Amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein levels in predicting long-term prognosis in fetal growth restriction and preterm birth: a preliminary study

Evaluation of urine biomarkers of kidney injury in polycystic kidney disease

Evaluation of amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein levels during pregnancy

See Article on Page 345-361 Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein belonging to the lipocalin family that is associated with human neutrophil gelatinase [1]. It is derived from neutrophils and expressed at low concentrations in various human tissues, including kidney, liver, and spleen [2]. NGAL plays roles in scavenging iron, inhibiting bacterial growth, and promoting epithelial cell growth [3]. Clinical studies have demonstrated the value of plasma and urine NGAL in the diagnosis and prognosis of acute kidney injury (AKI) [4,5]. The role of NGAL in predicting the progression of chronic kidney disease (CKD) has also been demonstrated [6,7]. However, the prognostic value of NGAL in patients with immunoglobulin A (IgA) nephropathy has not been established, and only a few studies of small populations have been published. Recently, The Korean Journal of Internal Medicine published two studies on the role of NGAL as a predictor of renal outcome in patients with IgA nephropathy. Park et al. [8] demonstrated that plasma NGAL was an independent predictor of adverse renal outcomes in patients with IgA nephropathy. They enrolled 91 patients with biopsy-proven IgA nephropathy, and analyzed the correlation of plasma NGAL levels with clinical factors and histological severity. An adverse renal outcome was defined as stage 3 or higher CKD. In their study, plasma NGAL showed good correlations with the estimated glomerular filtration rate, proteinuria, and tubular atrophy/interstitial fibrosis. Furthermore, the plasma NGAL level had a significant predictive value for adverse renal outcomes in a receiver operating characteristic curve analysis (area under the curve = 0.777; p = 0.001). An NGAL level exceeding 118.65 ng/mL predicted adverse renal outcomes with 84.6% sensitivity and 68.7% specificity. Rhee et al. [9] also reported the clinical value of serum and urine NGAL as an independent predictor of renal progression in 121 patients with IgA nephropathy. High serum NGAL was defined as a serum NGAL level exceeding 150 ng/mL. They defined high urine NGAL/creatinine as a urine NGAL/creatinine level higher than the median value for the cohort. In their study, the serum or urine NGAL level alone could not predict renal progression, while the high NGAL group, defined as having elevated levels of both serum and urine NGAL, independently predicted renal progression (hazard ratio [HR], 5.56; 95% confidence interval [CI], 1.42 to 21.73; p = 0.014) along with tubular damage (HR, 8.79; 95% CI, 2.01 to 38.51; p = 0.004). In addition, the Kaplan-Meier curve for renal survival showed significantly higher renal progression in the high NGAL group (log rank, p = 0.004). Both studies suggest that serum or urine NGAL levels at the time of kidney biopsy predict adverse renal outcomes in patients with IgA nephropathy; however, they have several limitations. First, both studies analyzed patients with IgA nephropathy retrospectively. Second, the numbers of enrolled patients were relatively small. In addition, the long-term results need to be confirmed. Furthermore, the value of NGAL per se has several limitations as a biomarker for kidney disease. The cutoff values for NGAL vary according to the timing of the measurement and clinical conditions [5]. The plasma NGAL level is increased in septic patients regardless of the presence of AKI, and septic AKI patients have higher plasma and urine NGAL levels than non-septic patients with AKI [10,11]. The NGAL level cannot differentiate AKI from AKI with CKD because the serum NGAL level is also increased in CKD patients [12]. Cardiomyocytes also express NGAL, and serum NGAL levels are increased in patients with heart failure [13]. In this context, NGAL might be a useful biomarker for kidney disease. However, clinicians should consider comorbid conditions when evaluating NGAL values because several clinical factors can affect serum and urine NGAL levels. In conclusion, an integrated analysis of combined biomarkers may enhance their predictive value for diagnosis and prognosis. Prospective well-designed studies of larger populations are needed to establish the usefulness of NGAL as a biomarker for kidney disease.

