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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2019  |  Volume : 30  |  Issue : 4  |  Page : 769-774
High Serum Endothelin-1 Level is Associated with Poor Response to Steroid Therapy in Childhood-Onset Nephrotic Syndrome


1 Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt

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Date of Submission27-Apr-2018
Date of Decision25-Jul-2018
Date of Acceptance26-Jul-2018
Date of Web Publication27-Aug-2019
 

   Abstract 


Nephrotic syndrome (NS) is one of the most common kidney diseases seen in children. It is a disorder characterized by severe proteinuria, hypoproteinemia, hyperlipidemia, and generalized edema resulting from alterations of permeability at the glomerular capillary wall. Endothelin-1 (ET1) has a central role in the pathogenesis of proteinuria and glomerulosclerosis and has a role in assessment of the clinical course of NS in children. This study aims to investigate the relationship between ET1 serum level and the response to steroid therapy in children with primary NS. Serum ET1 levels were evaluated in 55 children with NS. They were classified into two groups: 30 patients with steroid-sensitive NS (SSNS) and 25 patients with steroid-resistant NS (SRNS). The SSNS group was further divided into infrequent-relapsing NS (IFRNS) and steroid-dependent NS (SDNS), while the SRNS group was subdivided into two groups according to renal pathology. ET1 levels were significantly higher in the SRNS group (52.5 ± 45.8 pg/dL) compared to the SSNS group (18.3 ± 17 pg/dL) (P <0.001). Furthermore, ET1 levels were significantly higher in SDNS (54.3 ± 18.6) compared to IFRNS (11.9 ± 7.8, P = 0.001). There was no statistically significant difference in ET1 levels between minimal change disease group and focal segmental glomerulosclerosis group, (P = 0.28). Serum ET1 can be considered as a predictor for response to steroid therapy.

How to cite this article:
Ahmed HM, Morgan DS, Doudar NA, Naguib MS. High Serum Endothelin-1 Level is Associated with Poor Response to Steroid Therapy in Childhood-Onset Nephrotic Syndrome. Saudi J Kidney Dis Transpl 2019;30:769-74

How to cite this URL:
Ahmed HM, Morgan DS, Doudar NA, Naguib MS. High Serum Endothelin-1 Level is Associated with Poor Response to Steroid Therapy in Childhood-Onset Nephrotic Syndrome. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Dec 9];30:769-74. Available from: http://www.sjkdt.org/text.asp?2019/30/4/769/265451



   Introduction Top


Nephrotic syndrome (NS) is the most common primary kidney disease in children and characterized clinically by heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia.[1] Most of the patients with NS show a good response to steroid therapy and have a good prognosis. Unfortunately, approximately 10% of children and 40% of adults have steroid-resistant NS (SRNS) and a poor prognosis.[2]

Minimal change NS (MCNS) and focal segmental glomerulosclerosis (FSGS) are the most common causes of idiopathic NS in children.[3] The majority of children with minimal change disease (MCD) who present with NS respond to corticosteroid therapy, but a few have steroid-dependent NS (SDNS) or steroid-resistant NS (SRNS), while the majority of patients with FSGS are steroid resistant with a high possibility to progress to end-stage renal disease.[4] Alterations in the glomerular basement membrane and related cells (for example, podocytes) are supposed to be the cause of development of proteinuria in patients with NS.[5] Podocyte dysfunction has a key role in the development of proteinuria and glome-rulosclerosis.[6] In glomeruli, endothelin-1 (ET1) was found in the endothelium of capillary loops, and even though other glomerular cells were also shown to produce ET1, endothelial cells emerged as the principal site of ET1 secretion in normal human glomeruli. ET1 is a potent vasoconstrictor that modulates vasomotor tone.[7] Endothelins reduce renal blood flow and glomerular filtration rate (GFR) because of the induced vasoconstriction of both afferent and efferent renal arterioles.[8] Podocytes contain endothelin binding sites and express a fully functional endothelin system, including endothelin receptors, preproendo-thelin-1, and endothelin-converting enzyme- 1.[9] The actin cytoskeleton is crucial for podocyte function and structural integrity.[10] Endothelin production promotes podocyte actin cytoskeleton disruption and increases permeability to albumin.[11] Several endothelin-dependent mechanisms contribute to protei-nuria and glomerular injury, many of which involve activation of fibrogenic pathways in mesangial cells.[12] For example, endothelin stimulates collagen production[13] and glomerular fibronectin synthesis.[14] In addition, endo-thelin activates the formation of reactive oxygen species (ROS) and induces inflammation.[15]


