|Year : 2016 | Volume
| Issue : 1 | Page : 49-54
|Plasma neutrophil gelatinase-associated lipocalin as a marker for the prediction of worsening renal function in children hospitalized for acute heart failure
Sahar Elsharawy1, Lila Raslan1, Saed Morsy1, Basheir Hassan1, Naglaa Khalifa2
1 Pediatrics Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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|Date of Web Publication||15-Jan-2016|
| Abstract|| |
Acute heart failure (AHF) is frequently associated with worsening renal function in adult patients. Neutrophil gelatinase-associated lipocalin (NGAL) serves as an early marker for acute renal tubular injury. To assess the role of plasma NGAL in predicting worsening renal function (WRF) in children with AHF, we studied 30 children hospitalized for AHF; children with history of chronic renal disease or on nephrotoxic drugs were excluded. Twenty ageand sex-matched healthy children were included in the study as a control group. Echocardiographic examination was performed on admission. Blood urea nitrogen (BUN), serum creatinine, estimated glomerular filtration rate (eGFR) and plasma NGAL levels were measured on admission and 72 h later. Seventeen (56.6%) patients developed WRF within the three-day follow-up period. At presentation, plasma NGAL level was significantly elevated in children who developed WRF. Admission plasma NGAL level correlated with renal parameters (BUN, creatinine and eGFR) as well as with left ventricular systolic parameters (ejection fraction and fractional shortening). For prediction of WRF, admission plasma, NGAL level >27.5μg/L had sensitivity and specificity of 90% and 68%, respectively. The area under the receiver-operator curve was higher for NGAL (0.869) than for BUN (0.569) or eGFR (0.684). We conclude that admission plasma NGAL level can predict WRF in children hospitalized for AHF.
|How to cite this article:|
Elsharawy S, Raslan L, Morsy S, Hassan B, Khalifa N. Plasma neutrophil gelatinase-associated lipocalin as a marker for the prediction of worsening renal function in children hospitalized for acute heart failure. Saudi J Kidney Dis Transpl 2016;27:49-54
|How to cite this URL:|
Elsharawy S, Raslan L, Morsy S, Hassan B, Khalifa N. Plasma neutrophil gelatinase-associated lipocalin as a marker for the prediction of worsening renal function in children hospitalized for acute heart failure. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Aug 2];27:49-54. Available from: https://www.sjkdt.org/text.asp?2016/27/1/49/174071
| Introduction|| |
Renal dysfunction is common in patients with acute heart failure (AHF) and is associated with significant early and late morbidity and mortality. ,
The current most widely used biomarkers for the early detection of chronic kidney disease or AKI are proteinuria, serum creatinine and blood urea nitrogen (BUN).  All of these are not very sensitive parameters for the early detection of kidney injury when therapies may be more effective. 
If a marker that provided earlier detection of worsening renal function (WRF) than BUN or creatinine was available, it could identify the group of patients at risk of WRF and afford physicians an opportunity to change their treatment strategies to avoid further kidney damage and reduce the risk of adverse events. 
Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa lipocalin superfamily glycoprotein and acute phase reactant rapidly released in response to a variety of cellular stresses, including ischemia and inflammation. , Measurements of urinary and systemic NGAL levels have emerged as promising and sensitive biomarkers of early acute kidney injury (AKI) in a diverse range of settings, as NGAL rapidly appears in both blood and urine (rising tento 100-fold within hours, respectively) in response to renal tubular damage. ,
Despite the numerous publications that investigate the clinical utility of NGAL as a diagnostic and predictive marker for AKI in adult patients with AHF, there has been little data about WRF in pediatric patients.
Our study aimed to assess the role of serum NGAL in predicting WRF in children with AHF.
| Patients and Methods|| |
This case-control study was conducted at the Cardiology Unit, Zagazig University Children's Hospital during the period from March 2011 to November 2012. Thirty children aged three to 48 months and presenting with symptoms and signs of AHF were enrolled in the study. AHF was diagnosed according to the current European Society of Cardiology guidelines.  WRF was defined as an inhospital increase in serum creatinine ≥0.3 mg/dL more than the value at presentation.  The estimated filtration rate (eGFR) was calculated using the Schwartz formula. 