Background: In patients with heart failure plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are correlated to urine neutrophil gelatinase-associated lipocalin (NGAL) levels. We prospectively evaluated the relationship among glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (ACR), urine and serum NGAL and NT-proBNP levels in 20 type II diabetic patients with macroalbuminuria at 4-month intervals. Results: Compared with 20 age, gender-matched healthy controls, diabetic patients had higher urine and serum NGAL, serum NT-proBNP and lower eGFR. The eGFR of the patients at the baseline, the 4th and the 8th month were 29.6 ± 12.0, 27.8 ± 13.7 and 22.9 ± 10.4 mL/min/1.73 m2, respectively. No significant change in urine NGAL levels was detected (p > 0.05), whereas there were significant increases in NT-proBNP, serum NGAL and urine ACR and significant decrease in eGFR as the study progressed (p < 0.05). Both the baseline and the 4th month urine ACR were positively correlated to NT-proBNP levels measured at the same periods (r: 0.451; p: 0.046; r: 0.489; p: 0.029 respectively). In all measurements, urine ACR was negatively correlated to serum albumin levels measured at the same periods (r: −0.792; p: 0.000; r: −0.716; p: 0.000; r: −0.531; p: 0.016 respectively). None of eGFR measurements was correlated with NT-proBNP (p > 0.05). Neither serum NGAL nor urinary NGAL levels are associated with NT-proBNP (p > 0.05). Conclusion: Our findings show an association between NT-proBNP and proteinuria in type II diabetic patients with macroalbuminuria but not with serum and urine NGAL.

Can serum Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule−1 help in decision making for surgery in antenatally dedected hydronephrosis

Relation of Systemic and Urinary Neutrophil Gelatinase-Associated Lipocalin Levels to Different Aspects of Impaired Renal Function in Patients With Acute Decompensated Heart Failure

Background/Aims: The diagnosis of type 2 diabetic nephropathy (T2DN) patients is important to prevent the long-term damaging effects of kidney loss in patients with diabetes and is decisive for patient outcomes. The aim of this study was to explore urine retinol binding protein (RBP) and neutrophil gelatinase-associated lipocalin (NGAL) in T2DN patients with and without albuminuria. Methods: A total of 293 T2DN patients were divided into three groups according to their urine albumin/urine creatinine ratio (UACR): normoalbuminuria group (UACR<30 mg/g, n=100), microalbuminuria group (UACR 30–300 mg/g, n=100) and macroalbuminuria group (UACR>300 mg/g, n=93); 50 non-diabetic subjects were recruited as the control group. The levels of urine RBP, NGAL, TNF-α and IL-18 in T2DN patients and non-diabetic subjects were measured using ELISA assays. Results: We first analyzed the clinical characteristics of the control and T2DN groups and found that urine NGAL, RBP, TNF-α and IL-18 levels were significantly increased and significantly correlated with the degree of albuminuria. In addition, univariate linear regression analysis showed that urine RBP was associated with UACR, BMI, Scr, BUN, TG, disease duration, SBP, NGAL, TNF-α and IL-18 levels, and urine NGAL was positively correlated with UACR, Scr, BUN, RBP, TNF-α and IL-18 levels. Conclusion: The results indicate that urine levels of NGAL and RBP may be independently associated with albuminuria in T2DN and may serve as novel biomarkers for the identification of T2DN.

NGAL in Acute Kidney Injury: From Serendipity to Utility

Background: Prematurity at birth is a known risk factor for the development of an early chronic renal disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well established biomarker of kidney injury, while high blood levels of asymmetric dimethylarginine (ADMA) are associated with the future development of adverse cardiovascular events and cardiac death.Aims: (1) to verify the presence of statistically significant differences between urinary NGAL and hematic ADMA levels in young adults born preterm at extremely low birth weight (<1000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) (2) to seek correlations between NGAL and ADMA levels, which would indicate the presence of an early cardio-renal involvement in ex-ELBW.Methods: Twelve ex-ELBW subjects (six males and six female, mean age: 23.9 ± 3.2 years) were compared with 12 C (six males and six female). Urinary NGAL and hematic ADMA levels were assessed.Results: Urinary NGAL levels were higher in ex- ELBW subjects compared to C (p < 0.05), as well as hematic ADMA concentrations (p < 0.05). A statistically significant correlation was found between urinary NGAL and ADMA (r = −0.60, p < 0.04).Conclusions: Our preliminary findings support the hypothesis that in ex-ELBW subjects the development of an early chronic kidney disease contributes towards inducing an increase in the atherosclerotic process and in the risk of future adverse cardiovascular events.

To analyze the effectiveness of amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein as predictive factors for fetal inflammatory response syndrome. We classified single pregnancy cases into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups. We collected amniotic fluid at vaginal delivery and cesarean section and compared the patient characteristics, maternal white blood cell count, C-reactive protein level, and amniotic fluid interleukin-6; neutrophil gelatinase-associated lipocalin; and L-type fatty acid-binding protein levels between the groups. We further analyzed the relationship between L-type fatty acid-binding protein levels and neonatal clinical outcomes. We analyzed 129 pregnancies, of which 36 and 93 (27.9% and 72.1%, respectively) were classified into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups, respectively. We observed significant differences in the maternal white blood cell counts and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. On the multivariate analysis, the useful predictive factors were maternal white blood cell count and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. Furthermore, the level of L-type fatty acid-binding protein was significantly higher in the transient tachypnea of the newborn and postnatal respiratory support group than in the control group. The maternal white blood cell count and amniotic interleukin-6 and neutrophil gelatinase-associated lipocalin levels were effective predictors of fetal inflammatory response syndrome. Amniotic fluid L-type fatty acid-binding protein level was an effective predictor of neonatal respiratory support.

