Plasma Neutrophil Gelatinase-associated Lipocalin Concentrations Research Articles

Abstract TP220: Neutrophil Gelatinase-associated Lipocalin in Patients With Acute Ischemic Stroke

Introduction: Neutrophil gelatinase-associated lipocalin (NGAL) appears to be a promising biomarker in diagnosis and prognosis in kidney and cardiovascular disease. However, the relationship between NGAL concentration and ischemic stroke is poorly understood. Hypothesis: We investigated plasma NGAL concentration in patients with acute ischemic stroke in relation to medical history, risk factors, hematologic and biochemical tests, stroke severity and subtype. Methods: Clinical data of 139 patients who admitted to a tertiary hospital with TIA (n=17) and ischemic stroke (n=122) were collected. We evaluated the following parameters: A) Medical history and risk factors of the patients; B) Hematologic and biochemical blood test at the time of admission; C) Stroke severity which was assessed using the National Institutes of Health Stroke Scale (NIHSS); D) Stroke subtype which was decided by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Results: In our study (62% male, mean age 65 ± 14 years), median admission serum NGAL level was 75 ng/mL (interquartile range [IQR] 52-112 ng/mL). Serum NGAL level was elevated in 21 (15.1%) patients with the cutoff point of 150 ng/mL. High plasma NGAL concentrations were associated with age ( p = 0.018) and previous history of coronary artery occlusive disease ( p = 0.003). Mean NIHSS score in high NGAL group was higher than normal NGAL group (7.6 ±7.2 vs 4.4 ± 5.6, p = 0.021). We observed significant correlations between serum NGAL with C-reactive protein (spearman coefficient rho = 0.319, p < 0.001), erythrocyte sedimentation rate (r = 0.410, p < 0.001), creatinine (r = 0.237, p = 0.005), blood urea nitrogen (r = 0.353, p = 0.003), estimated glomerular filtration rate (r = -0.471, p < 0.001), fibrinogen (r = 0.327, p < 0.001) and homocysteine (r = 0.189, p = 0.032). There were no significant differences in mean serum NGAL level between TIA patients and stroke patients, and stroke subtypes by TOAST classification. Conclusions: Increased NGAL in acute ischemic stroke patients is associated with age, previous coronary artery occlusive disease history and stroke severity. Elevated plasma levels of NGAL appear to be correlated with some biomarkers associated with inflammation, coagulation and kidney dysfunction.

The Effect of Methylprednisolone on Plasma Concentrations of Neutrophil Gelatinase-Associated Lipocalin in Pediatric Heart Surgery.

Plasma neutrophil gelatinase-associated lipocalin is a kidney injury marker used in pediatric heart surgery. Neutrophil gelatinase-associated lipocalin is also a constituent of specific granules of neutrophils. Corticosteroids are widely used in pediatric heart surgery. Methylprednisolone inhibits degranulation of neutrophil-specific granules. Use of corticosteroids has not been taken into account in studies of neutrophil gelatinase-associated lipocalin in pediatric heart surgery. We studied the influence of systemically administered methylprednisolone on plasma neutrophil gelatinase-associated lipocalin concentrations in pediatric heart surgery. Two separate double-blinded randomized trials. PICU at a university-affiliated hospital. Forty neonates undergoing open-heart surgery and 45 children undergoing ventricular and atrioventricular septal defect correction. First trial (neonate trial), 40 neonates undergoing open-heart surgery received either 30 mg/kg IV methylprednisolone (n = 20) or placebo (n = 20). Second trial (ventricular septal defect trial), 45 children undergoing ventricular or atrioventricular septal defect correction received one of the following: 30 mg/kg of methylprednisolone IV after anesthesia induction (n = 15), 30 mg/kg methylprednisolone in the cardiopulmonary bypass prime solution (n = 15), or placebo (n = 15). Plasma neutrophil gelatinase-associated lipocalin and creatinine were measured in both series. Lactoferrin levels were measured as a marker of neutrophil-specific granules in the ventricular septal defect trial only. No differences in creatinine levels occurred between the groups of either trial. Preoperative, neutrophil gelatinase-associated lipocalin did not differ between the study groups of either trial. Preoperatively administered methylprednisolone in the neonate trial reduced neutrophil gelatinase-associated lipocalin by 41% at 6 hours postoperatively (p = 0.002). Preoperatively administered methylprednisolone in the ventricular septal defect trial reduced neutrophil gelatinase-associated lipocalin by 47% (p = 0.010) and lactoferrin by 52% (p = 0.013) 6 hours postoperatively. Lactoferrin levels in the ventricular septal defect trial correlated with neutrophil gelatinase-associated lipocalin (R = 0.492; p = 0.001) preoperatively and after weaning from cardiopulmonary bypass (R = 0.471; p = 0.001). Preoperatively administered methylprednisolone profoundly decreases plasma neutrophil gelatinase-associated lipocalin levels. Neutrophil gelatinase-associated lipocalin seems to originate to a significant extent from activated neutrophils. Preoperative methylprednisolone is a confounding factor when interpreting plasma neutrophil gelatinase-associated lipocalin levels as a kidney injury marker in pediatric heart surgery.