   Subjects and Methods Top


This study was conducted between February 2015 and January 2017 and included 55 patients with childhood-onset NS. Thirty of them (13 males and 17 females) had steroid-sensitive NS (SSNS) and 25 were with steroid-resistant NS (SRNS) (11 males and 14 females). Twenty age- and sex-matched healthy children (9 males and 11 females) were included as a control group. All patients with SRNS underwent renal biopsy (9 with MCD, 12 – FSGS, and 4 – mesangial proliferative glomerulonephritis). At the time of blood sampling, all patients were in remission stage to eliminate the effect of disease activity. Patients with SRNS were on immunosup-pressive therapy (20 on cyclosporine and five on mycophenolate mofetil).The SSNS group was divided into two groups: Group 1 (20 patients) had infrequent-relapsing NS (IFRNS) and Group 2 (10 patients) had SDNS. The SRNS group was further divided to two groups according to renal pathology: Group 1 (9 patients with MCD) and Group 2 (12 patients with FSGS) to assess the relation between renal pathology and serum ET1 level. Patients younger than one year or older than 18 years at time of presentation of first attack, patients with secondary NS, or those with reduced GFR were excluded from the study. For all children included in the study, a written consent was obtained from parents. Full history was taken laying stress on, age of onset of the disease, medical treatment, and number of relapses. Complete clinical examination was done including body weight, height, body mass index (BMI), blood pressure, and edema. Laboratory investigations including serum urea, creatinine, Na, K, albumin, cholesterol, urinary protein/creatinine ratio, and serum ET1 level were done for all children.

Sample collection

Venous blood sample of 4 mL was withdrawn from each child and allowed to clot for 2 h at room temperature before centrifugation for 15 min at 1000 centrifugal force (×g). Serum was separated, and samples were divided: one part sent for chemical analysis and the 2nd part was stored at -80°C till the end of the study for measurement of serum ET-1 levels by quantitative sandwich enzyme immunoassay technique using Endothelin-1 (ET-1) ELISA Kit, Thermo Fisher Scientific, USA.


   Statistical Analysis Top


Statistical analysis was done using Statistical Package for the Social Sciences version 22.0 (IBM Corp., Armonk, NY, USA). Data were described in the form of mean ± standard deviation for quantitative data and frequency and proportions for qualitative data. P <0.05 was considered statistically significant. Differences were analyzed between the groups by Student’s t-test as regards normally distributed data; otherwise, Mann–Whitney U-test was used. Correlations were analyzed by Spearman’s correlation coefficient test. The receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff value for ET-1 level distinguishing between the cases with SSNS and SRNS.