Children with a history of chronic kidney disease or on nephrotoxic drugs were excluded from the study. Twenty ageand sex-matched healthy children were included in the study as a control group.
Informed consents were obtained prior to enrolment in the study from the children's guardians. The study protocol was approved by the Pediatric Ethical Committee of Zagazig University.
The patients were subjected to full history taking and thorough clinical examination and imaging studies. Imaging studies included chest X-ray, electrocardiography and echocardiography. Blood urea nitrogen (BUN), serum creatinine and plasma NGAL levels were measured on admission and 72 h later.
All patients and controls underwent echocardiographic examination to assess the cardiac function. Echocardiography was performed using a GE vivid-7 multipurpose system with different probe sizes. Each child was examined according to the recommendations of the American Society of Echocardiography.  Echocardiographic examination included Mmode, two-dimensional and Doppler modes. The left ventricular end systolic and diastolic diameters, ejection fraction (EF) and fractional shortening (FS) were measured using the Mmode echocardiography in the left para-sternal view.
Blood samples were obtained, spun, separated and frozen at −20°C until analysis. The plasma NGAL level was measured by the enzyme-linked immunosorbent assay (ELISA) using the commercially available ELISA testkit (Cat. No. KIT 036, BioPorto Diagnostics, Gentofte Denmark/Human Lipocalin-2/NGALELISA).
| Statistical analysis|| |
Data were analyzed using the Statistical Package for Social Sciences (SPSS) release 16. Data showing normal distribution were presented as the means and standard deviation. For comparison between the means of two groups, the t-test was used. The non-parametric values were represented as medians and range and the medians of the two groups were tested using the Mann-Whitney-U test. To compare the median of the patients group, on admission and three days later, the Wilcoxon test was used. Qualitative data are represented by frequency and relative percentage and chi-square test was used for testing the association of the qualitative data. Correlations were performed using the Spearman rank correlation. Receiver- operating characteristic (ROC) analyses were performed to compare the potential of admission plasma NGAL, BUN and eGFR to predict the occurrence of WRF. In all analyses, Pvalues <0.05 were considered statistically significant.
| Results|| |
Detailed baseline characteristics of the study population are summarized in [Table 1]. The median age of the patients was eight months (range 3-48 months), and 15 (50%) patients were male. The patients were not different from controls with respect to age and gender. All patients were in modified Ross score class III or IV on admission (60% in class III and 40% in class IV). Values of EF and FS are significantly lower among patients as compared with their controls.
|Table 1: Demographic, clinical and echocardiographic data of the patients and controls.|
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There were significantly elevated levels of BUN, creatinine and plasma NGAL and significantly low eGFR in children with AHF on admission and three days later in comparison with the control group [Table 2].
|Table 2: Laboratory parameters of patients (Day 1 and Day 3) and controls.|
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Overall, 17 (57%) patients experienced WRF. There were significant increases in the levels of BUN, creatinine and plasma NGAL and a significant decrease in the eGFR levels in patients with WRF in comparison with that in patients without WRF on admission [Table 3]. There were significant positive correlations between the admission NGAL levels and the levels of BUN and creatinine. Also, there were significant negative correlations between the admission NGAL levels and fractional shortening, ejection fraction and eGFR [Table 4].
|Table 3: Comparison between cases with and without WRF with regards the on-admission renal parameters.|
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|Table 4: Correlations between admission NGAL level and echocardiographic and renal parameters.|
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To compare the potential of the levels of the admission plasma NGAL, BUN and eGFR to predict the occurrence of WRF, ROC analyses were performed. The ROC curve showed an optimal admission NGAL level cut-off at >27.5 μg/L, with sensitivity of 90% and specificity of 68%. The area under the ROC curve (AUC) was higher for NGAL (0.869) than for BUN (0.569) or eGFR (0.684) [Figure 1].