The consumption of a grape and blueberry polyphenol‐rich mixture is safe in dogs

Grape polyphenols have beneficial health effects, but grape ingestion has been associated with acute renal failure leading most often to fatal issue in dogs. The responsible factors are unknown.Our aim was to check the safety of a supplement of polyphenol‐rich mixture (grape and blueberry extracts (specific pet Neurophenols® blend)) in dogs.Seventeen dogs were given, for 12 wks, capsules containing 4 (n=5) or 20 (n=6) or 40 (n=6) mg/kg/d of the polyphenol mixture. Five control dogs were given maltodextrin capsules. Blood and 24‐h urine were taken before the beginning of the study (W0), then after 4 wks and 12 wks of supplementation. Plasma standard analysis (creatinine (Creat), urea, minerals (Na, K, Ca, P), total protein, hepatic biomarkers (ALT, ALP)) were assayed. New biomarkers that reveal early renal damage were measured : plasma and urinary cystatin C (CysC), clusterin (Clu), neutrophil gelatinase‐associated lipocalin (NGAL). Urinary biomarkers/Creat ratios were calculated. Data were compared with limits of reference intervals or with the highest values from our control dogs and experimental dogs at W0.Whatever the week, plasma standard analysis were below high limits of reference intervals. Plasma CysC concentration was below our own high limit. Plasma Clu and NGAL concentrations were below limits of reference intervals. Urinary CysC/Creat, Clu/Creat, NGAL/Creat ratios were below our own limit.Grape extract and blueberry extract (specific pet Neurophenols® blend) consumption was not associated with any sign of renal failure and can be consumed safely in dogs.

Testing and its clinical significance of plasma neutrophil gelatinase-associated lipocalin in patients with acute pancreatitis

Objective To quantify the concentration of peripheral blood plasma neutrophil gelatinase-associated lipocalin (NGAL) in patients with acute pancreatitis (AP) and to explore its value in assessment of the severity of AP.Methods From June 2011 to March 2012,83 patients with AP were selected,among those 43 cases were mild acute pancreatitis (MAP) and 40 were severe acute pancreatitis (SAP).The control group included 30 healthy individuals.The peripheral blood of patients with AP and healthy controls was collected,and plasma was isolated after centrifuged.The concentration of NGAL in plasma was detected by enzyme-linked immunosorbent assay (ELISA).The t-test was performed for comparison between groups.The correlation between the concentration of NGAL in plasma and clinical parameters of AP was analyzed by Spearman rank order correlation analysis.The diagnosis value of the concentration of NGAL in SAP was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC).Results The concentration of plasma NGAL in AP group ((10.30± 5.97)nmol/L) was higher than that in healthy control group ((1.94±1.35) nmol/L) and the difference was statistically significant (t=11.924,P＜0.01).The concentration of plasma NGAL in SAP group ((14.61 ±5.28) nmol/L) was higher than that in MAP group ((6.27±-3.09) nmol/L) and healthy control group,the differences was statistically significant (t=8.677 and 14.539,both P＜0.01).The concentration of plasma NGAL of AP patients was positively correlated with acute physiology and chronic health evaluation-Ⅱ score,Ranson score,bedside index for severity in acute pancreatitis score,computed tomography (CT) severity index,C-reactive protein,white blood cells and the days of hospitalization (r=0.651,0.556,0.514,0.620,0.320,0.458 and 0.346,all P＜0.05).The area under the ROC curve of plasma NGAL concentration in diagnosis of SAP was 0.926 (95％CI:0,870-0.983).The cutoff value of plasma NGAL level in diagnosis of SAP was 8.44 nmol/L.The sensitivity and specificity was 87.5 ％ and 88.9％,respectively.Conclusions Plasma NGAL level is correlated with the severity of patients with AP.NGAL may be one of the markers for the early diagnosis of SAP. Key words: Acute pancreatitis ; Neutrophil gelatinase-associated lipocalin ; Plasma concentration

