Plasma Neutrophil Gelatinase-associated Lipocalin Research Articles

Prognostic utility of neutrophil gelatinase-associated lipocalin (NGAL) levels for cardiovascular events in patients with stable coronary artery disease treated with percutaneous coronary intervention: a prospective longitudinal cohort study

IntroductionNeutrophil gelatinase-associated lipocalin (NGAL) modulates the enzymatic activity of matrix metalloproteinase-9, which is an important mediator of plaque instability in atherosclerosis. High NGAL levels can independently predict all-cause mortality and major adverse cardiac events (MACE) in patients with acute myocardial infarction (AMI). However, studies that have measured NGAL levels in patients with stable coronary artery disease (CAD) are limited. Furthermore, no significant prognostic predictive value between NGAL levels and stable CAD has been established.HypothesisWe aimed to investigate the prognostic role of NGAL levels in a prospective cohort study of patients with stable CAD treated with percutaneous coronary intervention (PCI).MethodsA total of 2,238 stable patients with CAD and a previous PCI were enrolled in a multicenter prospective observational study (The National Taiwan Biosignature Research, NTBR) in Taiwan. The primary outcome was the occurrence of MACE (cardiovascular death, nonfatal myocardial infarction, and ischemic stroke). The secondary outcome was a composite of cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure).ResultsDuring the mean follow-up period of 4.6 ± 1.7 years, 441 patients reached the primary endpoints. Kaplan-Meier analysis showed that event-free survival was significantly different between the first and third tertile groups (log-rank test, p < 0.001) in subjects categorized by NGAL levels. In a multivariate Cox proportional hazard regression analysis, plasma NGAL levels were independently associated with an increased risk of MACE [adjusted hazard ratio (aHR) = 1.35; 95% confidence interval (CI) = 1.18–1.54, p < 0.001], AMI (aHR = 1.34; 95% CI = 1.12–1.59, p < 0.001), and target vessel revascularization (aHR = 1.35; 95% CI = 1.19–1.53, p < 0.001). Addition of serum NGAL levels to the traditional risk model improved its prediction value for future cardiovascular events.ConclusionsHigh plasma NGAL levels were independently associated with the occurrence of MACE and composite cardiovascular events in patients with stable PCI-treat CAD.

Protective Effects of Melatonin on Kidney Function Against Contrast Media-Induced Kidney Damage in Patients With Chronic Kidney Disease: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Trial.

Patients with chronic kidney disease (CKD) are at increased risk of acute kidney injury following exposure to contrast media. We evaluated the effect of melatonin, a potent antioxidant, as a protective strategy against contrast-induced acute kidney injury (CI-AKI), with a focus on molecular mechanisms. We randomized patients with an eGFR < 60 mL/min/1.73 m2 undergoing coronary angiography (CAG) into melatonin (10 mg twice daily) or placebo groups. Treatment started 48 h before CAG and continued for a total of 6 days. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at the time of CAG, and at 6, 24, 48, 72 h, and Day 30 post-procedure. The primary outcome was the incidence of CI-AKI; secondary outcomes included kidney function, oxidative stress, mitochondrial function, and cell death pathways. Forty patients were randomized into either the treatment or placebo group. All subsequent analyses were conducted on an as-treat basis. The incidence of CI-AKI was significantly lower in the melatonin group compared to the placebo group (25% vs. 60%, p = 0.025). The melatonin group showed a significantly smaller percentage change in plasma neutrophil gelatinase-associated lipocalin (NGAL)at all time points. In the PBMC study, cellular oxidative stress was significantly reduced in the melatonin group at each time point, and mitochondrial oxidative stress was lower at 48-72 h. Mitochondrial respiration improved significantly, and both necrosis and necroptosis were reduced at 24 h. Melatonin administration effectively reduced the incidence of CI-AKI in CKD patients undergoing CAG. This protective effect was associated with decreased oxidative stress, enhanced mitochondrial function, and reduced cell death, suggesting melatonin as a promising preventive strategy for CI-AKI. Trial Registration: TCTR20210123004.

Plasma neutrophil gelatinase-associated lipocalin as a single test rule out biomarker for acute kidney injury: A cross-sectional study in patients admitted to the emergency department.

