|Year : 2017 | Volume
| Issue : 4 | Page : 121-129
Urinary neutrophil gelatinase-associated lipocalin as prognostic biomarker for idiopathic nephrotic syndrome in Egyptian children
Mohamed Abd Elaziz El-Gamasy, Maher Ahmed Abdelhafez, Mohammed M Barr, Mostafa Mansour Mehrez, Mohammed A Nassar, Mohsen M Eldeeb, Mohamed Abdelmageed
Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Gharbia Governorate, Egypt
|Date of Web Publication||29-Dec-2017|
Dr. Mohamed Abd Elaziz El-Gamasy
Department of Pediatrics, Tanta University Hospital, El Giesh Street, Tanta, Gharbia
Source of Support: None, Conflict of Interest: None
Background and Objectives: It is important to distinguish steroid sensitive nephrotic syndrome (SSNS) from steroid resistant nephrotic syndrome (SRNS) to avoid initial full dose steroid therapy in the latter. Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI) even on top of chronic kidney disease (CKD). The aim is to determine urinary NGAL level in children with idiopathic nephrotic syndrome (INS) as a prognostic factor for INS, it can predict steroid resistance early in the course of INS. Subjects and Methods: The present study was carried out on ninety children with INS who were admitted in Pediatric Nephrology Unit of Tanta University Hospital. Thirty healthy children of the same age and sex served as control group. The subjects were subdivided into three groups: Group 1 (SSNS), Group 2 (SRNS), and Group 3 (controls). Patients and controls were subjected to clinical evaluation, laboratory investigations which included 24 h urinary collection for urinary volume and protein, complete blood count, serum cholesterol, serum albumin, blood urea, serum creatinine, and urinary NGAL measurement by enzyme-linked immunosorbent assay. Results: There was a significant increase in uNGAL levels in SRNS when compared with SSNS or controls. There was no significant difference in uNGAL levels between Group 1 and Group 3. ROC curve of uNGAL to predict SRNS had cutoff value >315 at the area under the curve 0.9, sensitivity 86.7%, and specificity 93.3%. There was a significant positive correlation between urinary NGAL level and age of patients and disease duration and serum creatinine level. Conclusions: Urinary NGAL can predict SRNS in INS in children.
Keywords: Idiopathic nephrotic syndrome, neutrophil gelatinase-associated lipocalin, steroid resistance
|How to cite this article:|
Elaziz El-Gamasy MA, Abdelhafez MA, Barr MM, Mehrez MM, Nassar MA, Eldeeb MM, Abdelmageed M. Urinary neutrophil gelatinase-associated lipocalin as prognostic biomarker for idiopathic nephrotic syndrome in Egyptian children. J Integr Nephrol Androl 2017;4:121-9
|How to cite this URL:|
Elaziz El-Gamasy MA, Abdelhafez MA, Barr MM, Mehrez MM, Nassar MA, Eldeeb MM, Abdelmageed M. Urinary neutrophil gelatinase-associated lipocalin as prognostic biomarker for idiopathic nephrotic syndrome in Egyptian children. J Integr Nephrol Androl [serial online] 2017 [cited 2018 Jun 17];4:121-9. Available from: http://www.journal-ina.com/text.asp?2017/4/4/121/222062
| Introduction|| |
Steroid resistance in idiopathic nephrotic syndrome (INS) is strongly associated with poor outcome, including progression to end-stage renal disease (ESRD). The urine has yielded promising markers for the early detection of AKI  even on top of CKD They include Cystatin C, microalbuminuria, N-acetyl-β-D glucosaminidase, interleukin-18, Fetuin, retinol-binding protein, clusterin, cysteine-rich protein  and urinary neutrophil gelatinase-associated lipocalin (uNGAL). The latter is a marker for both early diagnosis and prognosis of AKI  where uNGAL correlates with the degrees of AKI and significantly increases in patients with progressive but not stable kidney failure., uNGAL was significantly increased in kidney transplant patients with tubular pathologies. Furthermore, uNGAL as a predictive biomarker of nephrotoxicity was confirmed in patients with contrast-induced nephrotoxicity  and cisplatin nephropathy. uNGAL levels were significantly elevated in children with decreased glomerular filtration rate (GFR).