The changes of neutrophil gelatinase-associated lipocalin in plasma and its expression in adipose tissue in pregnant women with gestational diabetes

AimsTo investigate plasma levels and the expression of neutrophil gelatinase-associated lipocalin (NGAL) in subcutaneous adipose tissue (SAT) in patients with gestational diabetes mellitus (GDM). MethodsThe study recruited 260 Chinese women divided into three groups: 96 were healthy pregnant women with pre-pregnancy body mass index (pre-pregnancy BMI) below 25kg/m2 (GROUP 1), 84 were women with GDM with pre-pregnancy BMI below 25kg/m2 (GROUP 2) and 80 were women with GDM with pre-pregnancy BMI over 25kg/m2 (GROUP 3). Laboratory and anthropometric measurements were recorded and NGAL plasma levels were determined by ELISA for subjects in all groups. Real-time RT-PCR and Western blotting were used to assess the relative mRNA and protein expression of NGAL and tumor necrosis factor-α (TNF-α) in SAT (30 cases in each group). ResultsOur results demonstrated statistically significant elevation in plasma NGAL concentrations in GROUP 2 and GROUP 3 compared with GROUP 1 (p<0.001 for both group comparisons). Moreover, SAT NGAL mRNA (p<0.001 and p<0.001, respectively) and protein (p<0.001 and p<0.001, respectively) expression levels were higher in GROUP 3 than in both GROUP 1 and GROUP 2. Correlations were noted between the plasma NGAL concentration and various parameters of insulin resistance. ConclusionsPlasma NGAL may play a role in the development of insulin resistance in GDM, and the high levels of NGAL expression in SAT in overweight women with GDM suggests that NGAL in SAT is associated with obesity in women with GDM.

Plasma and Urine Neutrophil Gelatinase–Associated Lipocalin (NGAL) in Dogs with Acute Kidney Injury or Chronic Kidney Disease

BackgroundNeutrophil gelatinase–associated lipocalin (NGAL) is a protein that is used in human medicine as a real‐time indicator of acute kidney injury (AKI).HypothesisDogs with AKI have significantly higher plasma NGAL concentration and urine NGAL‐to‐creatinine ratio (UNCR) compared with healthy dogs and dogs with chronic kidney disease (CKD).Animals18 healthy control dogs, 17 dogs with CKD, and 48 dogs with AKI.MethodsOver a period of 1 year, all dogs with renal azotemia were prospectively included. Urine and plasma samples were collected during the first 24 hours after presentation or after development of renal azotemia. Plasma and urine NGAL concentrations were measured with a commercially available canine NGAL Elisa Kit (Bioporto® Diagnostic) and UNCR was calculated. A single‐injection plasma inulin clearance was performed in the healthy dogs.ResultsMedian (range) NGAL plasma concentration in healthy dogs, dogs with CKD, and AKI were 10.7 ng/mL (2.5–21.2), 22.0 ng/mL (7.7–62.3), and 48.3 ng/mL (5.7–469.0), respectively. UNCR was 2 × 10−8 (0–46), 1,424 × 10−8 (385–18,347), and 2,366 × 10−8 (36–994,669), respectively. Dogs with renal azotemia had significantly higher NGAL concentrations and UNCR than did healthy dogs (P < .0001 for both). Plasma NGAL concentration was significantly higher in dogs with AKI compared with dogs with CKD (P = .027).Conclusions and Clinical ImportancePlasma NGAL could be helpful to differentiate AKI from CKD in dogs with renal azotemia.

