Neutrophil Gelatinase-associated Lipocalin Concentrations Research Articles

The Tubular Damage Markers: Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1 in Newborns with Intrauterine Growth Restriction

Background: Intrauterine growth restriction (IUGR) is a poorly understood complication of pregnancy. It may be associated with various diseases in adulthood, such as hypertension, cardiovascular disease, insulin resistance, and end-stage renal disease. Objectives: The aim of this study was to check whether IUGR affects the function of renal tubules, as assessed by the tubular damage markers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1). Methods: The study included 126 term neonates. Thirty-eight newborns were the result of pregnancies complicated by IUGR. Eighty-eight healthy newborns were the result of normal pregnancies with no prenatal or perinatal complications. The concentrations of urinary NGAL and KIM-1 were determined with a commercially available ELISA kit and were normalized for urinary creatinine (Cr) concentration. Results: We found a significantly higher urinary concentration of NGAL and NGAL/Cr ratio in newborns from pregnancies complicated by IUGR when compared to the reference group. We found that female gender was associated with a higher concentration of urinary NGAL and also urinary NGAL/Cr. Conclusions: This is the first work that demonstrates that urinary NGAL concentration and urinary NGAL/Cr are significantly higher in infants that are small for gestational age than in appropriate-for-gestational-age infants. This might indicate subclinical kidney damage in newborns with IUGR.

Ultra-high-performance liquid chromatography-mass spectrometry method for neutrophil gelatinase-associated lipocalin as a predictive biomarker in acute kidney injury

Neutrophil gelatinase associated lipocalin (NGAL) is a protein that was found to be overexpressed in acute kidney injury (AKI). The rise in NGAL concentration, both in urine or plasma, appears earlier than for other classical renal function markers such as serum creatinine, thus making it a suitable marker for early pathology detection.The aim of this study was to develop a method involving tryptic digestion, solid phase extraction and LC-MS/MS analysis to analyze NGAL in plasma medium using an isotope labeled surrogate protein, containing NGAL signature tags, as internal standard (QPrEST). The method was validated for the analysis of NGAL in an analytical range from 50 to 1250 ng/mL using two different proteotypic peptides.The method was further used to quantify the NGAL in human plasma samples for whom elevated NGAL values were expected. NGAL values were between 190.8 and 242.6 ng/mL for control group and between 228.1 and 3526.2 ng/mL for patient group. This study proved that the selection of the right internal standard is of utmost importance in targeted proteomics studies as the digestion steps might cause high variability. This study also confirmed that, although NGAL is highly resistant to proteases such as trypsin, the method could be fully validated according to FDA guidelines and subsequently used to assess NGAL levels in patient plasma with high analytical confidence.

Validation of an ELISA for detection of neutrophil gelatinase-associated lipocalin (NGAL) in equine serum.

Neutrophil gelatinase-associated lipocalin (NGAL) has been shown to be a useful marker of kidney injury in people and dogs, but has not been described in horses. The aim of the study was to validate a commercially available porcine-specific ELISA to measure serum concentrations of equine NGAL. Intra- and interassay imprecisions were evaluated by multiple measurements on equine serum pools. Assay inaccuracy was determined by the linearity under dilution. Overlapping performance was assessed by measuring NGAL concentrations in horses with normal and elevated serum creatinine levels. Intra- and interassay imprecision (coefficient of variation) ranged from 5.35% to 28.39%. The ELISA showed no signs of inaccuracy. Overlapping performance was acceptable, as the assay was able to detect the expected differences of NGAL levels in horses with normal and elevated serum creatinine concentrations. Equine serum NGAL concentrations could be quantified reliably using the porcine-specific ELISA.