The aim of the present work was to determine urinary NGAL levels in children with INS as a prognostic factor as it can predict steroid resistance early in the course of INS.
| Subjects and Methods|| |
Design of the study and setting
The present study was carried out after approval from research ethical committee centers of Tanta University Hospital and obtaining informed oral or written consent from parents of included children. It was conducted on 90 patients with idiopathic nephrotic syndrome (INS) admitted in Pediatric nephrology unit of Tanta University Hospital and 30 healthy children of the same age and sex served as control group. Their ages at the time of taking samples ranged from 1.5 years to 10 years. The subjects were subdivided into 3 groups, Group 1 which included 45 patients with steroid sensitive nephrotic syndrome (SSNS) (39 males and 6 females), Group 2 which included 45 patients with steroid resistant nephrotic syndrome (SRNS) (36 males and 9 females), and Group 3 which included 30 control subjects (24 males and 6 females).
All children admitted to Tanta university hospital with INS from June 2016 to June 2017 were included in the study.
Nephrotic syndrome presented before the age of 1 year, known cases of the secondary nephrotic syndrome, nephrotic syndrome which is associated with urinary tract infection (UTI), nephrotic syndrome in remission and patients with delayed diagnosis (More than 1 week of the onset of edema).
INS was diagnosed according to kidney disease improving global outcome guidelines by the presence of nephrotic range proteinuria (>40 mg/m 2 per hour), generalized edema, hyperlipidemia and hypoalbuminemia (<2.5 g/d). SSNS was diagnosed if the patients respond to the daily steroid full dose therapy (60 mg/m 2 per day) within 6 weeks of therapy. A complete remission was defined by a marked reduction in proteinuria (<4 mg/m 2 per hour or urinary albumin dipstick is trace for 3 consecutive days) in association with a resolution of edema. Steroid-dependent nephrotic syndrome (SDNS) was defined as an initial remission followed by two or more relapses during the steroid reduction period or within 15 days after tapering of prednisone therapy. A relapse was defined by the recurrence of severe proteinuria (>40 mg/m 2 per hour or urinary albumin dipstick >3+ on 3 successive days), often with a recurrence of edema. SRNS was considered after 6 weeks of daily full dose steroid therapy plus three methyl prednisone pulse therapy without improvement of proteinuria.
Protocol of treatment
All patients were initially at first episode of INS and were treated with prednisone (60 mg/m 2 per day) for a full duration of 30 days. While relapses were treated by oral prednisone at 60 mg/m 2 per day until remission plus 5 additional days, then the prednisone dose was tapered to 40 mg/m 2 every other day (EOD) for 4 weeks, followed by a reduction of 15 mg/m 2 EOD/week to the lowest dose necessary to maintain remission and ultimately discontinuation of treatment if appropriate.
Steroid-sparing agents were introduced if the patient presented frequent relapses (>2 relapses per year), if the steroid dosage to maintain remission was ≥20 mg/m 2 EOD, if steroid-related side effects were unacceptable in terms of growth retardation or obesity despite adequate diet or if SRNS was diagnosed. Cyclosporine A in dose of 4–6 mg/kg per day was used to treat high dose SDNS and its dose was adjusted to maintain a trough serum level of cyclosporine A between 100–150 ng/mL in the first 3 months of therapy and 50–100 ng/mL later on as long as the patient was in remission. Cyclophosphamide in a dose of 2 mg/m 2 per hour for 3 months can be used as an alternative [Figure 1].
|Figure 1: Flow chart of treatment of idiopathic nephrotic syndrome. INS: Idiopathic nephrotic syndrome, NS: Nephrotic syndrome|
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All patients and controls were subjected to the following
About age at onset of nephrotic syndrome, gender, presence of atopic disease (asthma, allergic rhinitis, allergic conjunctivitis and/or urticaria either in the patient or in one of his family members), duration of the disease, response to steroid therapy in the 1st presentation, frequency of relapses, immunosuppressive drugs used during course of therapy, steroid-related adverse effects (as obesity, hypertension, bone ache, or short stature), and adverse effects of other immunosuppressive drugs.