Serum and Plasma Neutrophil Gelatinase Associated Lipocalin (NGAL) Levels are Not Equivalent in Patients Admitted to Intensive Care

Neutrophil gelatinase associated lipocalin (NGAL) is proposed as a biomarker of acute kidney injury (AKI). NGAL has been studied in a range of body fluids including serum and EDTA plasma. The aim of the present study was to establish relationship between serum NGAL concentrations and EDTA plasma NGAL concentrations in patients admitted to intensive care units (ICUs) and whether these determinations are directly comparable in this setting. NGAL was measured in 40 paired samples of serum and EDTA plasma from 25 patients admitted to intensive care with a commercial particle-enhanced turbidimetric immunoassay (The NGAL Test™, BioPorto Diagnostics A/S, Gentofte, Denmark) on a Roche Hitachi 917 (Roche-Hitachi, Inc., Tokyo, Japan) analyzer. Serum NGAL concentrations ranged from 26.8 to 1,808 ng/ml (median 281 ng/ml, interquartile range (IQR) 453 ng/ml). EDTA plasma NGAL concentrations ranged from 25.7 to 1,752 ng/ml (median 225 ng/ml, IQR 352 ng/ml). The difference in NGAL concentrations in paired serum and EDTA plasma samples (serum- plasma) ranged from -13.8 to 321 ng/ml (median 79 ng/ml, IQR 116 ng/ml; difference from zero, P < 0.0001, Wilcoxon's signed rank test). Although serum and EDTA plasma values were correlated (Spearman's r = 0.95, P < 0.0001), Deming regression analysis showed a slope of 1.1 that was not significantly different from unity (95% confidence interval (CI) 1.0-1.1) and a highly significant intercept of 67.9 ng/ml with a wide confidence interval (95% CI 29.8-106). NGAL concentration values measured in serum and EDTA plasma cannot be directly compared and should not be used as equivalents in studies of patients admitted to intensive care.

Circulating Levels of Neutrophil Gelatinase–Associated Lipocalin (NGAL) Correlate With the Presence and Severity of Preeclampsia

Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a reliable marker of acute renal injury and is produced at the maternal-fetal interface but its role in preeclampsia has not been systematically examined. This study investigated whether plasma NGAL concentrations changed in patients with preeclampsia at diagnosis compared to normotensive controls. A case-control study was performed. Plasma was collected from women with preeclampsia and normotensive controls matched for age, gestational age, and body mass index. Plasma NGAL concentrations were measured by specific enzyme-linked immunosorbent assay. Patients with preeclampsia had significantly higher NGAL concentrations than controls (median [range]: 203.8 ng/mL [66.1-575.4] vs. 122.8 ng/mL [7.0-669.7]; P = .047). In subgroup analysis, patients with severe preeclampsia had significantly higher NGAL concentrations than those with mild preeclampsia. Plasma NGAL concentrations were positively correlated with the amount of proteinuria in women with preeclampsia (P = .003). Plasma NGAL concentrations were significantly elevated in women with preeclampsia versus normotensive controls, and concentrations appear to be associated with the severity of the disease.

Neutrophil gelatinase-associated lipocalin, a marker of tubular dysfunction, is not increased in long-term virologically controlled patients receiving a tenofovir/emtricitabine + nevirapine regimen

Tenofovir may be associated with nephrotoxicity. Several studies have shown that an early increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) may predict the occurrence of acute kidney injury. We investigated urine and plasma NGAL in patients on long-term treatment with nevirapine associated with either tenofovir/emtricitabine or abacavir/lamivudine. We studied 40 virologically controlled Caucasian patients on stable treatment (median >4 years) with tenofovir/emtricitabine + nevirapine (n = 20) or abacavir/lamivudine + nevirapine (n = 20), and no history of kidney disease, high blood pressure or diabetes. Plasma immunovirological parameters (NGAL and C-reactive protein) and urinary NGAL, β2-microglobulin and α1-microglobulin were measured during a routine clinical visit. Median concentrations of NGAL were in the normal range, but were significantly higher in the abacavir/lamivudine group compared with the tenofovir/emtricitabine group both in the plasma, at 74.9 and 66.0 ng/mL (P = 0.032), respectively, and in the urine, at 36.1 and 12.8 ng/mL (P = 0.017), respectively. Plasma and urinary NGAL concentrations remained in the normal range in this long-term virologically controlld population without any overt renal disease. The usefulness of NGAL in detecting sub-clinical renal dysfunction appears to be very limited.