Accuracy of different biomarkers for early diagnosis of acute kidney injury in patients undergoing cardiovascular surgery under cardiopulmonary bypass

Objective To evaluate the accuracy of different biomarkers for early diagnosis of acute kidney injury (AKI) in the patients undergoing cardiovascular surgery under cardiopulmonary bypass (CPB). Methods A total of 200 patients, aged 22-86 yr, weighing 46-87 kg, scheduled for elective cardiovascular surgery under CPB, were enrolled in this study.The concentration of serum creatinine was determined at 1 day before operation and 1-7 days after operation.At 1 day before operation and 0, 2, 6 and 12 h after operation, the concentrations of urine neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (Cys C), tissue inhibitor of matrix metalloproteinase type 2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) were determined.The TIMP-2 and IGFBP-7 product (TI) was calculated.AKI was diagnosed after surgery according to Kidney Disease Improving Global Outcomes criteria.The receiver operating characteristic curve was plotted, and the area under receiver operating characteristic curve (AUC) was calculated. Results The incidence of AKI was 20.5%.The AUC of AKI diagnosed by the concentration of urine NGAL was 0.689, 0.709, 0.713 and 0.803 at 0, 2, 6 and 12 h after operation, respectively (P<0.05). The AUC of AKI diagnosed by the concentration of urine Cys C was 0.639, 0.762, 0.774 and 0.812 at 0, 2, 6 and 12 h after operation, respectively (P<0.05). The AUC of AKI diagnosed by TI was 0.687, 0.721, 0.740 and 0.779 at 0, 2, 6 and 12 h after operation, respectively (P<0.05). The AUC of AKI diagnosed by combined three indices the parallel test was 0.694, 0.773 and 0.794 at 0, 2 and 6 h after operation, respectively (P<0.05). The AUC of AKI diagnosed by the serial test was 0.610, 0.631 and 0.667 at 0, 2 and 6 h after operation, respectively. Conclusion Urine NGAL or Cys C concentrations or TI single detection and parallel test have a certain accuracy for early diagnosis of AKI in the patients undergoing cardiovascular surgery under CPB. Key words: Lipocalins; Matrix metalloproteinases; Insulin-like growth factor binding proteins; Cardiopulmonary bypass; Acute kidney injury

Neutrophil gelatinase-associated lipocalin (NGAL) and cardiovascular events in patients with stable coronary artery disease

Inflammation is an important mediator in the pathogenesis of atherosclerosis. Neutrophil gelatinase-associated lipocalin (NGAL) is a small glycoprotein secreted by neutrophils. NGAL regulates the activity of matrix metalloproteinase-9, which plays a role in plaque instability. It has therefore been hypothesised that NGAL may modulate inflammation and promote the development and progression of atherosclerosis. Our aim was to assess the predictive value of plasma NGAL in a prospective cohort study of 876 high-risk patients with stable coronary artery disease (CAD). NGAL levels were measured using the NGAL TestTM from BioPorto Diagnostics. Clinical follow-up was performed after a median of 3.1 years. The endpoint was a combination of non-fatal acute myocardial infarction (MI), cardiovascular death (CVD), or ischaemic stroke. The NGAL concentration was (median [25;75%]: 64.3 µg/L [51.3;81.4]). The area under the receiver operating characteristic curve (AUC) was 0.56 (95% confidence interval (CI): 0.49;0.64) for the diagnosis of the composite endpoint and 0.66 (95% CI: 0.56;0.75) after adding NGAL to high-sensitive C-reactive protein (hs-CRP), leucocyte count, interleukin-6 (IL-6), calprotectin, age, sex, body mass index (BMI), diabetes mellitus, smoking and creatinine. However, the AUC for hs-CRP, leucocyte count, IL-6, calprotectin, age, sex, BMI, diabetes mellitus, smoking and creatinine without NGAL was similar at 0.66 (95% CI: 0.56;0.76). NGAL alone had no predictive value with respect to the composite endpoint of non-fatal AMI, ischaemic stroke, or CVD in stable CAD patients. NGAL did not add any predictive value to the endpoint compared with existing inflammatory biomarkers and cardiovascular risk factors.

Iron excretion in urine in patients with acute kidney injury after cardiac surgery.

