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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 2  |  Page : 290-296
Evaluation of serum soluble urokinase plasminogen activator receptor as a marker for steroid-responsiveness in children with primary nephrotic syndrome


1 Department of Pediatrics, Faculty of Medicine, Minia University, El-Minya, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Minia University, El-Minya, Egypt

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Date of Web Publication10-Apr-2018
 

   Abstract 

Nephrotic syndrome (NS) is the most common primary glomerular disease among children. It runs a relapsing course involving prolonged periods of treatment with corticosteroids and other immunosuppressive medications. Soluble urokinase plasminogen activator receptor (suPAR) has been regarded as an inflammatory as well as a permeability factor. The aim of our study was to evaluate serum suPAR levels in children with NS and its relation to steroid responsiveness. Our study was carried out on 75 children who were already diagnosed as having NS; they were classified into three groups (steroid sensitive, steroid dependent, and steroid resistant). Furthermore, 40 apparently healthy children, age and sex matched with the NS patients, were enrolled as controls. All children had undergone assessment of serum suPAR, renal function tests (urea and creatinine), serum albumin, C-reactive protein, and 24-h protein in urine. The study found that suPAR level was significantly different between the studied groups (P <0.05), being highest in steroid-resistant NS (66.52 ± 9.7 ng/mL), followed by steroid dependent (56.82 ± 11.09 ng/mL), and steroid-sensitive patients (26.22 ± 3.86 ng/mL), and lowest in the control group (20.29 ± 0.69 ng/mL). When receiver operating characteristics curves were plotted, suPAR had high sensitivities and specificities in predicting steroid responsiveness, [area under the curve (AUC) = 0.99, 95% confidence interval (CI) = 0.911–1.000, P <0.001], steroid dependence (AUC = 1.00, 95% CI = 0.929–1.000, P <0.001), and predicting steroid resistance. Our study indicates that suPAR is significantly higher in children with primary NS and varies according to their response to steroid therapy. It may act as a marker for steroid responsiveness in these children.

How to cite this article:
Mousa SO, Saleh SM, Aly HM, Amin MH. Evaluation of serum soluble urokinase plasminogen activator receptor as a marker for steroid-responsiveness in children with primary nephrotic syndrome. Saudi J Kidney Dis Transpl 2018;29:290-6

How to cite this URL:
Mousa SO, Saleh SM, Aly HM, Amin MH. Evaluation of serum soluble urokinase plasminogen activator receptor as a marker for steroid-responsiveness in children with primary nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2022 Jan 17];29:290-6. Available from: https://www.sjkdt.org/text.asp?2018/29/2/290/229266

   Introduction Top


Nephrotic syndrome (NS) is characterized by inflammation of the glomeruli, which causes blood cells and protein to escape from the glomerular capillaries into the urine; this leakage can be caused by damage to the glomeruli by inflammatory or noninflammatory processes.[1] A minority of children with the condition have only a single episode (20%–33%), with the remaining having, in order of increasing severity, infrequent relapses, frequent relapses, steroid dependence, or steroid resistance.[2]

Serum soluble urokinase plasminogen activator receptor (suPAR) is a glycoprotein secreted during infections and inflammation,[3] and has been found to work as a permeability factor on the glomerular filtration barrier.[4] suPAR is expressed in various cell types such as macrophages, monocytes, endothelial cells, neutrophils, certain cancer cells, and kidney podocytes.[5] Urokinase-type plasminogen activator (uPA) is secreted by polymorphonuclear neutrophils and macrophages where it binds to membrane urokinase-type plasminogen activator receptor (uPAR). suPAR is formed by getting cleaved from the uPAR.[3] In contrast to most other markers, circadian changes in plasma levels of suPAR are minimal.[6] Numerous studies have shown systemic levels of suPAR to be increased with various infectious and inflammatory diseases as in tuberculosis,[7] liver fibrosis,[8] inflammatory bowel disease,[9] focal and segmental glomerulosclerosis (FSGS), cardiovascular diseases, type 2 diabetes,[10] and ventilator-associated pneumonia with sepsis.[11]

The aim of our study was to answer the following questions: does suPAR level differ in children with primary NS? Is there a relation between suPAR level in the nephrotic children and their response to steroid therapy, regardless of the histopathological origin of the NS?


   Subjects and Methods Top


Subjects

This case–control study included 75 children who were already diagnosed as having NS and had regular follow-up visits at the nephrology outpatient clinic or were admitted to the nephrology unit at University Children's Hospital. The study was performed from July 2015 to January 2016.