BK virus‐associated nephropathy: neutrophil gelatinase‐associated lipocalin as a new diagnostic tool?

BK nephropathy has emerged as an important cause for allograft failure in renal transplant patients. The kidney tubules are the main target of BK virus infiltration. Neutrophil gelatinase-associated lipocalin (NGAL) has been proven to be a powerful biomarker for tubular damage. Therefore, we investigated the suitability of plasma NGAL as new diagnostic tool in patients with BK infection. We retrospectively analyzed 240 renal transplant recipients. Systematic BKV screening by plasma PCR was performed one month after transplantation and every three month thereafter for two yr. Plasma NGAL concentration was investigated using a commercial ELISA. Medical records and electronic databases were reviewed for clinical parameters. BK viremia (BKV+) was diagnosed in 5.0% (12/240) and BK nephropathy in 3.3% (8/240) of our patients. BKV+ patients received more induction therapy (p = 0.03) and experienced a higher rate of biopsy-proven rejections compared to 13 control patients with similar graft function but negative BKV PCR. Contrary to our hypothesis, there was no difference in plasma NGAL expression between both groups (128.6 vs. 172.2 ng/mL; p = 0.68). Intensified immunosuppressive therapy is associated with an increased risk for BK nephropathy. Plasma NGAL is neither suitable for diagnosing BK nephropathy nor helpful in predicting the individual course of patients with BKV infection.

The Ratio of Plasma Neutrophil Gelatinase-Associated Lipocalin Predicts Acute Kidney Injury in Patients Undergoing Liver Transplantation

BackgroundPostoperative acute kidney injury (AKI) is associated with high morbidity and mortality after liver transplantation (OLT). Previous studies have shown the value of plasma neutrophil gelatinase-associated lipocalin (NGAL) taken 2 hours after reperfusion of the liver graft as an early marker predicting AKI. The study was performed to determine whether plasma NGAL concentrations obtained as early as 1 hour after reperfusion was predictive of AKI and whether the NGAL ratio was an early predictor for AKI in the first 48 hours after OLT. MethodsTwenty-six liver transplant recipients donated plasma samples for NGAL determinations at induction (T1), at graft reperfusion (T3) as well as after 1 (T4) and hours 2 (T5), and at the end of the surgery (T7). AKI was defined at 48 hours after liver transplantation according to the acute kidney injury network criteria. Predictive ability was assessed using areas under the curve of receiver operator characteristic analyses. ResultsThe area under the curve of the receiver operator characteristics curve of (plasma NGAL concentration at T4)/(plasma NGAL concentration at T1) to predict AKI was 0.717 at T5, 0.765 at T7, 0.714 at T8 (24 hours post-OLT), and 0.781 at T9 (48 hours post-OLT). ConclusionThe plasma NGAL concentrations taken 1 hour after reperfusion of the liver graft seem to be predictive of AKI; the NGAL changing ratio may be an early predictor for AKI in the first 48 hours after OLT.

Plasma neutrophil gelatinase associated lipocalin (NGAL) is associated with kidney function in uraemic patients before and after kidney transplantation

BackgroundNeutrophil gelatinase associated lipocalin (NGAL) is a biomarker of kidney injury. We examined plasma levels of NGAL in a cohort of 57 kidney allograft recipients (Tx group, 39 ± 13 years), a uraemic group of 40 patients remaining on the waiting list (47 ± 11 years) and a control group of 14 healthy subjects matched for age, sex and body mass index (BMI). The kidney graft recipients were studied at baseline before transplantation and 3 and 12 months after transplantation and the uraemic group at baseline and after 12 months.MethodsNGAL was measured using a validated in-house Time-Resolved Immuno-flourometric assay (TRIFMA). Repeated measurements differed by < 10% and mean values were used for statistical analyses. Spearman rank order correlation analysis and the Kruskal-Wallis non-parametric test were used to evaluate the association of NGAL concentrations with clinical parameters.ResultsPlasma NGAL levels before transplantation in the Tx and uraemic groups were significantly higher than in the healthy controls (1,251 μg/L, 1,478 μg/L vs. 163 μg/L, p < 0.0001). In the Tx group NGAL concentrations were associated with serum creatinine (R = 0.51, p < 0.0001), duration of end-stage renal failure (R = 0.41, p = 0.002) and leukocyte count (R = 0.29, p < 0.026). At 3 and 12 months plasma NGAL concentrations declined to 223 μg/L and 243 μg/L, respectively and were associated with homocysteine (R = 0.39, p = 0.0051 and R = 0.47, p = 0.0007).ConclusionsPlasma NGAL is a novel marker of kidney function, which correlates to duration of end-stage renal failure (ESRD) and serum creatinine in uraemic patients awaiting kidney transplantation. Plasma NGAL is associated with homocysteine in transplanted patients. The prognostic value of these findings requires further studies.