Hemolysis during cardiopulmonary bypass may lead to acute kidney injury caused by an excessive amount of iron. The clinical usefulness of the measurement of total iron concentration in the urine with the use of the atomic absorption spectrometry method for early identification of patients with postoperative acute kidney injury is not well-established. An observational, prospective study was conducted on a group of 88 pre-selected adult patients undergoing a planned coronary artery bypass grafting (CABG) procedure. The amount and concentrations of total iron, creatinine and neutrophil gelatinaseassociated lipocalin (NGAL) were evaluated in urine samples. A comparative analysis of the evaluated biochemical parameters was performed in regard to the occurrence of acute kidney injury 48 h postoperatively. Patients in the acute kidney injury group presented more advanced age (p = 0.01), preoperative myocardial infarction (p = 0.02), diuresis reduction (p = 0.04), and lower total iron levels in the 48-hour urine sample (p = 0.01). There was no difference when considering iron concentration in single urine samples in the study group. The sole result of total iron concentration in single urine samples is unreliable for the diagnosis of acute kidney injury after cardiac surgery. Decreased excretion of iron in the urine seems to be an important additional element in the multifactorial pathogenesis of acute postoperative kidney failure.

Postpartum evaluation of cardiovascular disease risk for women with pregnancies complicated by hypertension.

Postpartum stratification of cardiovascular risk for women with pregnancies complicated by pre-eclampsia is challenging. Our aim was to identify potential clinical and biomarker predictors of future cardiovascular risk at six weeks postpartum in women with hypertensive pregnancies. Prospective longitudinal cohort. Ten year-Framingham cardiovascular risk scores were calculated for 477 women (94 with gestational hypertension, 288 with pre-eclampsia, 30 with superimposed pre-eclampsia, 51 with chronic hypertension, 14 women with uncomplicated pregnancies). B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL) and placental growth factor (PlGF) were quantified at six weeks postpartum. Framingham cardiovascular risk scores were not higher in women with pregnancies complicated by pre-eclampsia than healthy controls, nor were scores higher in women with pre-existing chronic hypertension complicated with superimposed pre-eclampsia compared with those without superimposed pre-eclampsia. Women with gestational hypertension had higher risk scores than women with pre-eclampsia and healthy controls. Established risk factors of cardiovascular disease including diastolic blood pressure and previously diagnosed chronic hypertension were associated with higher scores, and African ethnicity, parity and estimated glomerular filtration rate also were independently associated with higher Framingham risk scores at six weeks postpartum. PlGF, BNP and NGAL concentrations were not associated with Framingham cardiovascular risk scores after adjustment for independent variables. A history of pre-eclampsia or superimposed pre-eclampsia in most recent pregnancy was not associated with elevated Framingham risk score at six weeks postpartum. Established clinical predictors may enable risk stratification at six weeks postpartum, which are not enhanced by the biomarkers included in this study.

Urinary NGAL and KIM-1 Are Significantly Elevated in Young Adults (YA) with Type 1 (T1D) and Type 2 (T2D) Diabetes

Urinary (U) neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are markers of renal tubular injury. Whether NGAL and KIM-1 are elevated in early diabetic kidney disease (DKD) is not known. We performed a pilot study to compare the U concentrations (C) of NGAL and KIM-1 in YA with T1D or T2D from the SEARCH registry and healthy controls (n 45 in each group). The YA with diabetes were selected based on age at dx &amp;gt; 10 years and duration &amp;gt;8 years and were randomly selected across the quartiles of eGFR with similar age, gender and ethnicity. T1D (age 21 ± 2 years; duration 9.6 ± 1.0 years; HbA1c 9.3 ± 2.1% eGFR 126 ± 19 mL/min/1.73m2, UACR 11 ± 16 µg/mg), T2D (age 24 ± 3 years, duration 9.8 ± 1.2 years, HbA1c 8.5 ± 3.0%, eGFR 128 ± 21 mL/min/1.73m2, UACR 38 ± 71 µg/mg), controls (age 23 ± 3 years). In each group 50% were female, 41% white, 43% AA, and 16% Hisp. NGAL and KIM-1 were significantly elevated in T1D and T2D compared with controls (p &amp;lt; 0.001, p&amp;lt; 0.007). Although there was a trend for a greater UC of NGAL in T2D than T1D and a greater UC of KIM-1 in T1D than T2D, these differences were not statistically significant. Elevated UC of NGAL and KIM-1 are present in YA with T1D and T2D suggesting the presence of tubular damage early in the course of diabetes. Further investigation will determine if these markers can be used to assess the natural history of tubular injury or monitor therapeutic intervention in DKD. Disclosure N.M. Sheanon: None. A.K. Mottl: None. R. Dagostino: Consultant; Self; Teva Pharmaceutical Industries Ltd., Acelity, RedHill Biopharma, Edwards Lifesciences. C. Suerken: None. M. Afkarian: None. D. Dabelea: None. G. Imperatore: None. S.M. Marcovina: None. D.J. Pettitt: None. S. Saydah: None. L.M. Dolan: None.

