mean age 66 ± 14 years, 81% males). Short-term adverse outcomes were consistently increased in the high NGAL group with more acute kidney injury, lower mean left ventricular ejection fraction, higher 30-day mortality, and higher incidence for the composite outcome of major adverse cardiac events (MACE). In a multivariate logistic regression model, high NGAL emerged as a strong and independent predictor for MACE (OR 2.07, 95% CI 1.15–3.73, p = 0.014). Conclusions: Among STEMI patients undergoing primary PCI, elevated NGAL levels are associated with adverse renal and cardiovascular outcomes, independent of traditional inflammatory markers. Further studies are needed to assess the potentially unique role of NGAL in cardio–renal interactions.

The combined effects of exercise-induced muscle damage and heat stress on acute kidney stress and heat strain during subsequent endurance exercise.

The purpose of the study was to investigate the combined effect of downhill running and heat stress on muscle damage, as well as on heat strain and kidney stress during subsequent running in the heat. In a randomized cross-over study, ten non-heat-acclimated, physically active males completed downhill running in temperate (EIMD in Temp) and hot (EIMD in Hot) conditions followed by an exercise-heat stress (HS) test after 3-h seated rest. Blood and urine samples were collected immediately pre- and post-EIMD and HS, and 24h post-EIMD (post-24h). Core temperature and thermal sensation were measured to evaluate heat strain. Serum creatine kinase (CK), maximal voluntary isometric contraction of the quadriceps (MVC) and perceived muscle soreness were measured to evaluate muscle damage. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) levels were measured to indicate acute kidney stress. CK, MVC and perceived soreness were not different between conditions at any timepoints. In the EIMD in Hot condition, urinary NGAL was significantly elevated from pre- to post-HS (pre-HS: 6.56 {1.53-12.24}ng/min, post-HS: 13.72 {7.67-21.46}ng/min, p = 0.034). Such elevation of NGAL or KIM-1 was not found in the EIMD in Temp condition. As compared with downhill running in a temperate environment, downhill running in a hot environment does not appear to aggravate muscle damage. However, elevated NGAL levels following EIMD in a hot environment suggest such exercise may increase risk of mild acute kidney injury during subsequent endurance exercise in the heat.

Association between Neutrophil Gelatinase-Associated Lipocalin and Fetal Hemoglobin Levels in Patients with Type 2 Diabetes Mellitus.

The effect of neutrophil gelatinase-associated lipocalin (NGAL) on fetal hemoglobin (HbF) levels in diabetic patients is rarely investigated. This study is aimed at investigating the possible association between NGAL and HbF levels in type 2 diabetes mellitus (T2DM). A total of 160 patients with T2DM and 61 healthy individuals were evaluated. NGAL, HbF, tumor necrosis factor-α (TNF-α), interleukin-5 (IL-5), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and urine albumin levels were measured. HbF levels were significantly higher in patients with elevated NGAL than in those without elevated NGAL (1.44% versus 0.94%, P = 0.001). High HbF was 2.3 times more prevalent in patients with elevated NGAL than in those without elevated NGAL. In addition, NGAL, TNF-α, and IL-5 levels were significantly higher in patients with high HbF than in those with low HbF; however, there was no significant difference in HbA1c and FPG levels between the two groups. HbF was positively correlated with NGAL (r = 0.275, P < 0.001), TNF-α (r = 0.256, P < 0.001), and IL-5 (r = 0.212, P < 0.001), but not with HbA1c and FPG. An elevated NGAL level led to a 1.27-fold increase in the prevalence of high HbF (odds ratio: 1.27, 95% CI: 1.03–2.51, and P < 0.001). The diagnostic efficacy of NGAL to identify an elevated HbF level was superior to that of HbA1c (area under the curve: 0.697, 95% CI: 0.609–0.786 versus 0.584, 95% CI: 0.488–0.681, and P = 0.022). In conclusion, enhanced NGAL production may be closely linked to elevated HbF in conjunction with proinflammatory cytokines in patients with T2DM.

Elevated Neutrophil Gelatinase-Associated Lipocalin Is Associated With the Severity of Kidney Injury and Poor Prognosis of Patients With COVID-19