|Figure 1: Predictive value of admission neutrophil gelatinase-associated lipocalin (NGAL), estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) for worsening renal function in children hospitalized for AHF.|
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| Discussion|| |
To the best of our knowledge, this is the first study of children with AHF to undergo prospective evaluation of plasma NGAL as a biomarker for WRF. At the time of admission, the plasma NGAL levels were significantly elevated in these children compared with healthy controls, and the levels continued to rise through the third day of admission. Specifically, 17 (56.6%) of our patients developed WRF within the three-day hospital follow-up.
Our results resemble previous reports of the high prevalence of WRF in adult patients hospitalized for AHF. Aghel et al  investigated 91 adult patients with AHF for the presence of WRF and found that 35 (38%) patients developed WRF within the five-day hospital follow-up. Also, Metra et al  reported that 34% of the patients hospitalized for AHF developed WRF during their admission.
Traditional explanations regarding the mechanisms of WRF in the setting of AHF include overzealous diuresis, leading to reduced renal perfusion, and low cardiac output heart failure, resulting in acute tubular injury. These can result in excessive neurohormonal activation and altered tubuloglomerular feedback. In addition, more recent studies have demonstrated the association between venous congestion rather than low cardiac output with WRF in AHF. 
In our study, the patients who developed WRF had significantly higher admission plasma NGAL, serum creatinine and BUN levels and significantly lower eGFR values. Similarly, Breidthardt et al  had observed that all renal parameters including serum creatinine, BUN and NGAL were significantly higher, while eGFR values were significantly lower in AHF cases compared with cases without AKI. Aghel et al  and Macdonald et al  reported the same results regarding plasma NGAL levels.
As demonstrated in our results, the relationship between plasma NGAL levels and renal impairment indices was robust in the AHF patients. This finding is in agreement with the study of Shrestha et al. 
Up-regulation of NGAL systemically and in renal tubular epithelial cells is believed to constitute an important acute phase compensatory response, protecting against tubular cell death and enhancing re-epithelialization according to the abilities of NGAL-siderophore complexes to deliver iron into renal tubular cells. Furthermore, up-regulation signals antioxidant, anti-apoptotic and cell proliferative pathways in order to scavenge excess free intracellular and extracellular iron, limiting labile iron-mediated cytotoxicity.  This marked upregulation of NGAL in response to renal tubular cell injury has enabled its emergence as a sensitive biomarker of early acute kidney injury as well as chronic kidney disease. 
In our study, the ROC for prediction of WRF showed an optimal admission NGAL cut-off value at >27.5μg/L, with sensitivity and specificity of 90% and 68%, respectively, and with an AUC of 0.869. Macdonald et al  found admission NGAL >89 ng/mL to have 68% sensitivity and 70% specificity for prediction of WRF with AUC of 0.71 (0.58-0.84), and Aghel et al  concluded that admission NGAL ≥140 ng/mL had 86% and 54% sensitivity and specificity, respectively. Furthermore, a very recent study by Alvelos et al  found spot measurements of NGAL levels to powerfully predict AKI in 114 hospitalized AHF patients (AUC = 0.93). 
In contrast, Breidthardt et al  found that AUC was comparable for NGAL and creatinine (0.52 vs 0.54) and that the NGAL levels failed to predict WRF independently.
There were important differences from our study that may explain these discrepancies in the cut-off values. The different age groups (children in our study) and different diagnostic categories may contribute to these discrepancies. Moreover, differences in the calibration of assays and the antibodies used may result in markedly various NGAL cut-off values.
Regarding the ECHO parameters on admission, our study showed that NGAL levels had significant negative correlations with EF and FS. In contrast, Shrestha et al found no association between the NGAL levels and the echocardiographic parameters of systolic dysfunction. 
Potential benefits of identifying patients at risk of WRF in children hospitalized for AHF include the ability to modify treatment regimes to mitigate this risk.