The study complied with the Declaration of Helsinki principles. It was explained in detail to the parents, or legal guardians of the participant children and written consents were taken from them. The protocol of the study was approved by the Institutional Research Committee of Faculty of Medicine, Minia University.

The children were divided into the following groups according to Kidney Disease Improving Global Outcomes glomerulonephritis work group:[12]

  • - Steroid-sensitive NS (SSNS) - This included children who achieved complete remission within initial four weeks of corticosteroid therapy; there were 25 children in this group in our study. Children in this group either presented for the first time or had previous relapses
  • - Steroid-dependent NS (SDNS) – included children who had two consecutive relapses during corticosteroid therapy, or within 14 days of cessation of therapy; our study had 25 children with SDNS
  • - Steroid-resistant NS (SRNS): included children who failed to achieve complete remission after eight weeks of corticosteroid therapy; our study had 25 children with SRNS.


We excluded all nephrotic children with underlying secondary causes such as hepatitis B or hepatitis C or human immunodeficiency virus, and children with low serum C3 and/or C4. Furthermore, children with NS associated with systemic lupus erythematosus, Henoch–Schönlein purpura, poststreptococcal glomerulonephritis, or lymphoma, were also excluded from the study.

Over the same period, 40 apparently healthy children, age and sex matched with the nephrotic children, were recruited during routine health maintenance visits to serve as the control group. The possibility of inflammation or infection in the control group was excluded by thorough history taking, clinical examination and, their C-reactive protein (CRP) levels were below 6 ng/mL.

All nephrotic cases with first presentation or relapse were treated with initial therapy, consisting of daily administration of oral prednisone, 2 mg/kg/day, maximum 60 mg/m2 body surface area for 4–8 weeks, followed by gradual tapering on alternate days. Steroiddependent patients were on the alternate day of oral prednisone. This was gradually tapered to the minimum effective dose for preventing relapse. For children with frequent relapses, steroid resistance or those with serious side effect of steroids, cyclophosphamide therapy was initiated in an eight-week course.

Method

All children included in our study had undergone the following investigations: renal function test, serum albumin, CRP, suPAR, and 24-h protein in urine.

Sample collection

Blood sample: about 7 mL of venous blood was withdrawn after overnight fasting under complete aseptic technique. Five milliliters was collected in a plain tube for assessment of renal function and serum albumin using fully automated clinical chemistry auto-analyzer system (Konelab 20i; Thermo Electron Incorporation, Finland). Another 2 mL was collected in a plain tube for serum separation. This tube was centrifuged at 2000 × g for 10 minutes. The expressed serum was diluted 1:2 by MIX Diluent and then stored at -20°C for measuring serum soluble urokinase plasminogen activator receptor, which was assayed by enzyme-linked immunosorbent assay (ELISA) (Glory Science Co., USA)[13] and CRP was measured by NycoCard Reader II (Axis- Shield PoC AS, Oslo, Norway). Urine sample: 24-h urine was collected in a clean container for assessment of 24-h protein.[14]


   Statistical Analysis Top


Data entry and analysis were all done with IBM compatible computer. The collected data were statistically analyzed using Statistical Package for Social Sciences (SPSS) version 19.0 for Windows (SPSS Inc., Chicago, IL, USA). Quantitative results were presented as mean ± standard deviation while qualitative data were presented by frequency distribution as percent (%). Results were expressed as tables and figures. Graphics were made by Excel Microsoft Office 2010. Student Newman–Keuls ANOVA was used for comparative analysis among the three groups, post hoc test for each two groups. The correlation was performed using Pearson correlation coefficient (r). Receiver operating characteristic (ROC) curve analysis was performed using MedCalc version 12.1.4.0 (MedCalc software, Belgium) to determine: the optimal cutoff values, the predictive ability of suPAR and its sensitivities and specificities for steroid responsiveness. The probability of error <0.05 was used as a cutoff point for all statistically significant tests.


   Results Top


There were 14 males and 11 females with SSNS; they had a mean age of 7.9 ± 4.2 years (4–12 years). There were 14 males and 11 females with SDNS with a mean age of 8.4 ± 2.2 years (5–13 years.). There were 13 males and 12 females with SRNS with a mean age of 9.8 ± 1.5 years (8–13 years.). The control group included 10 males and 10 females, with a mean age of 8.6 ± 1.6 years (6–12 years). [Table 1] shows the laboratory data of the studied groups. We found that the nephrotic children had significantly lower serum albumin and significantly higher 24-h protein in urine than the control group (P <0.05). CRP was significantly higher in the nephrotic children when compared to the control group (P <0.001). [Figure 1] shows suPAR level in the studied groups; suPAR was highest in the SRNS group (66.52 ± 9.7 ng/mL), followed by the SDNS group (56.82 ± 11.09 ng/L), the SSNS group (26.22 ± 3.86 ng/mL), and lowest in the control group (20.29 ± 0.69 ng/mL).
Table 1: Comparison between the studied groups regarding laboratory data.