For blood pressure, weight, examination for edema, percussion for ascites, organomegaly, percussion for pleural effusion or chest infection, and percussion for pericardial effusion.
Laboratory investigations which included 24 h urinary collection for urinary volume and protein estimation, complete blood count (CBC), serum cholesterol, serum albumin, blood urea, serum creatinine, and urinary NGAL measurement by enzyme-linked immunosorbent assay (ELISA) kit.
Sampling for laboratory investigations
A volume of 6 ml venous blood sample was withdrawn from patients and controls, 2 mL blood sample was used for CBC estimation through using ethylenediaminetetraacetic acid vacationer tubes and the remainder of blood was put into plain tube for centrifugation and separation of serum which used for estimation of serum cholesterol, urea, creatinine, and albumin levels.
- Sampling of urine - The urine samples were collected from patients in the early morning during the 1st week of the attack of INS and also collected from controls. urine samples were collected by one of two techniques, clean catch mid-stream method or urinary catheterization method using 8 French polyethylene feeding tube
- Storage of urine - The urine samples were put into sterile containers then centrifuged for 20 min. The supernatants of urine samples were collected into clean tubes, aliquoted and frozen at −20°C till the time of urinary NGAL assay. Samples were thawed and mixed thoroughly just before the assay to avoid erroneous results of repeated freeze/thaw cycles. uNGAL measured by ELISA was performed using a commercially available assay (NGAL ELISA Kit 036; Bioporto, Grusbakken, Denmark) that specifically detects human NGAL.
Other 24 h urine collection samples were kept in sterile containers at refrigerator at degree from 2°C to 8°C and then, the samples were re-warmed to room temperature just before urinary assessment and urine protein/24 h collection.
Data were collected and analyzed using statistical package for social science (SPSS) version 16 for windows (SPSS, Inc., Chicago, IL, USA). All data were expressed as in terms of mean values ± SD Comparisons of parameters among groups were made using student t test, Chi-square, Mann-Whitney U-test, linear correlation coefficient (r), receiver operating characteristic (ROC) curve analysis and analysis of variance (ANOVA) tests. All statistical tests were two-tailed and P < 0.05 was considered to be statistically significant. Sensitivity is the probability that the test results will be positive when the disease is present (true positive rate, expressed as a percentage). Specificity is probability that the test results will be negative when the disease is present (true negative rate, expressed as a percentage). Positive predictive value (PPV) is probability that the disease is present when the test is positive. Negative predictive value (NPV) is probability that the disease is present when the test is negative. Accuracy is the ratio of the true positive and true negative on all patients.
| Results|| |
[Table 1] summarized demographic and clinical data of the studied patients and controls. There was no significant difference between the studied groups regarding age, sex distribution, positive family history of atopy or the frequency of side effect of corticosteroids therapy. There was a significant increase in the weight, systolic blood pressure, disease duration and number of relapses in SRNS as compared to SSNS (P < 0.05). Regarding steroid-sparing drugs received by patients, cyclosporine A was received by 39 steroid-resistant patients with a percentage of 86.7%, but not received by any steroid-sensitive patients. No subject in our study has received either cyclophosphamide or mycofenolate mofetil. Angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor 2 blockers (ARBs) was received not only by 21 (46.7%) of SRNS patients but also received by any of SSNS patients. [Table 2] summarized laboratory data of the studied patients and controls.