Acute kidney injury (AKI) is a syndrome with high mortality and morbidity in part due to delayed recognition based on changes in creatinine. A marker for AKI based on a single measurement is needed and therefore the performance of a single measurement of plasma neutrophil gelatinase-associated lipocalin (pNGAL) to predict AKI in patients admitted to the emergency department was tested. Samples from the Triage study which included 6005 consecutive adult patients admitted to the emergency department were tested for pNGAL. The optimal cutoff for pNGAL was determined by the AUC and compared to AKI based on creatinine using different estimations of the premorbid kidney function. In 4833 patients, two or more plasma creatinine (pCr) measurements were available allowing the detection of AKI. The highest prevalence of AKI (10%) was found when defining AKI as an increase in pCr ≥26.5 μmol/L from the prior year's mean pCr. At these conditions the AUC for pNGAL to predict AKI was 85% giving an optimal cutoff of 142.5 ng/mL with a negative predictive value of 0.96, a positive predictive value of 0.35, a specificity of 0.87 and a sensitivity of 0.70. The study illustrates that the value of a single measurement of pNGAL is primarily in excluding AKI whereas it`s poorer in predicting the presence of AKI. When diagnosing AKI with pCr the optimal baseline pCr level is the mean of available pCr (mb-pCr) measurements from up to a year prior to the current event.

Plasma Levels of Propionylcarnitine Improved Prediction of Heart Failure and All-Cause Mortality in Patients with Stable Coronary Artery Disease.

Plasma metabolites could be suitable as predictive biomarkers for cardiovascular pathologies or death, thereby improving the prediction of protein biomarkers. The release of acylcarnitines may be altered after coronary artery disease (CAD) in subjects with recurrent clinical outcomes, and this could be used as a prognosis tool. Patients with stable coronary artery disease (SCAD) who had suffered an acute coronary syndrome 6-9 months before were followed for up to 4.3 years for adverse events. Soluble pro-inflammatory/fibrotic proteins, and a panel of 13 amino acids and 13 acylcarnitines, were evaluated by ELISA and metabolomics analyses as potential predictors of a primary outcome [heart failure (HF) or death]. Among 139 patients (67.0 years old, BMI = 28.6 kg/m2, and 71.2% male), 25 developed the primary outcome after a mean follow-up of 2.2 years. These patients showed increased plasma levels of NT-proBNP (1300 vs. 250 pg/mL; p < 0.001), pro-inflammatory/fibrotic MCP-1 (1.7 vs. 1.4 × 102 pg/mL; p = 0.043), Gal-3 (12.7 vs. 7.9 ng/mL; p < 0.001), and NGAL (2.7 vs. 1.6 × 102 ng/mL; p < 0.001), and lower acetyl- and propionylcarnitines (0.59 vs. 0.99 µM, p = 0.007, and 3.22 vs. 6.49 × 10-2 µM, p < 0.001, respectively). Instead, plasma amino acids were not significantly changed. Through a multivariable logistic regression analysis, a combined model of age, Gal-3, and the NGAL/propionylcarnitine ratio showed the highest prediction for HF or death (AUC = 0.88, sensitivity = 0.8, and specificity = 0.81; p < 0.001). Patients with SCAD led to recurrent HF or all-cause death. Interestingly, increased levels of plasma NGAL and Gal-3, and a reduction in propionylcarnitine, could predict the occurrence of these events.

Reduction in Renal Heme Oxygenase-1 Is Associated with an Aggravation of Kidney Injury in Shiga Toxin-Induced Murine Hemolytic-Uremic Syndrome.

Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the relevance of the heme-degrading enzyme heme oxygenase-1 (HO-1, encoded by Hmox1) in HUS has not yet been investigated. We hypothesized that HO-1, also important in acute phase responses in damage and inflammation, contributes to renal pathogenesis in HUS. The effect of tamoxifen-induced Hmox1 gene deletion on renal HO-1 expression, disease progression and AKI was investigated in mice 7 days after HUS induction. Renal HO-1 levels were increased in Stx-challenged mice with tamoxifen-induced Hmox1 gene deletion (Hmox1R26Δ/Δ) and control mice (Hmox1lox/lox). This HO-1 induction was significantly lower (-43%) in Hmox1R26Δ/Δ mice compared to Hmox1lox/lox mice with HUS. Notably, the reduced renal HO-1 expression was associated with an exacerbation of kidney injury in mice with HUS as indicated by a 1.7-fold increase (p = 0.02) in plasma neutrophil gelatinase-associated lipocalin (NGAL) and a 1.3-fold increase (p = 0.06) in plasma urea, while other surrogate parameters for AKI (e.g., periodic acid Schiff staining, kidney injury molecule-1, fibrin deposition) and general disease progression (HUS score, weight loss) remained unchanged. These results indicate a potentially protective role of HO-1 in the pathogenesis of Stx-mediated AKI in HUS.