Neutrophil Gelatinase-associated Lipocalin and Acute Kidney Injury after Cardiac Surgery

To the Editor: We read with great interest the review of Cardiopulmonary Bypass-associated Acute Kidney Injury by Kumar and Suneja,1published in the April 2011 issue, and we thank the authors for their excellent work. However, with regard to early detection of acute kidney injury (AKI) in adults by means of neutrophil gelatinase-associated lipocalin (NGAL), we feel that there has been a positive selection bias in their review of the available evidence.Although they imply that, in adult patients after cardiopulmonary bypass cardiac surgery, plasma and urine NGAL concentrations are good predictors of renal injury with area under the receiver-operating characteristic curve (AUCROC) of 0.80 and 0.96, respectively, that is in fact an exceptional result from a single, small study.2Wagener et al. reported an AUCROCfor early diagnosis of AKI by urinary NGAL of 0.61 at 18 h postcardiopulmonary bypass. The sensitivity and specificity of urinary NGAL in predicting AKI, as judged by AUCROC, was poor, varying from 0.57 to 0.61.3Koyner et al. 4reported an AUCROCof 0.54 at 6 h postcardiopulmonary bypass for the diagnosis of AKI by plasma NGAL. Perry et al. 5documented increased plasma NGAL levels in patients who suffered AKI but the sensitivity was as low as 38.7%. Haase et al. 6in a recent meta-analysis derived an AUCROCof 0.78 for early diagnosis of AKI after cardiac surgery by plasma and urinary NGAL.Given the limited sensitivity and specificity of individual biomarkers, it may be more realistic to use a panel of biomarkers to predict AKI and outcome. Furthermore, a number of key issues, including the wide variability in reported diagnostic performance, require clarification before adoption of NGAL into clinical practice.

Increased plasma levels of NGAL, a marker of neutrophil activation, in patients with abdominal aortic aneurysm

Objective Neutrophil gelatinase-associated lipocalin (NGAL) plasma concentrations have been associated with cardiovascular diseases. We aimed to assess the association of NGAL with abdominal aortic aneurysm (AAA). Methods NGAL concentrations were analyzed by Western blotting in conditioned medium of polymorphonuclear neutrophils (PMNs) from AAA patients ( n = 22) and controls ( n = 11), and also in aortic biopsies from AAA patients and healthy controls ( n = 10). Plasma NGAL concentrations were measured by ELISA in three groups of subjects from France ( n = 60), Spain ( n = 75) and Australia ( n = 100) and associated with AAA presence and growth. Results PMNs isolated from AAA patients secreted significantly greater amounts of NGAL than PMNs from controls. Luminal thrombus released large amounts of NGAL compared to abluminal AAA thrombus, AAA wall and healthy aortic media. Plasma NGAL concentrations were significantly higher in patients with AAA than controls from France [115 (78–200) vs. 94 (72–114) ng/ml, p < 0.001]. NGAL plasma concentrations in AAA patients from Spain correlated with other markers of thrombus activity (plasmin–antiplasmin complexes and D-dimer). Furthermore, a positive correlation between plasma NGAL and retrospective AAA growth (rho = 0.4, p = 0.01) was observed, which remained significant after adjusting for other risk factors. Plasma NGAL was only weakly associated with prospective growth in both Spanish and Australian patients. Conclusions NGAL is released by PMNs and by the luminal part of AAA thrombus. NGAL plasma levels were increased in AAA patients compared with healthy subjects and correlated with retrospective AAA growth. Further studies in larger subjects groups are needed to confirm the association between NGAL and AAA presence and growth.