Value of urinary KIM-1 and NGAL combined with serum Cys C for predicting acute kidney injury secondary to decompensated cirrhosis

Urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and serum cystatin C (Cys C) are biomarkers of acute kidney injury (AKI). However, the efficacy of combining these indices to diagnose decompensated cirrhosis is unknown. This study involved 150 patients divided into AKI and non-AKI, and healthy individuals. Urinary KIM-1 and NGAL, serum Cys and creatine, and glomerular filtration rate (GFR) were compared based on Child-Pugh liver function class. Urinary KIM-1 and NGAL concentrations and serum Cys C levels were significantly higher in patients with AKI secondary to decompensated cirrhosis than in those with AKI not secondary to decompensated cirrhosis (p < 0.01). These were significantly associated with higher kidney injury index stages (p < 0.01) and negatively correlated with GFR in secondary AKI patients. Urinary KIM-1 and NGAL and serum Cys C increased significantly and GFR decreased as Child-Pugh class of decompensated cirrhosis significantly increased (p < 0.05). SCr levels were significantly increased in Child-Pugh class C patients (p < 0.05). Urinary KIM-1, urinary NGAL, serum Cys C, and the combined detection factor, as screening indices, could aid in the early diagnosis of AKI secondary to decompensated cirrhosis.

Serum NGAL can act as an early renal safety biomarker during long-term nucleos(t)ide analogue antiviral therapy in chronic hepatitis B.

Tubular renal toxicity is a side-effect of long-term therapy with nucleos(t)ide analogue(s) (NA) in chronic hepatitis B (CHB). There are no established surrogate markers in plasma of early NA-related toxicity. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein produced by tubular cells following renal damage. We aimed therefore to retrospectively compare conventional renal markers (estimated glomerular filtration rates (eGFR) and urinary protein/creatinine ratio uPCR) with a sensitive biomarker (NGAL) in CHB patients on long-term NA therapy and assess the ability of new markers to predict NA-related renal toxicity (new onset of nonalbumin proteinuria). A total of 192 naïve CHB patients (median age 41years, 78% males, 25% HBeAg+, 35% cirrhosis) were NA treated for at least 5years (median 8.34years, range 5.54-11.1years). The eGFR and uPCR were compared at baseline and last clinical visit with serum NGAL concentrations measured by ELISA at same time-points and assessed according to the presence/absence of nonalbumin proteinuria at last visit. While baseline and last visit eGFR were similar (median:78 vs 84mL/min), serum NGAL concentrations increased during therapy (median:9.4 vs 16.4ng/mL, P<.05). The proportion of patients with proteinuria (uPCR>15) increased between baseline and last visit (4.6% vs 21.4%, P<.05), with 30 (16%) patients having de novo nonalbumin proteinuria at last visit. High baseline NGAL concentrations were exclusive to patients with de novo nonalbumin proteinuria (median:31.7 vs 7.8ng/mL, P<.01) and baseline NGAL levels >25mg/mL were predictive of nonalbumin proteinuria at last visit (AUROC=0.813). In conclusion, serum NGAL can act as a surrogate marker of early renal injury (de novo nonalbumin proteinuria) in CHB on long-term NA therapy.

Efficacy of corticosteroids in prevention of acute kidney injury in neonates undergoing cardiac surgery-A randomized controlled trial.