Nephroprotective effects of the soluble guanylyl cyclase stimulator, riociguat in doxorubicin-induced acute kidney injury in rats

This study aimed to investigate the potential protective effects of riociguat, a soluble guanylyl cyclase (sGC) stimulator, on kidney function and structure in rats with acute kidney injury (AKI) induced by the chemotherapeutic drug doxorubicin (DX). Rats were subjected to a single intraperitoneal injection of DX (13.5 mg/kg) on the 5th day, either alone or in combination with low-dose riociguat (3 mg/kg/day), or high-dose riociguat (10 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Kidney tissues were examined histopathologically. DX-induced nephrotoxicity was characterized by increased plasma urea, creatinine, uric acid and neutrophil gelatinase-associated lipocalin (NGAL). DX also decreased creatinine clearance and albumin levels and increased urinary N-acetyl-β-D-glucosaminidase (NAG) activity. Furthermore, DX increased the inflammatory markers interleukin 1 beta (IL-1 β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). DX further induced oxidative stress injury evidenced by decreased glutathione reductase (GR) activity, total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase levels and increased malondialdehyde (MDA) levels. Concomitant treatment with riociguat ameliorated these DX-induced changes with parallel histopathological improvements but the effects were more favorable with high-dose riociguat. The observed renoprotective effects of riociguat can be partly attributed to the anti-inflammatory and anti-oxidant properties of this drug.

Assessment of Neutrophil Gelatinase Associated Lipocalin in Children with Acute Gastroenteritis and Dehydration to Identify Early Signs of Acute Kidney Injury

Background: Gastroenteritis often correlates with acute kidney injury (AKI) in children who are hospitalized. The primary diagnostic test for acute kidney injury (AKI) in modern times is serum creatinine (SCr), which increases in the presence of AKI and is eliminated by glomerular filtration. SCr is an unsuitable biomarker for renal sickness because it lacks specificity and a slow response to disease severity or treatment changes. NGAL, or neutrophil gelatinase-associated lipocalin, is a molecular weight of 25 kDa protein and forms a covalent bond with neutrophil gelatinase. Elevations in NGAL levels due to kidney injury have important predictive value and may forecast the onset of acute kidney injury (AKI) 24-72 hours before an increase in diagnostic serum creatinine (SCr) values. Aim and objectives: This study aims to determine whether plasma NGAL concentrations in mild, moderate, or severe dehydrated acute gastroenteritis patients may indicate acute kidney damage (AKI). The research will investigate whether acute renal injury and plasma NGAL concentrations are connected. Patients and methods: The cross-sectional design was employed in this study and included 80 patients who attended the pediatric gastrointestinal clinic at Babylon Children's Hospital. Between November 2022 and June 2023, all patients had gastroenteritis symptoms accompanied by different dehydration levels. Results: Patients with severe dehydration had considerable higher level of NGAL than those with mild to moderate dehydration (p&lt;0.001). There was a notable inverse relationship (p = 0.046) between the NGAL level and potassium but a considerable direct link (p&lt;0.001) between the NGAL level and creatinine. However, no significant correlation was seen between the NGAL level and urea (p = 0.404 and 0.062, respectively). The confidence range for the area under the curve (AUC) is 0.940 to 0.981, with a confidence level of 95%. The p-value is less than 0.001. The sensitivity is 88%. An accuracy of 88.4% has been attained. The NGAL cut-off point is 3.9832. Conclusion: An analysis of plasma neutrophil gelatinase-associated lipocalin (NGAL) in individuals with gastroenteritis and varied degrees of dehydration indicated a clear and direct link between the two parameters. Specifically, when dehydration worsened, the average NGAL value increased

Validation of Neutrophil gelatinase-associated lipocalin (NGAL) for Diabetes-associated Acute Kidney Injury

