Users Online: 623
Home Print this page Email this page
Home About us Editorial board Search Browse articles Submit article Ahead of Print Instructions Subscribe Contacts Login 


 
Previous article Browse articles Next article 
ORIGINAL ARTICLE
Adv Biomed Res 2014,  3:66

Urine and serum neutrophil gelatinase-associated lipocalin cut-off point for the prediction of acute kidney injury


1 Department of Nephrology, Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
2 Isfahan University of Medical Sciences, Isfahan, Iran

Date of Submission04-Jul-2012
Date of Acceptance06-Nov-2012
Date of Web Publication27-Jan-2014

Correspondence Address:
Hamideh Mousazadeh
Number 74, Banafsheh Alley, Azadegan Alley, Hezarjarib Street, Isfahan
Iran
Login to access the Email id

Source of Support: This project was a residency thesis that performed by financial support from Vice Chancellery for Research of Isfahan University of Medical Sciences, Isfahan, Iran. (Grant no: 390537), Conflict of Interest: None


DOI: 10.4103/2277-9175.125847

Rights and Permissions
  Abstract 

Background: The aim of the present study was to determine the optimum cut-off point of urine and serum neutrophil gelatinase-associated lipocalin (NGAL) for the predictive diagnosis of acute kidney injury (AKI).
Materials and Methods: This study was a prospective observational study which was performed at Alzahra hospital and Emam Hussein Hospital, Isfahan, Iran. During a period of 4 months, from February 2012 to May 2012, consecutive patients admitted to pediatric intensive care unit (PICU) aged between 1 month and 15 years with glomerular filtration rate (GFR) more than 90 ml/min were enrolled in the study. In all the patients who were enrolled in the study, blood and urine samples were attained on the first, third, and fifth day of admission. Serum and urine NGAL were assessed and compared between patients who developed AKI and who didn't.
Results: Of 25 patients who enrolled in the study, 13 developed AKI. For the serum NGAL, the most accurate cut-off point was the fifth day cut-off point which was 163 375 pg/ml (sensitivity: 61.5%, specificity: 94.6%, AUC: 0.76) and urine NGAL cut-off point was 86 040 pg/ml (sensitivity: 50%, specificity: 92.5%, AUC: 0.73).
Conclusions: In conclusion, we deduced that serum NGAL level significantly elevates in critically ill patients admitted in PICU who develop AKI. Serum and urine NGAL on the fifth day are the best predictors for the AKI with cut-off points 163 375 and 86 040.

Keywords: Acute kidney injury, neutrophil gelatinase-associated lipocalin, sensitivity and specificity, RIFLE


How to cite this article:
Merrikhi A, Gheissari A, Mousazadeh H. Urine and serum neutrophil gelatinase-associated lipocalin cut-off point for the prediction of acute kidney injury. Adv Biomed Res 2014;3:66

How to cite this URL:
Merrikhi A, Gheissari A, Mousazadeh H. Urine and serum neutrophil gelatinase-associated lipocalin cut-off point for the prediction of acute kidney injury. Adv Biomed Res [serial online] 2014 [cited 2019 Oct 21];3:66. Available from: http://www.advbiores.net/text.asp?2014/3/1/66/125847


  Introduction Top


Acute kidney injury (AKI) has been defined as the rapid loss of kidney function that results in the retention of urea and other nitrogenous waste products. [1],[2],[3] The loss of renal function is detected by measurement of the serum creatinine, but there are several limitations; first, serum creatinine level widely varies among individuals according to the muscle mass, age, and sex; second, serum creatinine level does not change until a considerable proportion of kidney function has been lost; third, renal function is overestimated at lower rates of glomerular filtration rate (GFR) due to rise in intubular secretion of creatinine. [4] Nowadays, serum creatinine is considered as a delayed and unreliable marker for the diagnosis of AKI, and to rely solely on this marker may lead to delay in the initiation of therapeutic interventions. [5],[6]

Recent studies focused on finding new biomarkers for early detection of AKI. Several markers have been recognized such as interleukin-18 (IL-18), [7] kidney injury molecule-1 (KIM-1), [8],[9] liver-type fatty acid-binding protein (L-FABP), [10] and neutrophil gelatinase-associated lipocalin (NGAL).