   Results Top


Patient data showed that there were no statistically significant differences in age, gender, and height between the three groups; however, weight and BMI were significantly higher in the SSNS and SRNS groups than controls. Although there was no significant difference between the three groups as regarding systolic and diastolic blood pressures, six patients in the SRNS group (24%) needed antihypertensive therapy. There was no significant difference between the three groups as regarding blood urea, creatinine, Na, and K serum levels. Serum cholesterol and urinary protein/crea- tinine levels were significantly higher in both the patient groups than controls (P <0.001 and <0.001) and were higher in the SRNS group than the SSNS group (P = 0.005 and <0.001). Furthermore, serum albumin levels were significantly lower in the SRNS group as compared to both the SSNS and control groups. Serum ET-1 levels were significantly higher in both the SSNS and SRNS groups as compared to controls, and it was significantly higher in the SRNS group than the SSNS group [Table 1]. When comparing patients with MCNS and patients with FSGS as regarding serum ET1 levels, it was statistically insignificant [Table 2]. Meanwhile, it was significantly higher in the SDNS group as compared to the IFRNS group [Table 3]. Serum ET1 had a significant positive correlation coefficient for urinary protein/urinary creatinine (UP/UC) and cholesterol. On the other hand, it had a significant negative correlation coefficient for serum albumin levels [Table 4]. ROC curves were used to define the possible value of serum ET1 level above which a poor response to steroid therapy could be expected. The area under the ROC curve of serum ET1 levels was 0.88 (95% confidence interval, 0.75–0.95). The analysis rendered an optimal cutoff value of 24.6 pg/mL corresponding to 90.5% sensitivity and 84% specificity [Figure 1].
Table 1: Clinical and laboratory data of the three study groups.

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Table 2: Comparison of serum endothelin-1 between minimal change disease and focal segmental glomerulosclerosis groups.

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Table 3: Comparison of serum endothelin-1 between infrequent-relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome groups.

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Table 4: Correlations between serum endothelin-1 levels and laboratory data.

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Figure 1: ROC curve for serum endothelin-1 levels.
ROC: Receiver operating characteristic.


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   Discussion Top


NS is the most common kidney disease in childhood. In the current study, we examined the effect of serum ET 1 levels on the response to corticosteroid treatment in children with NS. Our results showed that higher ET1 levels are associated with poor response to steroid therapy. In general, serum ET1 levels were higher in patients with NS than in controls as reported in other studies.[5],[16] We also found that serum ET1 levels were significantly higher in patients with SRNS than in patients with SSNS. On the other hand, patients with SSNS who were frequent relapsing or SDNS showed significantly higher ET1 levels than those who were nonfrequent relapsing. These findings strongly support the association between serum ET1 levels and poor response to steroid therapy. In addition, we found no differences in ET1 levels between patients with MCD and FSGS, indicating that this poor response is mainly related to ET1 levels and not to the underlying pathology. However, a study done by Chen et al[17] had reported that FSGS is associated with higher ET1 levels but in comparison with normal controls not with patients suffering from MCD. In this study, results showed that, using a cutoff value of 24.6 pg/mL, serum ET1 level can be used to predict the response to steroid therapy with an AUC of 0.88 and an optimized sensitivity of 90.5% and specificity of 84%. In our study, the significant positive correlations between ET1 and proteinuria support the hypothesis that upregulation of the renal ET system exacerbates proteinuria. Through its hemodynamic effects, ET-1 increases the glomerular capillary pressure and increases the glomerular permeability resulting in excessive protein filtration.[18] The development of proteinuria is also contributed to the damage of renal podocyte, a highly specialized glomerular epithelial cell that maintains an intact filtration barrier under normal conditions.[19] In addition, endothelin activates other pathways that are involved the pathophysiology of renal diseases, such as the formation of ROS and inflammation that has a fundamental role in the development of glomerulosclerosis and can be inhibited by ETA receptor antagonists.[9] The observation that all patients with SRNS were on immuno-suppressive therapy mostly cyclosporine confirms the findings reported by Kim et al that cyclosporine has no effect on ET1 levels in patients with SDNS.[20] All these findings support the emerging role of ET1 as an indicator of steroid therapy response in primary childhood-onset nephrotic syndrome.

In conclusion, our study demonstrated that serum ET1 levels were significantly higher in patients with SRNS than in patients with SSNS or in healthy controls. A cutoff value of 12.6 pg/mL corresponding to 90.5% sensitivity and 84 % specificity with AUC = 0.88 signifies that serum ET1 can be considered as a reliable indicator for the response to steroid therapy in childhood-onset primary nephrotic syndrome.

Conflict of interest: None declared.