Abstract Introduction/Objective This study aimed to evaluate the analytical and clinical performance of the BioPorto NGAL Test on the Beckman Coulter AU480 to correlate plasma neutrophil gelatinase-associated lipocalin levels (pNGAL) with clinical progression and severity of diabetes-associated acute kidney injury (AKI) with hospitalized patients at an East Central Georgia Medical Center Methods/Case Report Analytical validation of the BioPorto NGAL Test was carried out on the AU480 and was based on imprecision, limit of blank, limit of detection, functional sensitivity, carryover, and specificity. Clinical validation studies included 45 patients hospitalized between January and November 2023 with and without diabetes at risk for developing AKI. All patients’ pNGAL levels were measured at admission until 96 hours post admission. Receiver operating characteristics and likelihood ratio methods were used to determine optimal sensitivity, specificity, cutoff value, and the discriminatory power of pNGAL. Results (if a Case Study enter NA) The intra-assay and inter-assay imprecision percent relative standard deviation was between 0.8 (2.7%) and 3.7 (4.2%). The limit of blank and limit of detection of Bioporto NGAL was 2.2 ng/mL and 15.4 ng/mL, respectively. An analytical coefficient of variation of 20% corresponded to a pNGAL value of 9.9 ng/mL. The optimal cutoff value for pNGAL to predict AKI for patients with DM was 293 ng/mL, with a sensitivity of 80% and specificity of 87%; AUC: 0.85, p &amp;lt; 0.001. In a multivariate logistic regression model, pNGAL levels at 48 hours post admission were a risk factor for diabetes-associated AKI (OR 1.012, 95% CI:1.000 – 1.023; p = 0.051). Conclusion These results show that pNGAL levels at 48h are an independent risk factor for diabetes-associated AKI, and the optimal cutoff for this condition is 293 ng/mL. The optimal cutoff values for AKI for early diagnosis and risk stratification, along with its association with comorbidities, are important to improve patient outcomes and diagnosis accuracy.

A Prospective Comparative Study on the Clinical Diagnostic Performance of Blood Inflammatory Markers in Acute Appendicitis.

Despite the substantial advancements in imaging techniques for the diagnosis and differential diagnosis of acute appendicitis (AA) over recent decades, the specificity and sensitivity of widely utilized laboratory biomarkers in clinical practice remain inadequate.This study aimed to investigate the diagnostic utility of commonly employed blood inflammatory markers for AA. A total of 399 participants who either sought medical care or underwent health examinations were enrolled in this prospective study. The cohort comprised 200 patients diagnosed with AA (AA group), 100 patients presenting with abdominal pain but without AA (AP group), and 99healthy individuals undergoing routine health check-ups (HC group). For all subjects, the following biomarkers were measured: plasma neutrophil gelatinase-associated lipocalin (NGAL), white blood cell count (WBC), neutrophil count (NEU), percentage of neutrophils (NEU%), neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP). The diagnostic performance of the observed indicators, both individually and in combination, was assessed for the diagnosis of AA using Receiver Operating Characteristic (ROC) curves analysis and Delong's test. The laboratory indicators demonstrated a progressive increase from the HC group to the AP group, and further to the AA group (all p<0.05). Multifactorial logistic regression analysis identified NEU% and plasma NGAL as significant risk factors for the occurrence of AA. ROC curve analysis and Delong's test indicated that, in distinguishing the AA group from the HC group, the diagnostic performance of plasma NGAL, CRP, and NLR was equally substantial and superior to that of NEU and WBC. Within the AP group, plasma NGAL and CRP exhibited comparable diagnostic efficacy, outperforming NEU, WBC, and NLR. When differentiating AA in the non-appendicitis group (ie HC group + AP group), NGAL and CRP demonstrated comparable diagnostic efficacy, surpassing that of NEU, white WBC, and NLR. While the integration of multiple diagnostic tests can potentially improve overall diagnostic accuracy, the observed enhancement in the AUC is not statistically significant. NGAL, CRP, WBC, NEU% and NLR were significantly increased in patients with acute abdomen. NGAL and NEU% may function as independent risk factors for predicting the incidence of AA, with NGAL and CRP demonstrating similar and favorable diagnostic performance. While the combined evaluation of these biomarkers may enhance the diagnostic value for AA, the improvement in the area under the curve (AUC) is not substantial.

Impacts of age, type 2 diabetes, and hypertension on circulating neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 after prolonged work in the heat in men.