NGAL is known as well-established marker for early detection of AKI and several studies have been performed in this field. [11],[12],[13]

NGAL is a 25-kDa protein that bounds to matrix metalloproteinase-9 from neutrophils [14] which is expressed at a very low level in some tissues, and its level rises in injured epithelial cells, including the liver, lung kidney, and colon. [15] Previous studies mentioned that NGAL increases significantly in urine and serum compared with healthy controls and is correlated with serum creatinine. Its level rises 24 to 48 hours before creatinine level rises in AKI condition. [16] This marker helps the physician to early diagnose and manage AKI.

AKI occurs in approximately 80% of severely ill children in pediatric intensive care unit (PICU) which results in long hospital stay and increased patients' mortality rate. [17],[18],[19] Due to these rationales, AKI among these patients became one of the major concerns for physicians. As is it mentioned, it seems to be necessary to perform research projects in this field. In this study, we aimed to determine the optimum cut-off point of urine and serum NGAL for diagnosis of AKI.


  Materials and Methods Top


This study was a prospective observational study which was performed at Alzahra hospital and Emam Hossein Hospital, Isfahan, Iran.

Patients and setting

During a period of 4 months, from February 2012 to May 2012, consecutive patients admitted to pediatric intensive care unit (PICU) aged between 1 month and 15 years with GFR more than 90 ml/min were enrolled in the study. Patients were excluded if any of the following criteria were present: Patient dies before the end of study sampling, cannot obtain the blood sample, pre-existing renal insufficiency, and rejection of the patients' parents to participate in a research project.

Intervention and assessments

Of all patients, who were enrolled in the study, blood and urine samples were attained on the first, third, and fifth day of admission. Both samples were obtained by one of the research investigators (HM) at 20 O'clock on each day. Five milliliters of urine specimens were obtained from urine catheter. Three milliliters blood sample was withdrawn under aseptic conditions by suitable syringe according to patients' age and weight and immediately sent to hospital laboratory for further evaluations. Plasma NGAL level was assessed using human lipocalin-2/NGAL ELISA (Boster Biological Technology. Co., Ltd, USA).

Development of AKI was diagnosed using pediatric RIFLE classification, correspondence to the risk phase. Risk phase is defined as reduction in GFR ≥25% or creatinine rise ≥50% from baseline level, or a fall in urine output to <0.5 ml/kg/h for at least 8 hours. GFR were calculated using the Schwartz formula. [20]

The following data were also evaluated in all patients: Blood urea nitrogen (BUN), creatinine, urine output, urine creatinine. Severity of disease was assessed by the Acute Physiologic and Chronic Health Evaluation (APACHE) score [21] and the observational scale to identify serious illness in febrile children. [22] Further data including blood culture results, vasopressin, antibiotic and anti-seizure drug usage during ICU stay were also gathered.

Sample size were calculated using statistical formula considering α = 0.05 and β = 0.2 to be 25 in this study. In this study, we also had 25 patients as the control group to evaluate the baseline NGAL in serum and urine. This control group consists of healthy children who came into Alzahra hospital with their parents for various reasons.

Statistical analysis

Data analysis was performed using Statistical Package for Social Sciences (SPSS) version 16 software. Comparisons were made using Student t-test, ANOVA, Pearson regression, logistic regression, multiple regression analysis test as needed. Differences considered were significant if P value was <0.05. To calculate the diagnostic values for the plasma and urine NGAL levels at the cut-off points, receiver operating characteristic (ROC) curves were generated and the area under the curves (AUC) were calculated to determine the accuracy of NGAL as a biomarker.

Written informed consents were obtained from all patients and parents as needed, for authorize use of their medical records for research purposes with approval of the protocol by ethical committee of our university.