Plasma neutrophil gelatinase-associated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia

Although plasma neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for early detection of acute kidney injury, its ability to predict recovery is unknown. Using RIFLE criteria to define kidney injury, we tested whether higher plasma NGAL concentrations on the first day of RIFLE-F would predict failure to recover in a post hoc analysis of a multicenter, prospective, cohort study of patients with community-acquired pneumonia. Recovery was defined as alive and not requiring renal replacement therapy during hospitalization or having a persistent RIFLE-F classification at hospital discharge. Median plasma NGAL concentrations were significantly lower among the 93 of 181 patients who recovered. Plasma NGAL alone predicted failure to recover with an area under the receiver operating characteristic curve of 0.74. A clinical model using age, serum creatinine, pneumonia severity, and nonrenal organ failure predicted failure to recover with area under the curve of 0.78. Combining this clinical model with plasma NGAL concentrations did not improve prediction. The reclassification of risk of renal recovery, however, significantly improved by 17% when plasma NGAL was combined with the clinical model. Thus, in this cohort of patients with pneumonia-induced severe acute kidney injury, plasma NGAL appears to be a useful biomarker for predicting renal recovery.

Neutrophil gelatinase-associated lipocalin clearance during veno-venous continuous renal replacement therapy in critically ill patients

Dear Editor, Predicting recovery of renal function in patients with acute kidney injury (AKI) supported with renal replacement therapy (RRT) is one of the top ten questions in the field of current AKI research. However, defining renal recovery and accordingly the best time for discontinuation of RRT is difficult, as reliable biomarkers are lacking. The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study identified urine production (>500 mL/24 h) as the best predictor for successful discontinuation of RRT [area under the curve (AUC) 0.81] in contrast to serum creatinine (SCr, AUC 0.64); however, its predictive value is severely confounded by the use of diuretics [1]. Neutrophil gelatinase-associated lipocalin (NGAL), a 25-kDa protein involved in iron transportation, is a potential tool for determination of initiation of RRT [2, 3]. However, once a patient is initiated on RRT, it remains to be elucidated how plasma NGAL concentrations will change. To determine plasma NGAL clearance and sieving coefficient (SQ) during continuous RRT (CRRT), we measured prefilter and effluent NGAL concentrations in three subjects after informed consent was obtained. Patients were hemofiltered with zero fluid balance, 2 L postdilution mode in continuous veno-venous hemofiltration. Blood flow was set at 200 mL/min, and regional citrate anticoagulation was used. The filters were ethylene oxide (ETO)-sterilized Aquamax HF 19 with an in vitro cutoff point of 55 kDa. NGAL levels were measured using a research-based enzyme-linked immunosorbent assay with detection limit of 10–4,000 ng/mL. NGAL clearance per minute was estimated using the assumed stable plasma concentrations during CRRT over the first 12 h and the calculated amount of NGAL present in the total effluent. SQ was calculated by dividing the NGAL effluent concentration by the NGAL prefilter plasma concentration. Three male anuric patients were studied (age 40–64 years). Their admission diagnoses were hemorrhagic shock, cardiopulmonary resuscitation, and multitrauma. Baseline SCr values were 0.57, 0.66, and 0.68 mg/dL, with SCr at time of CRRT initiation of 3.7, 9.7, and 12.3 mg/dL. Estimated median (standard deviation, SD) plasma NGAL clearance was 4.8 (1.89) mL/min with median (SD) SQ of 0.147 (0.04). The prefilter and effluent NGAL concentrations are plotted against time in Fig. 1. Fig. 1 Temporal patterns of the prefilter plasma and effluent NGAL concentrations (ng/ml) in hours after initiation of continuous veno-venous renal replacement therapy in three individuals with anuric AKI Normally, plasma NGAL is cleared through glomerular filtration and entirely processed by proximal tubular cells [4]. However, in case of AKI, plasma concentrations rise quickly, even when estimated glomerular filtration rate (eGFR) is still normal, and tend to decrease quickly when the injurious event subsides [5]. Therefore, NGAL might have potential to be an early indicator of renal recovery in critically ill patients supported by RRT. Our results suggest that plasma NGAL is hardly cleared during continuous veno-venous hemofiltration. A possible explanation lies in the fact that larger serum proteins effectively lower the passage of small proteins by forming a gel layer over the membrane pores. In conclusion, we have shown that CRRT does not substantially influence plasma NGAL concentration and therefore does not need to be taken into account when kinetics of plasma NGAL levels are used as an indicator for persistent renal injury or renal recovery in hemofiltered critically ill patients.