Prolonged work in the heat increases the risk of acute kidney injury (AKI) in young men. Whether aging and age-associated chronic disease may exacerbate the risk of AKI remains unclear. We evaluated plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum kidney injury molecule-1 (KIM1) before and after 180min of moderate-intensity work (200W/m2) in temperate (wet-bulb globe temperature [WBGT] 16°C) and hot (32°C) environments in healthy young (n = 13, 22years) and older men (n = 12, 59years), and older men with type 2 diabetes (T2D; n = 9, 60years) or hypertension (HTN; n = 9, 60years). There were no changes in NGAL or KIM1 concentrations following prolonged work in temperate conditions in any group. Despite a similar work tolerance, the relative change in NGAL was greater in the older group when compared to the young group following exercise in the hot condition (mean difference + 82ng/mL; p < 0.001). Baseline concentrations of KIM1 were ~ 22pg/mL higher in the older relative to young group, increasing by ~ 10pg/mL in each group after exercise in the heat (both p ≤ 0.03). Despite a reduced work tolerance in the heat in older men with T2D (120 ± 40min) and HTN (108 ± 42min), elevations in NGAL and KIM1 were similar to their healthy counterparts. Age may be associated with greater renal stress following prolonged work in the heat. The similar biomarker responses in T2D and HTN compared to healthy older men, alongside reduced exercise tolerance in the heat, suggest these individuals may exhibit greater vulnerability to heat-induced AKI if work is prolonged.

Plasma and Urinary Neutrophil Gelatinase-Associated Lipocalin as Predictors of Renal Parenchymal Involvement in Children with Febrile Urinary Tract Infection: A Pilot Study.

Urinary tract infections (UTIs) are very common bacterial infections in children. Early detection of renal parenchymal involvement in this setting can help clinicians make more effective treatment choices. The aim of this pilot study was to assess the ability of plasma and urinary neutrophil gelatinase-associated lipocalin (pNGAL and uNGAL) levels, measured using an automated system, to accurately predict renal parenchymal involvement in children with febrile UTIs. This prospective single-center study included 28 children aged ≥ 4 years with a first episode of febrile UTIs. All patients underwent magnetic resonance imaging. pNGAL, uNGAL, procalcitonin, C-reactive protein (CRP), and white blood cells were measured before antibiotic therapy. The receiver operating characteristic (ROC) area under the curve for predicting acute pyelonephritis was 0.6 for pNGAL, 0.8 for CRP, 0.4 for PCT, and 0.4 for uNGAL. The ROC analyses showed an optimal cutoff of 141.0 ng/mL for pNGAL (sensitivity, 54.2%; specificity, 75.0%; positive predictive value, 92.9%; and negative predictive value, 21.4%). pNGAL and uNGAL did not effectively aid the early prediction of renal parenchymal involvement in children ≥ 4 years with febrile UTIs. The novelties of this study were the use of MRI as the gold standard and an automated biochemical method to measure NGAL.

Abstract P119: The Heart Failure with Preserved Ejection Fraction Induced By High-Fat Diet and L-NAME in Mice Does not Induce a Renal Damage

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome, without effective therapy, characterized by diastolic dysfunction, a chronic low-grade inflammation and comorbidities such as hypertension. At the present time, few experimental models of HFpEF represent the hallmarks of patients. Recently, it has been described that the administration of a high-fat diet (HFD) in conjunction with an endothelial nitric oxide synthase inhibitor (L-NAME) can adequately reproduce the pathophysiological features of HFpEF. However, the effects on at renal level in HFpEF models have not been fully described. Our goal was to evaluate the kidney damage in a HFpEF model induced by HFD+L-NAME. Male C57BL/6N mice (12 weeks old, n=4-6) were treated with control diet or HFD (60% in fat calories) plus L-NAME (0.65 g/L in drinking water) for 15 weeks. We evaluated cardiac function (echocardiographic analysis), systolic blood pressure (SBP, plethysmography), cardiac and renal hypertrophy (morphometry and histology), plasma creatinine, blood urea nitrogen (BUN), plasma neutrophil gelatinase-associated lipocalin (pNGAL), proteinuria, and kidney immune cells infiltration (flow cytometry). All data are presented by mean±standard deviation. After 15 weeks of HFD+L-NAME we observed diastolic dysfunction (p&lt;0.001), an increased SBP (control=128.0±15.3 vs. HFD+L-NAME=155.7±9.8 mmHg; p&lt;0.01), without changes in ejection fraction and shortening fraction. In addition, we did not observe cardiac or renal hypertrophy, nor apparent histological changes in the renal structure between both groups of animals. No differences were found between groups regarding plasma creatinine, pNGAL or BUN, however, we observed that HFD+L-NAME induced proteinuria in compared to control mice (p&lt;0.05). Finally, when we evaluated the immune cells population in kidney of both groups, we observed no differences in dendritic cells, macrophages, or neutrophils. Nevertheless, the HFD+L-NAME treatment was associated to a significant rising of Ly6G + CD11b - cells population (CD45 + MHC-II - CD11c +/- F4/80 - ) compared to control mice (p&lt;0.05). In conclusion, our results indicate that there is no renal inflammatory damage after 15 weeks of in HFpEF experimental model. However, to our knowledge, an uncharacterized population of Ly6G cells could be participating at this stage which could trigger a long-term renal damage . FONDECYT 1221585 (MPO), 1231604 (JJ), 1231909 (CAA), 11241074 (PA) and FONDAP 15130011(MPO, LG).