Our study had potential limitations that merit consideration. Firstly, the small number of patients limited the number of predictors that can be analyzed in a multivariable model. Secondly, we did not have information on the baseline renal function in the patients. Thus, we used worsening from admission level to define WRF. Finally, data related to the utilized treatment modalities during hospitalization and outcome are lacking in our study.
In conclusion, WRF is a frequent finding in children hospitalized for AHF. Plasma NGAL levels on admission can predict WRF in these patients. Future studies should consider the role of NGAL levels in guiding therapeutic decisions that could alter the course of WRF and improve outcomes.
| Acknowledgments|| |
The authors would like to express their gratitude to all staff members of the Pediatric Cardiology Unit.
Conflict of Interest: None declared.
| References|| |
Damman K, van Veldhuisen DJ, Navis G, Voors AA, Hillege HL. Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure. Eur J Heart Fail 2008;10:997-1000.
Damman K, Voors AA, Hillege HL, et al. Congestion in chronic systolic heart failure is related to renal dysfunction and increased mortality. Eur J Heart Fail 2010;12:974-82.
Macdonald S, Arendts G, Nagree Y, Xu XF. Neutrophil Gelatinase-Associated Lipocalin (NGAL) predicts renal injury in acute decompensated cardiac failure: A prospective observational study. BMC Cardiovasc Disord 2012;12:8.
Rosner MH. Urinary biomarkers for the detection of renal injury. Adv Clin Chem 2009;49:73-97.
Collins SP, Hart KW, Lindsell CJ, et al. Elevated urinary neutrophil gelatinase-associated lipocalcin after acute heart failure treatment is associated with worsening renal function and adverse events. Eur J Heart Fail 2012;14:1020-9.
Xu S, Venge P. Lipocalins as biochemical markers of disease. Biochim Biophys Acta 2000;1482:298-307.
Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 1993;268: 10425-32.
Schmidt-Ott KM, Mori K, Li JY, et al. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2007;18:407-13.
Mori K, Lee HT, Rapoport D, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 2005;115:610-21.
McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-847.
Breidthardt T, Socrates T, Noveanu M, et al. Effect and clinical prediction of worsening renal function in acute decompensated heart failure. Am J Cardiol 2011;107:730-5.
Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987;34:571-90.
Gottdiener JS, Bednarz J, Devereux R, et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004; 17:1086-119.
Aghel A, Shrestha K, Mullens W, Borowski A, Tang WH. Serum neutrophil gelatinase-associated lipocalin (NGAL) in predicting worsening renal function in acute decompensated heart failure. J Card Fail 2010;16:49-54.
Metra M, Nodari S, Parrinello G, et al. Worsening renal function in patients hospitalized for acute heart failure: Clinical implications and prognostic significance. Eur J Heart Fail 2008;10:188-95.
Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53: 589-96.
Breidthardt T, Socrates T, Drexler B, et al. Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure. Crit Care 2012;16:R2.
Shrestha K, Borowski AG, Troughton RW, Thomas JD, Klein AL, Tang WH. Renal dysfunction is a stronger determinant of systemic neutrophil gelatinase-associated lipocalin levels than myocardial dysfunction in systolic heart failure. J Card Fail 2011;17:472-8.
Haase M, Bellomo R, Haase-Fielitz A. Novel biomarkers, oxidative stress, and the role of labile iron toxicity in cardiopulmonary bypassassociated acute kidney injury. J Am Coll Cardiol 2010;55:2024-33.
Bolignano D, Lacquaniti A, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 2009;4:337-44.
Alvelos M, Pimentel R, Pinho E, et al. Neutrophil gelatinase-associated lipocalin in the diagnosis of type 1 cardio-renal syndrome in the general ward. Clin J Am Soc Nephrol 2011;6:476-81.
Pediatrics Department, Faculty of Medicine, Zagazig University, Zagazig
[Table 1], [Table 2], [Table 3], [Table 4]
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