[Table 3] compared between the studied groups as regard uNGAL levels, there was a highly significant increase in uNGAL levels in Group 2 when compared to Group 1 and Group 3 (P < 0.01). There was no significant difference in uNGAL levels between Group 1 and Group 3 (P > 0.05).
|Table 3: Urinary neutrophil gelatinase-associated lipocalin levels in patients and controls|
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Regarding estimated glomerular filteration rate (eGFR) in our study, there was no statistically significant difference between SSNS, SRSN patients or controls as regard eGFR (mean values were 150, 146, and 156 mL/m 2 per minute in SSNS, SRSN patients and control groups, respectively).
[Table 4] and [Figure 2] and [Figure 3] show ROC curve of uNGAL to predict SRNS with cutoff value >315 ng/mL, sensitivity 86.7%, specificity 93.3%, PPV 92.9%, NPV 87.5%, accuracy of 92.4%, and area under the curve 0.9.
|Table 4: Receiver operating characteristic curve of predictor factors of steroid dependence or resistant nephrotic syndrome|
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|Figure 2: Receiver operating characteristic curve of urinary neutrophil gelatinase-associated lipocalin of studied patients. Sens: Sensitivity, Spec: Specificity|
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|Figure 3: Area under curve, specificity and sensitivity of urinary neutrophil gelatinase-associated lipocalin of studied patients|
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[Table 5] summarized correlations of uNGAL levels with clinical and laboratory data of the studied patients: There was a significant positive correlations between urinary NGAL level and age of patients and disease duration in SRNS (P < 0.05) [Figure 4]. There was also highly significant positive correlation between urinary NGAL level and serum creatinine level (P < 0.01) [Figure 5].
|Table 5: Correlations between u neutrophil gelatinase associated lipocalin and studied items|
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|Figure 4: Correlation between urinary neutrophil gelatinase-associated lipocalin and disease duration. *Statistically significant|
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|Figure 5: Correlation between urinary neutrophil gelatinase-associated lipocalin and serum creatinine in patient group. *Statistically significant|
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| Discussion|| |
Steroid resistant or steroid dependent NS are strongly associated with poor outcomes including side effects of immunosuppressant drugs and progression to ESRD. No diagnostic markers exist to distinguish SSNS from SRNS. However, pathological diagnosis can help in predicting steroid resistance as approximately 70% of cases of FSGS are significantly associated with poor outcome.
Children, however, are not generally biopsied at presentation unless they have atypical features, because response to steroids is a better predictor than histology in long-term prognosis.
A single renal biopsy in children tends to underdiagnose FSGS, because of the focal nature of the disease.
The initial prolonged daily course of high dose steroid therapy serves both a therapeutic and diagnostic purposes.
Identification of markers that predict steroid responsiveness would benefit patients with INS with better design of therapeutic strategy for the individual. NGAL has been demonstrated to be a powerful independent risk marker for progression in CKD.
In this study, we aimed to determine if urinary NGAL measurements could be used to distinguish SRNS from SSNS. The study results show that urinary NGAL is markedly increased in patients with SRNS when compared to SSNS and controls.
In the present study, uNGAL levels were statistically and significantly increased in patients with SRNS when compared to both SSNS and control groups (P < 0.05). No statistically significant difference between SSNS and control groups (P > 0.05). As regard to the concomitant evolution of the major end-points values of other urinary indicators for SRNS, there was no statistically significant difference between SSNS, SRSN patients or controls as regard urinary protein per 24 h collected urine analysis. Regarding eGFR in our study, there was no statistically significant difference between SSNS, SRSN patients or controls as regard eGFR (mean values were 150, 146, and 156 mL/m 2 per minute in SSNS, SRSN patients and control groups, respectively).
Urinary NGAL levels showed a strong predictor of steroid resistance in INS at cutoff value >315 ng/mL with sensitivity 86.7% and specificity 93.3%. These results are consistent with our hypothesis that nephrotic patients who are steroid resistant have a high risk of progression, while patients with SSNS are typically not progressive and higher levels of urinary NGAL were found in patients with progressive CKD.