Protective effect of β-sitosterol against high-fructose diet-induced oxidative stress, and hepatorenal derangements in growing female sprague-dawley rats

BackgroundChronic consumption of a high-fructose diet causes oxidative stress that compromises kidney and liver health. β-sitosterol (Bst), a phytosterol, is a functional nutrient with health benefits. β-sitosterol antioxidant activity protects the liver and kidney from ROS-mediated damage and lipid peroxidation. We evaluated the potential renoprotective and hepatoprotective effects of orally administrated β-sitosterol in high-fructose diet-fed growing female rats. Thirty-five 21-day old female Sprague-Dawley rat pups were randomly assigned to and administered the following treatments for 12 weeks: group I- standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group II- SRC + 20% w/v fructose solution (FS) as drinking fluid + PC; group III- SRC + FS + 100 mg/kg body mass (BM) fenofibrate in gelatine cube; group IV- SRC + FS + 20 mg/kg BM β-sitosterol gelatine cube (Bst) and group V- SRC + PW + Bst. The rats were fasted overnight, weighed then euthanised. Blood was collected, centrifuged and plasma harvested. Livers and kidneys were excised, weighed and samples preserved for histological assessments. Plasma biomarkers of oxidative stress, liver and kidney function and renal tubular injury were assessed.ResultsHigh fructose diet fed rats had increased plasma KIM-1, NGAL (p < 0.001) and MDA levels (p < 0.05). Dietary fructose caused microvesicular and macrovesicular steatosis, and reduced glomerular density, Bowman’s capsule area and urinary space. β-sitosterol protected against the high-fructose diet-induced hepatic steatosis and glomerular disturbances without adverse effects on liver and kidney function.Conclusionsβ-sitosterol, as a dietary supplement, could potentially be exploited to prevent high-fructose diet-induced NAFLD and to protect against high-fructose diet-induced renal tubular injury.

Early Detection of Chronic Kidney Disease Using Plasma Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1 in Small-Breed Dogs: A Retrospective Pilot Study.

Multiple diagnostic modalities are urgently needed to identify early-stage kidney diseases. Various molecules have been investigated; however, most studies have focused on identifying specific biomarkers in urine. Considering that assessing the symmetrical dimethylarginine (SDMA) plasma concentration is more suitable as an early diagnostic test for chronic kidney disease (CKD) in routine veterinary practice, we aimed to investigate the clinical usefulness of plasma neutrophil gelatinase-associated lipocalin (pNGAL) and plasma kidney injury molecule-1 (pKIM-1) concentrations for CKD detection in small-breed dogs. Through a retrospective analysis, we found that numerous clinicopathological data showed a log-normal distribution, even when they satisfied normality tests. Moreover, the log-transformed pNGAL and pKIM-1 concentrations successfully identified CKD International Renal Interest Society (IRIS) stages 1-4 and the risk group with underlying CKD risk factors. Correlation analysis and group comparison of other factors confirmed the possibility of using these two biomarkers for detecting the CKD risk group and IRIS stage 1. Receiver operating characteristic curve analysis revealed that the diagnostic accuracy for discriminating the risk group was superior in the order of pKIM-1, pNGAL, SDMA, and serum creatinine levels. In conclusion, these results suggest that pKIM-1 and pNGAL are possible early or quantifiable markers of insignificant CKD or can be at least used as an adjunct with traditional indicators.