Anesthesia Literature Review

Anesthesia Literature Review

Clinical implication of plasma neutrophil gelatinase-associated lipocalin (NGAL) concentrations in patients with advanced carotid atherosclerosis

Neutrophil gelatinase-associated lipocalin (NGAL) is well established as an early and specific biomarker of kidney disease. Recent evidence further suggests that NGAL may play a crucial role in vascular remodeling and plaque instability during the development of atherosclerosis. Plasma NGAL concentrations measured using a solid-phase enzyme-linked immunosorbent assay (ELISA) were correlated with medical history, risk factors and medication intake in 141 patients with advanced carotid atherosclerotic lesions who underwent carotid endarterectomy for vascular repair. Plasma NGAL concentrations were associated with patient age (R(s)=0.2055, p=0.0144), plasma homocysteine (R(s)=0.4274, p<0.00001) and serum creatinine (R(s)=0.4640, p<0.00001) concentrations and estimated glomerular filtration rate (eGFR) (R(s)=-0.4911, p<0.00001). Hypertensive patients, as well as those receiving therapy with angiotensin converting enzyme (ACE) inhibitors, presented with significantly enhanced plasma NGAL concentrations when compared to normotensive (p=0.0341) patients and those not treated (p=0.0004). Enhanced NGAL concentrations did not meet statistical significance for patients with advanced stenosis grade (p=0.0971) or a history of peripheral artery disease (p=0.0827). Multiple regression analysis identified homocysteine, creatinine, eGFR and treatment with ACE inhibitors (p=0.0019, <0.00001, 0.0005 and 0.0219, respectively) as independent predictors of NGAL concentration. Plasma NGAL concentrations were associated with patient age, hypertension, eGFR, creatinine and homocysteine concentrations and therapy with ACE inhibitors. The role of NGAL in the development of atherosclerosis needs to be further explored taking into consideration the uncontrolled effect of renal disease in atherosclerotic patients with multiple risk factors.

The Diagnostic Accuracy of Plasma Neutrophil Gelatinase–Associated Lipocalin in the Prediction of Acute Kidney Injury in Emergency Department Patients With Suspected Sepsis

We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted.

Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population

PurposeNeutrophil gelatinase-associated lipocalin (NGAL) is a useful marker for acute kidney injury (AKI), particularly when the timing of renal insult is known. However, its performance in an adult critical care setting has not been well described. We performed this study to estimate the diagnostic accuracy of plasma NGAL for early detection of AKI and need for renal replacement therapy (RRT) in an adult intensive care unit (ICU).MethodsWe enrolled 307 consecutive adult patients admitted to a general medical-surgical ICU; 301 were included in the final analysis. Serial blood samples were analyzed for plasma NGAL using a standardized clinical platform. The primary outcome was AKI, defined as an increase in creatinine of at least 50% from baseline or a reduction in urine output to <0.5 ml/kg/h for >6 h.ResultsOf 301 patients, 133 (44%) had AKI during their ICU stay. Plasma NGAL was a good diagnostic marker for AKI development within the next 48 h (area under ROC 0.78, 95% CI 0.65–0.90), and for RRT use (area under ROC 0.82, 95% CI 0.70–0.95). Peak plasma NGAL concentrations increased with worsening AKI severity (R = 0.554, P < 0.001).ConclusionsPlasma NGAL is a useful early marker for AKI in a heterogeneous adult ICU population, in which the timing of renal insult is largely unknown. It allows the diagnosis of AKI up to 48 h prior to a clinical diagnosis based on AKI consensus definitions. Additionally, it predicts need for RRT and correlates with AKI severity. Early identification of high risk patients may allow potentially beneficial therapies to be initiated early in the disease process before irreversible injury occurs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-009-1711-1) contains supplementary material, which is available to authorized users.