Heart surgery requiring cardiopulmonary bypass (CPB) causes an inflammatory response which may further induce acute kidney injury (AKI). In the present randomized controlled study we evaluated whether corticosteroids can prevent CPB related AKI in neonates undergoing heart surgery. Forty neonates were randomized to receive 2 mg/kg methylprednisolone followed by hydrocortisone infusion 0.2 mg/kg/h perioperatively with tapering doses for 5 days, or placebo administered in a similar fashion. The primary outcome was the inflammatory response (plasma concentrations of interleukins 6 and 10). The correspondence of the interleukin concentrations with AKI was analysed as secondary outcome. In addition, plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), plasma cystatin C, and urine kidney injury molecule-1 (KIM-1) levels were measured. Six patients (15%) developed post-operative AKI. No significant difference in the AKI occurrence between the treatment (n = 2) and the placebo (n = 4) groups could be found (risk ratio 2.00, 95% confidence interval 0.41-9.71; P = .661) despite significant reduction in inflammatory response in the treatment group. One patient in the treatment group and two patients in the placebo group required acute peritoneal dialysis. Plasma creatinine and cystatin C or urine NGAL and KIM-1 concentrations did not differ between the treatment and the placebo group. Significantly reduced inflammatory reaction induced by corticosteroid treatment in neonates undergoing cardiac surgery did not reduce the incidence of AKI defined by KDIGO classification or decrease the rise of AKI biomarkers.

Renoprotective Effects of Artesunate against Renal Ischemia-Reperfusion Injury in Rat Model

Renal ischemia-reperfusion (Renal I/R) leads to acute kidney injury (AKI),a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models,both in vitro and in vivo,have been used to study the pathogenic mechanisms of ischemic AKI and to test reno-protective strategies. Aim: To study potential protective effects of artesunate on renal I/R injury. Renal I/R injury was unilaterally induced in adult (3 to 5 months) male Sprague-Dawely rats,whose weights ranged from 180 to 390 g. Thereafter,the animals were pre-treated with artesunate intra-peritoneally,and at the end of reperfusion sacrificed humanely. Plasma,serum and tissue samples were obtained for analysis. Plasma concentrations of NGAL (neutrophil gelatinase associated lipocalin),an iron-trafficking protein involved in multiple processes such as apoptosis,innate immunity and renal development,and tissue concentrations of IL-18 (Interleukin-18) were measured via ELISA analysis. Serum urea and creatinine were also measured in the samples. Artesunate improved renal ischemia reperfusion,including renal function and brought about reductions in inflammatory mediators and kidney tissue injury. Plasma concentrations of NGAL and tissue concentrations of IL-18 were significantly (p &lt; 0.05) lower in the artesunatepretreated group than in the vehicle and control groups. Furthermore,serum concentrations of urea and creatinine were significantly (p &lt; 0.05) decreased in the pretreated group as compared to the control group. Artesunate can significantly improve renal function following I/R through down-regulation of inflammatory parameters and NGAL expression. Furthermore,it could serve as a potential therapy in ischemia reperfusion-induced acute kidney injury.

Urinary Biomarkers of Kidney Tubular Damage and Risk of Cardiovascular Disease and Mortality in Elders

Novel urinary biomarkers have enabled earlier detection of kidney tubular damage, but their prognostic value for adverse cardiovascular outcomes is uncertain. We hypothesized that tubular damage, measured by urine α1-microglobulin (A1M), amino-terminal propeptide of type III procollagen (PIIINP), and neutrophil gelatinase-associated lipocalin (NGAL), would be associated with higher risks for cardiovascular events and mortality among elders. Case-cohort study. This study included a randomly selected subcohort (n=502), cardiovascular disease (CVD) cases (n=245), and heart failure cases (n=220) from the Health, Aging, and Body Composition (Health ABC) Study. Baseline urine A1M, PIIINP, and NGAL concentrations. Incident CVD, heart failure, and all-cause mortality. Cox proportional hazards models were used to evaluate biomarker associations with each outcome. At baseline, mean age was 74 years and estimated glomerular filtration rate was 73mL/min/1.73m2. After adjustment for demographics, estimated glomerular filtration rate, albumin-creatinine ratio, and other cardiovascular risk factors, each doubling in biomarker concentration was associated with the following adjusted HRs for CVD: A1M, 1.51 (95% CI, 1.16-1.96); PIIINP, 1.21 (95% CI, 1.00-1.46); and NGAL, 1.12 (95% CI, 1.05-1.20). There were 248 deaths in the subcohort during a median follow-up of 12.4 years. Adjusted associations of each biomarker (HR per doubling) with all-cause mortality were: A1M, 1.29 (95% CI, 1.10-1.51); PIIINP, 1.05 (95%, 0.94-1.18); and NGAL, 1.07 (95% CI, 1.02-1.12). Biomarker concentrations did not have statistically significant associations with heart failure after multivariable adjustment. Urine biomarkers were measured at a single time point; no validation cohort available. Kidney tubular damage is an independent risk factor for CVD and death among elders. Future studies should investigate mechanisms by which kidney tubular damage may adversely affect cardiovascular risk.