  Results Top


A total number of 25 patients including 18 (72%) males and 7 (28%) females were enrolled in the study. Of these patients who were admitted in ICU, 8 had multiple trauma, 11 were with sepsis, and 6 were with cardiac diseases. 25 healthy children were also considered as the control group. Detailed data about age and sex of study participants and the control group are shown in [Table 1].
Table 1: Comparison of age, sex and BMI among study groups


Click here to view


Patients in the two study groups were compared for various characteristics and clinical outcomes including: Duration of ICU admission, deaths, APACHE score, observational scale, mechanical ventilation, and the administration of antibiotic, anti-seizure drugs, and vasopressin agents; however, none of them has statistically significant difference between two groups. Detailed data are shown in [Table 2].
Table 2: Patients characteristic and clinical outcome


Click here to view


Data analysis for the correlation between serum and urine NGAL with APACHE score and observational scale was performed. Results showed that there is statistically significant correlation in the fifth day serum NGAL level with APACHE score and the observational scale; the others didn't have any significant correlation [[Table 3] and Diagrams 1, 2].
Table 3: Serum and urine NGAL correlation with APACHE score and observational scale


Click here to view






We compared the values of urine and serum NGAL on the first, third, and fifth day of admission and baseline NGAL of the control group. We found a significant increase in serum NGAL on the third and fifth day compared with two other groups. Detailed data are shown in [Table 4].
Table 4: The comparison of serum and urine NGAL among study patients and the control group


Click here to view


We analyzed data for the optimum cut-off point of serum NGAL for the prediction of AKI. Serum NGAL on the fifth day of admission was the most accurate for the prediction of AKI (AUC = 0.79); ROC curve of fifth day is presented in [Figure 1].
Figure 1: ROC curve for serum NGAL level on the fifth day of admission

Click here to view


The best cuts-off points for the first, third, and fifth day are 177755 pg/ml, 92720 pg/ml, and 163375 pg/ml, respectively, and the diagnostic values of these points and AUC are explained in [Table 5].
Table 5: Diagnostic value of serum NGAL at the cutoff point values for the prediction of AKI


Click here to view


Cut-off points for optimum accuracy were also determined for urine NGAL; fifth day urine NGAL is the most accurate for the prediction of AKI [Figure 2].
Figure 2: ROC curve for urine NGAL on the fifth day of admission

Click here to view


Optimum cut-off points for the first, third, and fifth day of admission were 65820 pg/ml, 66810 pg/ml, and 86040 pg/ml, respectively. Detailed data about the diagnostic value of NGAL for the prediction of AKI and AUC are shown in [Table 6].
Table 6: Diagnostic value of urine NGAL at the cutoff point values for the prediction of AKI


Click here to view



  Discussion Top


The aim of the present study was to determine the optimum cut-off point of urine and serum NGAL for the prediction of AKI. Our data showed that serum NGAL level significantly elevates in patients who develop AKI compared to those who do not. However, the increase in urine NGAL was not statistically significant. Although urine NGAL in AKI patients was at least 50-fold more than control value, the difference was not statistically significant in comparison to patients who didn't develop AKI. Serum and urine NGAL levels in the fifth day were the best predictors for the AKI with the cut-off values of 163 375 and 86 040.

The cut-off point for serum NGAL is within the range as the previous study. [23],[24] Mc Donald et al. revealed the cut-off point of 89 000 pg/ml with the sensitivity of 68% and specificity of 70%, and AUC of 0.71. [23] In comparison to our data, they had relatively higher sensitivity and lower specificity and AUC values. The authors didn't report the PPV and NPV value at this cut off point. On the other hand, Fadel et al. suggested the value of 100 000 pg/ml as the cut-off point with the sensitivity and specificity of 100% and 90.5%, respectively. [24]