Urinary neutrophil gelatinase-associated lipocalin as early biomarker for renal disease in dogs with leishmaniosis

Canine leishmaniosis (CanL), caused by Leishmania sp., presents a wide array of symptoms; renal dysfunction is frequently observed in these dogs and is associated with a poor prognosis and increased mortality. The traditional biomarkers namely urea and creatinine can detect renal damage but only in advanced stages of the disease. However, it has been shown that the symmetric dimethylarginine assay (SDMA) or the protein/creatinine ratio (UPC) and are early biomarkers of renal dysfunction. Their elevation occurs earlier than that of creatinine, but other novel biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) are currently under investigation. Our objective was to determine whether the urine NGAL-creatinine ratio (uNGAL/c) can provide very early diagnosis of kidney disease in CanL. In total, 68 dogs were included in the study: 15 healthy dogs and 53 dogs with CanL who were classified according to International Renal Interest Society (IRIS) classification: IRIS 1 (N= 34), IRIS 2 (N= 9) and IRIS 3/4 (N= 10). IRIS 1 was subdivided according to proteinuria in IRIS 1NP (13 dogs with UPC < 0.2), IRIS 1BL (8 dogs with UPC = 0.2–0.5) and IRIS 1 P (13 dogs with UPC > 0.5). Blood samples were collected for complete hematological and biochemistry analysis including plasma NGAL. Urinalysis included specific gravity, UPC, CysC and NGAL expressed as a ratio with creatinine. The mean concentrations of pCysC and SDMA in CanL, show a statistically significant increase from IRIS 1NP, not being statistically significant for pCysC in the IRIS 1BL group. The UPC show a statistically significant increase from IRIS 1NP. In all groups with CanL for uCysC/c and uNGAL/c was observed a statistically significant increase. The uNGAL/c in the group proteinuric animals, presents a positive correlation with all renal biomarkers studied. In the group of non-proteinuric animals, the uNGAL/c presents a positive correlation with SDMA and UPC. The uNGAL/c can be considered a reliable indicator of renal disease in dogs diagnosed with CanL who are non-azotemic and non-proteinuric.

Early neutrophil gelatinase-associated lipocalin (NGAL) measurement could rule out future acute kidney injury in patients with acute coronary syndrome-Prospective observational study.

The diagnosis of acute kidney injury (AKI) is of importance among patients with ST segment elevation (STEMI) undergoing primary coronary intervention (PCI). It is often delayed given the need in serial measurements of creatinine or other serum markers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proven marker for AKI, although its role as an early predictor in this setting was scarcely addressed before and was the aim of our study. Prospective observational study including 133 patients with STEMI treated with PCI. Plasma NGAL was drawn immediately before PCI (NGAL-0) and 24 h after (NGAL-24). Similar analysis of C-reactive protein (CRP) was performed for additional comparison. Mean age was 62 ± 13 years, 78% were men, and 20 (15%) developed AKI after admission. Patients with AKI after admission demonstrated higher levels of NGAL-0 (164 vs. 95 ng/mL; p < 0.001) and NGAL-24 (142 vs. 93 ng/mL; p < 0.001). Levels of NGAL-0 and NGAL-24 were similar within the AKI and non-AKI groups. Using ROC curve analysis, NGAL-0 had best predictive ability for AKI development (AUC 0.841, 95% CI 0.80-0.96), compared with NGAL-24 (0.783, 95% CI 0.74-0.85), CRP-0 (0.701, 95% CI 0.58-0.83), and CRP-24 (0.781, 95% CI 0.66-0.90). The optimal NGAL-0 cutoff for AKI prediction was 125 ng/mL, with 70% sensitivity, 84% specificity, and 94% negative predictive value. Among STEMI patients, NGAL measurement upon admission are associated with AKI and may serve as a reliable marker for early AKI detection. Future studies may direct risk stratification using this single test can direct personalized evaluations during the admission, and focused interventions to prevent AKI.

Tachycardia and Acute Kidney Injury among Critically Ill Patients with Sepsis: A Prospective Observational Study

Introduction: Tachycardia caused by sympathetic overactivity impairs myocardial function and raises septic patients’ mortality. This study examined whether tachycardia is associated with acute kidney injury (AKI) period-prevalence among critically ill patients with and without sepsis. Methods: In 328 patients (119 sepsis and 209 non-sepsis) admitted to our intensive care unit (ICU), we assessed heart rate at ICU admission, plasma neutrophil gelatinase-associated lipocalin (NGAL) and N-terminal pro-B-type natriuretic peptide, and urinary L-type fatty acid-binding protein and N-acetyl-β-d-glucosaminidase (NAG) at 0 and 48 h after admission. Tachycardia was defined as a heart rate above 100 beats/min. Results: Tachycardia was independently correlated with AKI prevalence during the first week after ICU admission in the septic patients, but not in the non-septic patients. A dose-dependent increase in AKI period-prevalence was observed across ascending heart rate ranges. Furthermore, we discovered a dose-dependent increase in renal biomarker-positive patients regarding plasma NGAL and urinary NAG over increasing heart rate ranges 48 h after admission. Conclusion: The findings revealed an independent relationship between tachycardia and AKI prevalence during the first week of ICU in septic patients. Heart rate was found to have a dose-dependent effect on AKI prevalence and renal insult monitored by biomarkers.