IntroductionLoss of kidney function is a common feature of COVID-19 infection, but serum creatinine (SCr) is not a sensitive or specific marker of kidney injury. We tested whether molecular biomarkers of tubular injury measured at hospital admission were associated with acute kidney injury (AKI) in those with COVID-19 infection.MethodsThis is a prospective cohort observational study consisting of 444 consecutive patients with SARS-CoV-2 enrolled in the Columbia University emergency department (ED) at the peak of the pandemic in New York (March 2020–April 2020). Urine and blood were collected simultaneously at hospital admission (median time: day 0, interquartile range: 0–2 days), and urine biomarkers were analyzed by enzyme-linked immunosorbent assay (ELISA) and a novel dipstick. Kidney biopsies were probed for biomarker RNA and for histopathologic acute tubular injury (ATI) scores.ResultsAdmission urinary neutrophil gelatinase-associated lipocalin (uNGAL) level was associated with AKI diagnosis (267 ± 301 vs. 96 ± 139 ng/ml, P < 0.0001) and staging; uNGAL levels >150 ng/ml had 80% specificity and 75% sensitivity to diagnose AKI stages 2 to 3. Admission uNGAL level quantitatively associated with prolonged AKI, dialysis, shock, prolonged hospitalization, and in-hospital death, even when admission SCr level was not elevated. The risk of dialysis increased almost 4-fold per SD of uNGAL independently of baseline SCr, comorbidities, and proteinuria (odds ratio [OR] [95% CI]: 3.59 [1.83–7.45], P < 0.001). In the kidneys of those with COVID-19, NGAL mRNA expression broadened in parallel with severe histopathologic injury (ATI). Conversely, low uNGAL levels at admission ruled out stages 2 to 3 AKI (negative predictive value: 0.95, 95% CI: 0.92–0.97) and the need for dialysis (negative predictive value: 0.98, 95% CI: 0.96–0.99). Although proteinuria and urinary (u)KIM-1 were implicated in tubular injury, neither was diagnostic of AKI stages.ConclusionIn the patients with COVID-19, uNGAL level was quantitatively associated with histopathologic injury (ATI), loss of kidney function (AKI), and severity of patient outcomes.

Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury.

Background and purpose:The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats.Experimental approach:Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/kg) and VIL (10 mg/kg) for 2 weeks.Findings/Results:DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity via alleviation of all the above-mentioned parameters when compared to DXR-control rats.Conclusion and implications:The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1β, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.

Neutrophil Gelatinase-Associated Lipocalin Contributes to Increased Risk of Cardiovascular Death After Acute Coronary Syndrome.

BackgroundNeutrophil gelatinase-associated lipocalin (NGAL) has been suggested to reflect early renal dysfunction. We investigated the predictive significance of serum NGAL in predicting cardiovascular (CV) death in an old-age population with coronary heart disease (CHD).MethodsIn total, 633 CHD patients with a stable clinical condition were enrolled. The measurements of serum NGAL and other laboratory indices were performed within 24 hours after admission. Adjusted analysis was used to assess relationships between serum NGAL and CV death during the 10-year follow-up period.ResultsMultivariate logistic regression analysis demonstrated that elevated NGAL levels were related to a higher prevalence of CV disease history [quartile 4, 2.41 (1.60–4.59), P-trend <0.001]. The Kaplan–Meier curve indicated that patients with high NGAL levels tended to have a higher rate of CV death than patients with low NGAL levels. A multivariate Cox model suggested that increased levels of NGAL were independently linked with elevated risk of CV death (HR=2.62, 95% CI 1.51–4.96, P<0.001) during the 10-year follow-up period, after adjusting for related confounding factors using sensitivity analysis. Furthermore, the receiver operating characteristics (ROC) curve demonstrated that serum NGAL (AUC=0.917, 95% CI 0.895–0.940, P<0.001) had an ideal predictive value in predicting CV death.ConclusionSerum levels of NGAL were elevated in patients with CHD and may be a new parameter that could independently predict CV death in these patients, which may strengthen its potential application in clinical practice.

Plasma Neutrophil Gelatinase-Associated Lipocalin Is Useful for Predicting Mortality in Critically Ill Patients.

Elevated neutrophil gelatinase-associated lipocalin (NGAL) occurs in a wide range of systemic diseases. This study examined the clinical utility of plasma NGAL to predict intensive care unit (ICU) and in-hospital mortality in critically ill patients. A total of 62 patients hospitalized in a mixed ICU were included; pNGAL, creatinine, and C-reactive protein (CRP) were assayed on four consecutive days (D1-D4) following ICU admission. APACHE II score (Acute Physiology and Chronic Health Evaluation) was calculated 24 h post-admission. ICU mortality reached 35% and in-hospital mortality was 39%. The median pNGAL at admission was 142.5 (65.6–298.3) ng/mL. pNGAL was significantly higher in non-survivors compared to survivors. The highest accuracy for ICU mortality prediction was achieved at the pNGAL cutoff of 93.91 ng/mL on D4 area under the curve (AUC) = 0.89; 95%CI 0.69–0.98 and for in-hospital mortality prediction was achieved at the pNGAL cutoff of 176.64 ng/mL on D3 (AUC = 0.86; 95%CI 0.69–0.96). The APACHE II score on ICU admission predicted ICU mortality with AUC = 0.89 (95%CI 0.79–0.96) and in-hospital mortality with AUC = 0.86 (95%CI 0.75–0.94). Although pNGAL on D1 poorly correlated with APACHE II (R = 0.3; p = 0.01), the combination of APACHE II and pNGAL on D1 predicted ICU mortality with AUC = 0.90 (95%CI 0.79–0.96) and in-hospital mortality with AUC = 0.95 (95%CI 0.78–0.99). Maximal CRP during study observation failed to predict ICU mortality (AUC = 0.62; 95%CI 0.49–0.74), but helped to predict in-hospital mortality (AUC = 0.67; 95%CI 0.54–0.79). Plasma NGAL with combination with the indices of critical illness is a useful biomarker for predicting mortality in heterogeneous population of ICU patients.