Urinary NGAL (neutrophil gelatinase-associated lipocalin) levels have been shown to predict renal damage in various medical conditions. The present study was conducted to study the role of urinary NGAL levels in children with bladder exstrophy-epispadias complex post single-stage total reconstruction (SSTR) as markers of early renal functionreduction. Urine samples were collected from children with bladder exstrophy before SSTR (Group A, n = 11), 5years post SSTR (Group B, n = 40) and controls (Group C, n = 41) and stored at - 20°C. NGAL levels were estimated using double antibody sandwich ELISA. Mean NGAL levels in Groups A, B and C were 1.39, 34.24 and 2.58ng/ml, respectively. Mean NGAL levels among Group B subjects with glomerular filtration rate (GFR) ≥ 80ml/min/1.73m2 body surface area (BSA) was 29.8ng/ml, while it was 31.74ng/ml in those with GFR < 80ml/min. Urine samples were also evaluated 6months post SSTR. Mean NGAL at 6months was 6.76ng/ml, while at 12months it was 30.3ng/ml, remaining > 30ng/ml at 18 and 24months. Dimercaptosuccinic acid (DMSA) scans did not show any scarring, and GFRon diethylenetriamine pentaacetate (DTPA) scans remained stable. Increasing levels of urinary NGAL following bladder-exstrophyandepispadias complex repair suggest that NGAL detects the earliest signs of renal damage even before any deterioration is observed in DMSA and/or DTPA-GFR scans. Further studies with an adequate sample size and periodic measurement of NGAL need to be performed before any definitive conclusion can be drawn.

Urinary Tubular Biomarkers of Kidney Damage: Potential Value in Clinical Practice

Objective: We examined the value of two potential novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid binding protein (L-FABP), in diagnosing acute kidney injury (AKI) in liver transplant recipients.Methods: NGAL and L-FABP in urinary sample from Twenty-five patients before surgery and at 2, 4, 6, 12, 24, 48, 72 and 120 h after the anhepatic phase were tested. Standard statistics were used along with receiver-operating characteristic (ROC) analysis to evaluate the diagnostic value of selected markers.Results: Urinary NGAL was only slightly elevated at 2 h in the non-AKI group while rose and stayed high from 2–6 h in the AKI group. However, urinary L-FABP rose transiently in both groups 2–120 h following surgery. The level of urinary NGAL presented differences at 2–6 h (p < 0.05) and urinary L-FABP at 4 h (p < 0.05) between AKI and non-AKI groups. ROC analysis showed that area under the curves (AUCs) of NGAL were 0.766, 0.773, and 0.773 at 2, 4 and 6 h respectively while 0.760 of L-FABP at 4 h.Conclusion: Urinary NGAL rather than L-FABP appeared to be a sensitive and specific marker of AKI in liver transplant recipients.

Novel biomarkers of acute kidney injury: time for implementation?

The invasive, expensive, and time-consuming nature of radiological examinations for vesicoureteral reflux (VUR) has compelled researchers to search for new markers to predict VUR. This study was designed to evaluate the usefulness of serum and urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL) in predicting the existence of VUR. This cross-sectional study involved all patients with a first febrile urinary tract infection (UTI) referred to Ali Asghar Children's Hospital. Each patient included in the study had clinical symptoms of pyelonephritis and a positive urine culture. The patients were divided into 2 groups: VUR and non-VUR. The serum and urinary NGAL levels were calculated in both groups. The receiver operating characteristic (ROC) curve was used to look for serum and urinary NGAL cut-points that differentiated the VUR group from the non-VUR group. Among the 40 children in the study, 23 belonged to the VUR group. The median age was 2.5 years (range, 0.3-8 years), and 35 patients were girls. ROC curve analysis showed that only the urinary NGAL level was significantly related to VUR. There was no association between serum NGAL levels and VUR. According to the ROC curve, a urinary NGAL level cut-off value of 15 ng/mL was likely to be diagnostic of VUR with 82.6% sensitivity and 58.8% specificity. The urinary NGAL level, specifically with a cut-off value of 15 ng/mL, can indicate the existence of VUR in patients with UTI with near-acceptable levels of sensitivity and specificity.