Urinary Biomarkers of Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin

Aminoglycosides are commonly used for the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, they are potentially nephrotoxic. This prospective observational cohort study aimed to investigate the potential validity of two urinary renal biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in identifying aminoglycoside-induced nephrotoxicity in children with CF. Children and young adults up to 20 years of age with a confirmed diagnosis of CF were recruited from ten United Kingdom hospitals. Participants provided urine samples for measurement of KIM-1 and NGAL concentrations, at baseline, at regular outpatient appointments, and before, during and after exposure to clinically-indicated treatment with the aminoglycoside tobramycin. 37/158 patients recruited (23.4%) received at least one course of IV tobramycin during the study. The median peak fold-change during tobramycin exposure for KIM-1 was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) for NGAL, in the absence of serum creatinine changes. Baseline KIM-1 was positively associated with cumulative courses of IV aminoglycosides (R2 = 0.11; β = 0.03; p < 0.0001). KIM-1, in particular, may be a useful, non-invasive, biomarker of acute and chronic proximal tubular injury associated with exposure to aminoglycosides in patients with CF, but its clinical utility needs to be further evaluated in prospective studies.

Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders.

Distinguishing between urinary tract infection (UTI) and colonization (UTC) in patients with neurogenic bladders who require clean intermittent catheterization (CIC) is difficult. Urinary neutrophil gelatinase-associated lipocalin concentrations (uNGAL) are increased in UTIs. Our objective was to determine the predictive accuracy of uNGAL for UTI in CIC-dependent children. Cross-sectional study of CIC-dependent patients from August, 2015 to November, 2016. UTI was defined as (1) growth of ≥ 50,000cfu/mL of a uropathogen, (2) > 10 urinary white blood cells/hpf, and (3) ≥ 2 of the following: temperature > 38°C, abdominal pain, back pain, worsened incontinence, pain with catheterization, or malodorous/cloudy urine. Positive urine cultures that did not meet these criteria were grouped as UTC, and negative cultures were grouped as no growth. Two hundred one patients were included (no growth = 100, UTC = 77, UTI = 24). Median (interquartile range) uNGAL was higher in the UTI group (UTI 1361 (931, 2516)μg/g creatinine, UTC 246 (106, 548)μg/g creatinine, no growth 36 (11, 179)μg/g creatinine, p < 0.01 for all comparisons). The area under the ROC curve for uNGAL for UTI versus no UTI was 0.89, 95% CI (0.80-0.98). uNGAL is elevated in CIC-dependent children with UTI compared to those with negative cultures and those with UTC.

Serum neutrophil gelatinase-associated lipocalin (NGAL) concentration is independently associated with mortality in patients with acute coronary syndrome