The urine NGAL in our study had the best optimum cut-off point of 86 040 pg/ml with the sensitivity of 46.1% and specificity of 91.6%. In a study conducted by Zapitelli et al. the highest and lowest cut-off points for sensitivity varied from 54% to 85% and for specificity varied from 97% to 44%. In their study, the AUC value for prediction of AKI was 0.79, which was higher than our study. [16] Another study performed by Wagener et al. suggested the cut-off point of 213 000 pg/ml for urine NGAL with sensitivity and specificity of 73% and 78%, respectively. [25]

We also analyzed several parameters between two study groups. Data showed that the only parameter that had a significant difference between two groups was the patient's age which was significantly lower in patients who developed AKI. This point was not revealed in previous studies. [26]

Our study had some strength. First, all patients had normal kidney function at the beginning of the study, and the study design allowed us for the precise comparison with following changes. Second, in this study, we evaluated critically ill patients in PICU from various etiologies which differs our study from previous ones. We also had some limitations that were with our study design which was unblinded and observational. We suggest further multicenter studies with more powerful design for this purpose.


  Conclusion Top


We deduced that serum NGAL level significantly elevates in patients who in critically ill patients who develop AKI when admitted in PICU. Serum and urine NGAL on the fifth day are the best predictors for the AKI with the cut-off points of 163 375 pg/ml and 86 040 pg/ml.

 
  References Top

1.Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.  Back to cited text no. 1
[PUBMED]    
2.Chan JC, Williams DM, Roth KS. Kidney failure in infants and children. Pediatr Rev 2002;23:47-60.  Back to cited text no. 2
[PUBMED]    
3.Andreoli SP. Acute renal failure. Curr Opin Pediatr 2002;14:183-8.  Back to cited text no. 3
[PUBMED]    
4.Devarajan P. Emerging urinary biomarkers in the diagnosis of acute kidney injury. Expert Opin Med Diagn 2008;2:387-98.  Back to cited text no. 4
[PUBMED]    
5.Nickolas TL, Barasch J, Devarajan P. Biomarkers in acute and chronic kidney disease. Curr Opin Nephrol Hypertens 2008;17:127-32.  Back to cited text no. 5
[PUBMED]    
6.Devarajan P. Neutrophil gelatinase-associated lipocalin-an emerging troponin for kidney injury. Nephrol Dial Transplant 2008;23:3737-43.  Back to cited text no. 6
[PUBMED]    
7.Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005;16:3046-52.  Back to cited text no. 7
[PUBMED]    
8.Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Kidney Int 2002;62:237-44.  Back to cited text no. 8
[PUBMED]    
9.Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: A tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol 2004;286:F552-63.  Back to cited text no. 9
[PUBMED]    
10.Nakamura T, Sugaya T, Node K, Ueda Y, Koide H. Urinary excretion of liver-type fatty acid-binding protein in contrast medium-induced nephropathy. Am J Kidney Dis 2006;47:439-44.  Back to cited text no. 10
[PUBMED]    
11.Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14:2534-43.  Back to cited text no. 11
[PUBMED]    
12.Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin: A novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 2004;24:307-15.  Back to cited text no. 12
    
13.Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 2005;115:610-21.  Back to cited text no. 13
[PUBMED]    
14.Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, et al. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2004;15:3073-82.  Back to cited text no. 14
[PUBMED]    
15.Devarajan P. Review: Neutrophil gelatinase-associated lipocalin: A troponin-like biomarker for human acute kidney injury. Nephrology (Carlton) 2010;15:419-28.  Back to cited text no. 15
    