 
   References Top

1.
Jaffer A, Unnisa W, Raju DS, Jahan P. NPHS2 mutation analysis and primary nephrotic syndrome in Southern Indians. Nephrology (Carlton) 2014;19:398-403.  Back to cited text no. 1
    
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Mekahli D, Liutkus A, Ranchin B, et al. Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: A multicenter study. Pediatr Nephrol 2009;24:1525-32.  Back to cited text no. 2
    
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Ranganathan S. Pathology of podocytopathies causing nephrotic syndrome in children. Front Pediatr 2016;4:32.  Back to cited text no. 3
    
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The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the international study of kidney disease in children. J Pediatr 1981;98:561-4.  Back to cited text no. 4
    
5.
Yang F, Lai X, Deng L, et al. Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children. Life Sci 2014;118:446-50.  Back to cited text no. 5
    
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Shankland SJ. The podocyte’s response to injury: Role in proteinuria and glomerulo-sclerosis. Kidney Int 2006;69:2131-47.  Back to cited text no. 6
    
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Rankinen T, Church T, Rice T, et al. Effect of endothelin 1 genotype on blood pressure is dependent on physical activity or fitness levels. Hypertension 2007;50:1120-5.  Back to cited text no. 7
    
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Lüscher TF, Wenzel RR. Endothelin in renal disease: Role of endothelin antagonists. Nephrol Dial Transplant 1995;10:162-5.  Back to cited text no. 8
    
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Barton M. Reversal of proteinuric renal disease and the emerging role of endothelin. Nat Clin Pract Nephrol 2008;4:490-501.  Back to cited text no. 9
    
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Kalluri R. Proteinuria with and without renal glomerular podocyte effacement. J Am Soc Nephrol 2006;17:2383-9.  Back to cited text no. 10
    
11.
Morigi M, Buelli S, Zanchi C, et al. Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol 2006;169:1965-75.  Back to cited text no. 11
    
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Benigni A, Remuzzi G. How renal cytokines and growth factors contribute to renal disease progression. Am J Kidney Dis 2001;37:S21-4.  Back to cited text no. 12
    
13.
Gutierrez S, Palacios I, Egido J, et al. Endothelin-1 induces loss of proteoglycans and enhances fibronectin and collagen production in cultured rabbit synovial cells. Eur J Pharmacol 1996;302:191-7.  Back to cited text no. 13
    
14.
Chang JM, Chiu YW, Tsai JC, Chen HC. Effects of endothelin-1 on thymidine uptake and fibronectin production of diabetic glomeruli. Nephrology (Carlton) 2007;12:62-6.  Back to cited text no. 14
    
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Lattmann T, Hein M, Horber S, et al. Activation of pro-inflammatory and anti-inflammatory cytokines in host organs during chronic allograft rejection: Role of endothelin receptor signaling. Am J Transplant 2005;5: 1042-9.  Back to cited text no. 15
    
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Arumugam V, Saha A, Kaur M, et al. Endothelin 1 and endothelial dysfunction in children with idiopathic nephrotic syndrome. Artery Res 2017;18:36-40.  Back to cited text no. 16
    
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Chen HC, Guh JY, Chang JM, Tsai JC, Hwang SJ, Lai YH. Plasma and urinary endothelin-1 in focal segmental glomerulosclerosis. J Clin Lab Anal 2001;15:59-63.  Back to cited text no. 17
    
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Benigni A. Defining the role of endothelins in renal pathophysiology on the basis of selective and unselective endothelin receptor antagonist studies. Curr Opin Nephrol Hypertens 1995;4: 349-53.  Back to cited text no. 18
    
19.
Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: Is the podocyte the culprit? Kidney Int 1998;54:687-97.  Back to cited text no. 19
    
20.
Kim JW, Kim JH, Lee JS, Kim PK, Kim HS. Effect of cyclosporine a on plasma and urine levels of endothelin-1 in steroid dependent minimal change nephrotic syndrome. Child hood Kidney Dis 1998;2:20-5.  Back to cited text no. 20
    

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Correspondence Address:
Heba Mostafa Ahmed
Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni Suef
Egypt
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DOI: 10.4103/1319-2442.265451

PMID: 31464232

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