BackgroundCirculating neutrophil gelatinase-associated lipocalin (NGAL) concentration increases in cardiovascular disease, but the long-term prognostic value of NGAL concentration has not been evaluated in acute coronary syndrome (ACS). We examined the association between NGAL concentration and prognosis in patients with ACS after non-ST-elevation myocardial infarction (NSTEMI) or STEMI. Methods and resultsNGAL concentration was measured in blood from 1121 consecutive ACS patients (30% women, mean age 65 years) on the first morning after admission. After adjustment for 14 variables, NGAL concentration predicted long-term (median 167 months) mortality (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.10–1.61, P = 0.003) for quartile (q) 4 of NGAL concentration. NGAL concentrations also predicted long-term mortality (HR = 1.63, 95% CI 1.31–2.03, P < 0.001, N = 741) when adjusting for Global Registry of Acute Coronary Events (GRACE) score, left ventricular ejection fraction (LVEF), and pro-B-type natriuretic peptide (proBNP) and C-reactive protein (CRP) concentrations. With these adjustments, NGAL concentration predicted long-term mortality in NSTEMI patients (HR = 2.02, 95% CI 1.50–2.72, P < 0.001) but not in STEMI patients (HR = 1.32, 95% CI 0.95–1.83, P = 0.100). In all patients, the combination of NGAL concentration and GRACE score yielded an HR of 5.56 (95% CI 4.37–7.06, P < 0.001) for q4/q4 for both variables. ConclusionNGAL concentration in ACS is associated with long-term prognosis after adjustment for clinical confounders. Measuring circulating NGAL concentration may help to identify patients—particularly those with NSTEMI—needing closer follow-up after ACS.

Increased blood lactate is prevalent and identifies poor prognosis in patients with acute heart failure without overt peripheral hypoperfusion.

Lactate is produced by anaerobic metabolism and may reflect inadequate tissue perfusion in conditions such as acute heart failure (AHF). We evaluated the prevalence and clinical significance of elevated blood lactate on admission in patients with AHF. We enrolled 237 patients with AHF (mean age 67 ± 12 years; 70% men) presenting without overt clinical evidence of peripheral hypoperfusion ('warm haemodynamic profile'). Median (upper and lower quartiles) blood lactate on admission was 1.8 (1.5; 2.4) mmol/L; 103 (43%) patients had an elevated blood lactate (≥2 mmol/L). Patients with an elevated lactate had higher blood high-sensitivity troponin I [15.4 (8.5; 26.1) vs. 9.9 (4.3; 19.6) pg/mL], aspartate aminotransferase [28 (20; 44) vs 24 (19; 36) IU/L] and endothelin-1 (12.1 ± 6.2 vs. 9.3 ± 3.9 pg/mL) (all P< 0.05). In this group plasma concentration of neutrophil gelatinase-associated lipocalin increased during the first 48 h, whereas values fell for those with normal baseline lactate [1.9 (-3.2; 9.7) vs. -1.3 (-13.9; 5.6) μg/dL; P< 0.05). One-year mortality was higher amongst patients with an elevated blood lactate (36% vs. 21%; P< 0.05). After adjustment for other well-established prognostic variables, blood lactate on admission predicted poor outcome (hazard ratio 1.24, 95% confidence interval 1.08-1.41; P< 0.05). An elevated blood lactate on admission is common in AHF patients without overt clinical evidence of peripheral hypoperfusion and is associated with markers of organ dysfunction/damage and a worse prognosis.

Usefulness and limitations of neutrophil gelatinase-associated lipocalin in the assessment of kidney diseases

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa glycoprotein expressed and secreted by renal tubular cells, immune cells and cancer cells under various pathologic states. NGAL plays important roles in renal tubular epithelial recovery, bacterial defense and inflammation. Currently, NGAL is considered as an accurate early biomarker for acute renal disease, and also shows great potential in improving the assessment of risk groups and the short-term and the long-term prognosis of chronic renal disease. Systemic reviews and meta-analysis illustrated that systemic and urinary NGAL have similar sensitivity and specificity for assessing renal damage, however, emerging studies found that they behaved dissimilar in certain patients, suggesting they may have different clinical significances. Moreover, plenty of studies have found that pathologic conditions, like inflammation, sepsis and cancer also upregulate NGAL protein, which caused the fluctuations of systemic and urinary NGAL concentrations and blurred the accuracy of NGAL as renal damage indicator. The purpose of this review article is to examine the different performances of systemic and urinary NGAL in diagnosis and prognosis of renal diseases and summarize the current knowledge on factors affecting NGAL as sensitive renal damage biomarker.