16.Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, et al. Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: A prospective cohort study. Crit Care 2007;11:R84.  Back to cited text no. 16
[PUBMED]    
17.Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007;71:1028-35.  Back to cited text no. 17
[PUBMED]    
18.Schneider J, Khemani R, Grushkin C, Bart R. Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit. Crit Care Med 2010;38:933-9.  Back to cited text no. 18
[PUBMED]    
19.Goldstein SL, Devarajan P. Pediatrics: Acute kidney injury leads to pediatric patient mortality. Nat Rev Nephrol 2010;6:393-4.  Back to cited text no. 19
[PUBMED]    
20.Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-12.  Back to cited text no. 20
[PUBMED]    
21.Zimmerman JE, Kramer AA, McNair DS, Malila FM. Acute Physiology and Chronic Health Evaluation (APACHE) IV: Hospital mortality assessment for today's critically ill patients. Crit Care Med 2006;34:1297-310.  Back to cited text no. 21
[PUBMED]    
22.McCarthy PL, Sharpe MR, Spiesel SZ, Dolan TF, Forsyth BW, DeWitt TG, et al. Observation scales to identify serious illness in febrile children. Pediatrics 1982;70:802-9.  Back to cited text no. 22
[PUBMED]    
23.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.  Back to cited text no. 23
[PUBMED]    
24.Fadel FI, Abdel Rahman AM, Mohamed MF, Habib SA, Ibrahim MH, Sleem ZS, et al. Plasma neutrophil gelatinase-associated lipocalin as an early biomarker for prediction of acute kidney injury after cardio-pulmonary bypass in pediatric cardiac surgery. Arch Med Sci 2012;8:250-5.  Back to cited text no. 24
[PUBMED]    
25.Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen RN, et al. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006;105:485-91.  Back to cited text no. 25
[PUBMED]    
26.Wheeler DS, Devarajan P, Ma Q, Harmon K, Monaco M, Cvijanovich N, et al. Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock. Crit Care Med 2008;36:1297-303.  Back to cited text no. 26
[PUBMED]    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


This article has been cited by
1 Development of a novel ssDNA aptamer targeting neutrophil gelatinase-associated lipocalin and its application in clinical trials
Xiaoqian Hong,Huihui Yan,Fuan Xie,Kaiyu Wang,Qiang Wang,Huijuan Huang,Kunrong Yang,Suhong Huang,Tingting Zhao,Junkai Wang,Yunyun Chen,Kuancan Liu,Xiaopeng Lan
Journal of Translational Medicine. 2019; 17(1)
[Pubmed] | [DOI]
2 The future for diagnostic tests of acute kidney injury in critical care: evidence synthesis, care pathway analysis and research prioritisation
Peter S Hall,Elizabeth D Mitchell,Alison F Smith,David A Cairns,Michael Messenger,Michelle Hutchinson,Judy Wright,Karen Vinall-Collier,Claire Corps,Patrick Hamilton,David Meads,Andrew Lewington
Health Technology Assessment. 2018; 22(32): 1
[Pubmed] | [DOI]
3 Neutrophil gelatinase-associated lipocalin in dogs with chronic kidney disease, carcinoma, lymphoma and endotoxaemia
A. R. Cobrin,S. L. Blois,A. C. G. Abrams-Ogg,S. A. Kruth,C. Dewey,M. K. Holowaychuk,V. Gauthier
Journal of Small Animal Practice. 2016;
[Pubmed] | [DOI]
4 Urinary neutrophil gelatinase-associated lipocalin identifies critically ill young children with acute kidney injury following intensive care admission: a prospective cohort study
Alexandra JM Zwiers,Saskia N de Wildt,Joost van Rosmalen,Yolanda B de Rijke,Erik AB Buijs,Dick Tibboel,Karlien Cransberg
Critical Care. 2015; 19(1)
[Pubmed] | [DOI]
5 Dexmedetomidine on renal ischemia-reperfusion injury in rats: assessment by means of NGAL and histology
Ana Lygia R. de Carvalho,Roberto B. Vital,Cláudio M. Kakuda,José R.C. Braz,Yara M.M. Castiglia,Leandro G. Braz,Marília P. Módolo,Odilon R.G. Ribeiro,Maria A. Domingues,Norma S.P. Módolo
Renal Failure. 2015; : 1
[Pubmed] | [DOI]



 

Top
Previous article  Next article
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1077    
    Printed17    
    Emailed0    
    PDF Downloaded298    
    Comments [Add]    
    Cited by others 5    

Recommend this journal