Trajectory pattern of serially measured acute kidney injury biomarkers in critically ill patients: a prospective observational study

BackgroundThe clinical value of the trajectory of temporal changes in acute kidney injury (AKI) biomarkers has not been well established among intensive care unit (ICU) patients.MethodsThis is a single-center, prospective observational study, performed at a mixed ICU in a teaching medical institute in Tokyo, Japan. Adult ICU patients with an arterial line and urethral catheter were enrolled from September 2014 to March 2015. Patients who stayed in the ICU for less than 48 h and patients with known end-stage renal disease were excluded from the study. Blood and urine samples were collected for measurement of AKI biomarkers at 0, 12, 24, and 48 h after ICU admission. The primary outcome was major adverse kidney events (MAKE) at discharge, defined as a composite of death, dialysis dependency, and persistent loss of kidney function (≥ 25% decline in eGFR).ResultsThe study included 156 patients. Serum creatinine-based estimated glomerular filtration rate (eGFR), plasma neutrophil gelatinase-associated lipocalin (NGAL), and urinary liver-type fatty acid-binding protein (uL-FABP) were serially measured and each variable was classified into three groups based on group-based trajectory modeling analysis. While the trajectory curves moved parallel to each other (i.e., “low,” “middle,” and “high”) for eGFR and plasma NGAL, the uL-FABP curves showed distinct trajectory patterns and moved in different directions (“low and constant,” “high and exponential decrease,” and “high and exponential increase”). These trajectory patterns were significantly associated with MAKE. MAKE occurred in 16 (18%), 16 (40%), and 9 (100%) patients in the “low and constant,” “high and exponential decrease,” and “high and exponential increase” groups, respectively, based on uL-FABP levels (p-value < 0.001). The initial value and the 12-h change in uL-FABP were both significantly associated with MAKE, even after adjusting for eGFR [Odds ratio (95% confidence interval): 1.45 (1.17–1.83) and 1.43 (1.12–1.88) for increase of initial value and 12-h change of log-transformed uL-FABP by 1 point, respectively].ConclusionsTrajectory pattern of serially measured urinary L-FABP was significantly associated with MAKE in ICU patients.

#554 Baseline neutrophil gelatinase-associated lipocalin (NGAL) levels for early prediction and ruling out future contrast nephropathy

Abstract Background and aims Neutrophil gelatinase-associated lipocalin (NGAL), is an early marker of acute kidney injury (AKI). There is only limited data, however, on the optimal timing for assessment, the cut-off values and its utilization for ruling out AKI We aimed to investigate the diagnostic utility of sequential NGAL measurements for both prediction and ruling out of AKI among patients with ST segment elevation (STEMI) undergoing primary coronary intervention (PCI). Methods We included 133 patients with STEMI treated with PCI. Blood samples for plasma NGAL were drawn immediately before PCI (NGAL 0) and 24 hours after PCI (NGAL 24). Optimal threshold for the development of AKI were determined using receiver operating characteristic curves (ROC). Patients were also assessed for the dynamics between NGAL 0 and NGAL 24 levels. Results Mean age was 62 ± 13 years and 78% were men, and a total of 20 (15%) developed AKI. Patients with AKI demonstrated higher plasma NGAL 0 levels (164 ± 42 vs. 95 ± 30 ng/mL; p &amp;lt; 0.001) as well as NGAL 24 levels (142 ± 41 vs. 93 ± 36 ng/mL; p &amp;lt; 0.001). There were no significant changes between NGAL 0 &amp; 24 hours within the 2 groups (Fig. 1). According to the ROC curve analysis NGAL 0 performed better than NGAL 24 for AKI prediction (Fig. 2). The optimal NGAL 0 level for AKI prediction was &amp;gt;125 ng/mL (AUC 0.841, 95% CI 0.801–0.961, p &amp;lt; 0.001), with a sensitivity of and specificity of 70% and 84% respectively, while the negative predictive value of NGAL 0&amp;lt;125 ng/mL was 94%. Conclusions Among STEMI patients, NGAL levels before primary PCI may be utilized both for ruling out and for the prediction of AKI.

#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 (&amp;gt;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 &amp;lt; 0.001 vs. OR 17.6, p &amp;lt; 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 &amp;lt; 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.