Urinary versus plasma neutrophil gelatinase-associated lipocalin (NGAL) as a predictor of mortality for acute kidney injury in intensive care unit patients

ObjectiveTo examine urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL) levels in predicting ICU mortality. DesignProspective observational. SettingUniversity Critical Care setting. Participants50 patients with acute kidney injury (AKI). InterventionsNone. Measurements and main resultsSerial urinary and plasma concentrations of NGAL were measured. Twenty-five patients had early progression (EP) and 25 patients had early improvement (EI) of AKI. Plasma concentrations of NGAL in the EP group (N=25) were significantly higher than those in the EI group (129 [IQR; 20] vs. 111 [IQR; 32] ng/mL; P=0.009), while urine NGAL levels on admission were similar in both groups (61 [IQR; 20] vs. 65 [IQR; 20] ng/mL; P=0.767). Plasma NGAL concentrations rapidly decreased to 87 [32] ng/mL in the EI group (P<0.001) and while it remained elevated in the EP group (138 [21] ng/mL). Within 28-days, 50% of the patients died in the EP group, whereas no patient died in the EI group (P<0.001). Plasma NGAL was a fair predictor for progression of AKI (AUC; 0.719±0.063; P=0.006). 48-hour changes in plasma NGAL levels predicted death within 28-days of ICU admission (AUC; 0.874±0.048; P<0.001). ConclusionEarly progression of AKI was associated with more death within 28 and 90days. While one time measurement of plasma NGAL levels at the time ICU admission may represent the kidney health status in critical care settings, it does not reliably predict mortality. On the other hand, changes in plasma NGAL within 48h of admission improve the value of this biomarker in predicting ICU mortality.

NGAL как маркер некоторых внепочечных осложнений при остром коронарном синдроме

To study the role of neutrophil gelatinase-associated lipocalin (NGAL) as a marker for extrarenal complications in patients with acute coronary syndrome (ACS). For 110 patients with ACS on days 1-3 of hospitalization, concentrations of NGAL, serum (s-NGAL) and urinary (u-NGAL) NGAL, and N-terminal fragment of pro-B natriuretic peptide (NT-proBNP) were measured, and transthoracic echocardiography was performed. Incidence of cardiovascular complications was determined during the stay in the hospital; hemodynamic parameters (systolic and diastolic blood pressure, heart rate) were measured on admission. Concentrations of u-NGAL were significantly higher in acute heart failure (AHF) [10.4 (2.7; 51.2) ng/ml] than in absence of AHF [3.8 (1.7; 8.6) ng/ml, р=0.03]. Concentrations of u-NGAL and NT-proBNP were higher in patients with [10.17 (4.87; 51.2 ng/ml) and 744.6 (368.7; 2034.9) pg/ml] than without signs of pulmonary hypertension [3.41 (1.72; 7.39) ng/ml; р=0.004 and 431.8 (99.6; 780.1) pg/ml; р=0.012]. The u-NGAL values >9.96 ng / ml were shown to be predictive for AHF, and values >5.81 ng/ml - for pulmonary hypertension. Levels of u-NGAL significantly, directly correlated with values of end-diastolic dimensions and end-systolic dimensions and inversely correlated with values of end-diastolic volume and ejection fraction; levels of s-NGAL positively correlated with cardiac output and heart index. Levels of u-NGAL significantly, directly correlated with NT-proBNP values. Urinary levels of NGAL were significantly higher in ACS patients with than without AHF or signs of pulmonary hypertension. NGAL values >9.96 ng/ml were associated with an increased probability of AHF during stay in the hospital, and NGAL values >5.81 ng/ml - with a higher incidence of ACS patients with signs of pulmonary hypertension. In ACS, direct correlations of blood and urinary levels of NGAL with some echocardiographic parameters reflecting the systolic function and the LV dimensions and geometry were identified. Levels of u-NGAL were found to be positively correlated with blood levels NT-proBNP. NGAL may be used as a supplementary marker not only for acute kidney injury and chronic kidney disease but also for severity of cardiovascular conditions and heart remodeling in patients after exacerbation of ischemic heart disease.