In the present study, there was a significant relationship between increasing urinary NGAL levels and severity of disease as measured by serum ceratinine (P = 0.004). This is consistent with other studies showing that urine NGAL levels are inversely associated with renal function as evidenced by eGFR in CKD.
The role of cyclosporine A in elevation of urinary NGAL in SRNS is controversial. Cyclosporine A nephrotoxicity can increase urinary NGAL levels due to the progressive glomerular vasoconstriction and tubular atrophy.
In the present study, we followed the serum trough levels of cyclosporine A every 3 months. Our protocol was to control serum levels >100 ng/mL in the first 3 months of treatment and we accepted levels <100 ng/mL as long as patient was controlled in remission. These low doses of cyclosporine A would make the possibility of calcineurin inhibitor (CNI) associated increase in NGAL is less likely. However, a special study design will be needed to determine the role of CNI in elevated NGAL levels in SDNS and SRNS.
Kuwabara et al. found elevated uNGAL in five cases of NS at presentation, which decreased after the treatment.
Bolignano et al. found a positive correlation between uNGAL and serum creatinine levels in proteinuric patients with idiopathic glomerulonephritis.
Most studies that have investigated the correlations of NGAL and other parameters of kidney function have found correlations between uNGAL and serum creatinine level, eGFR, and proteinuria. We also confirmed the positive correlation between NGAL and serum creatinine levels which is in agreement with results reported by other authors, for example., Bolignano et al. and Malyszko et al.,
Our goal was to use this pilot data to highlight the importance for a multi-center prospective study where we can capture a large number of INS patients and obtain NGAL levels at baseline before treatments are administered and follow the progress of the disease and NGAL levels longitudinally. We could use this study model to determine whether higher initial NGAL levels predict worsening renal function as was found by Bolignano et al. in the other forms of CKD.
An additional benefit of tracking NGAL levels of these patients over time would be to determine if NGAL could be used to detect early response to therapy. Biomarkers that can be used as surrogate endpoints are valuable in clinical trials and can allow for more rapid drug development. Data gleaned from a longitudinal study would also allow us to determine if urine NGAL levels could be utilized to predict therapeutic response. While the presence of a urine biomarker is not likely to take the ultimate place of a biopsy for definitive diagnosis in conjunction with other clinical findings it can offer the physician valuable information to more effectively plan personalized treatment strategies in the care of patients with NS.
ACEIs and ARBs did not bias the interpretation of data as regard serum creatinine, proteinuria, e GFR and uNGAL as ACEIs, for example, captopril or enalopril in dose of 0.25–0.5 mg/kg per day were reported to dramatically decrease nephrotic range proteinuria by 50% from baseline caused by renovascular hypertension and secondary FSGS and lead even to complete remission in patients with SRNS. They are a renoprotective agent by reducing GFR, but further studies on wider sale are needed to confirm these observations. ACEIs can also decrease serum lipid levels. ARBs, for example, losartan in dose of 0.75–1 mg/kg per day has similar action like ACEIs.
Our study is not without limitations. First, this was a single center, cross-sectional pilot study with a small group of patients who had already begun treatment at enrollment. This limits the conclusions we can draw about the value of urine NGAL to predict steroid responsiveness in NS patients. Second, there is a great degree of variability in both the ages of the patient groups and the NGAL data obtained from the SRNS group. Since the data were not normally distributed, we used nonparametric statistics to analyze our data. This variability is inherent when studying steroid responsiveness in INS and can be magnified in a small patient population.
| Conclusions|| |
Urinary NGAL can be used as a useful diagnostic biomarker to predict steroid responsiveness or resistance in children with INS (uNGAL is a differentiating marker between SSNS and SRNS) at cutoff value >315 ng/mL with sensitivity 86.7% and specificity 93.3%.
There are diagnostic and prognostic values for urinary NGAL levels as it can predict of steroid responsiveness or resistance in INS in children.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]