Click here to view
Figure 1: Soluble urokinase plasminogen activator receptor levels in the studied groups.
In each group (n = 25) except control group (n = 40); P <0.001 by ANOVA; P <0.001 by post hoc between every two groups except p for steroid sensitive nephrotic syndrome vs. control = 0.01.


Click here to view


We observed a significant positive correlation between suPAR and proteinuria (r = 0.83, P = 0.001) and a significant negative correlation between suPAR and serum albumin (r = -0.75, P = 0.001). Furthermore, CRP had a significant positive correlation with suPAR (r =0.42, P =0.001).

The ROC curve was plotted to describe sensitivities and specificities of different cutoff points of suPAR levels among the studied children with steroid nonresponsive NS. Accordingly, as shown in [Table 2], the area under the curve (AUC) of suPAR performance in predicting steroid dependence was 0.99 with 95% confidence interval (CI) = 0.911–1.000 and P < 0.001. suPAR level of >32.4 ng/mL was the best cutoff point that gave a sensitivity of specificity of 96%. While the AUC of suPAR performance in predicting steroid resistance was 1.00 with 95% CI = 0.929–1.000 and P <0.001. suPAR level of >33.17 ng/mL was the best cutoff point that gave the sensitivity and specificity of 100%.
Table 2: Receiver operating characteristic curve plots of soluble urokinase plasminogen activator receptor among the studied children with steroid nonresponsive nephrotic syndrome.

Click here to view



   Discussion Top


Steroids are the cornerstone treatment in NS. Any marker that helps in prediction of steroid nonresponsiveness can save unnecessary time wasted on steroid trial with all its possible side effects. The objective of this study was to evaluate serum suPAR level in children with NS and its relation to steroid responsiveness. In this study, suPAR level was significantly higher in nephrotic children than the control group. Moreover, its level differed significantly between the nephrotic groups according to their response to steroid therapy. suPAR level was highest in SRNS group, followed by SDNS group, the SSNS group and lowest in the control group. These results were in agreement with a previous study that found a significant difference in plasma suPAR concentration between SRNS and SSNS with higher levels of suPAR in SRNS[15] and explained that higher the serum suPAR concentration, the more severe the podocyte injury, and hence, high suPAR level might be associated with steroid resistance.[15] Others found that soluble urokinase receptor might be the most likely causative circulating factor for primary FSGS, which is the most common cause of SRNS in the pediatric population.[16]

suPAR had a significant positive correlation with proteinuria and a significant negative correlation with serum albumin. Our results were in agreement with the results obtained by Maas et al[17] and Huang et al.[18] Urokinase receptor has been shown to play a direct role in regulating podocyte foot process structure and function, which plays a critical role in maintaining the selectively of glomerular permeability.[19] In NS, suPAR recognizes the podocyte actin cytoskeleton causing podocyte foot process effacement, which leads to proteinuria,[20] causing secondary hypoalbuminemia.[4] On the other hand, other studies did not find correlations between suPAR levels and proteinuria or serum albumin levels.[15],[21] They attributed this to either the presence of circulating factors other than suPAR[22] or the presence of a specific suPAR fragment that is not detected by ELISA, which can cause proteinuria.[23]

In our study, we found a significant positive correlation between suPAR and CRP. This was in agreement with the results described by Sinha et al in 2014[21] who reported that the levels of suPAR were directly and significantly correlated with CRP, suggesting that inflammation-induced synthesis might contribute to elevated levels of suPAR.[24]

On the other hand, Wei et al in 2012,[16] showed that CRP levels were low and did not correlate with serum suPAR levels. They explained that inflammation was not the major cause of the elevated suPAR levels in patients with NS and suPAR may work as a permeability factor rather than an inflammatory marker.[16]

Regarding the ability of suPAR to predict steroid responsiveness in the studied children with NS, ROC curves were plotted to describe sensitivities and specificities of different cutoff points of suPAR levels. suPAR showed high sensitivity and specificity in predicting steroid dependence (at a cutoff point of >32.4 ng/mL) and steroid resistance (at a cutoff point of >33.17 ng/mL). Previous studies reported that high levels of suPAR play a significant role in steroid resistance in primary NS patients. They hypothesized that the high serum suPAR concentration is associated with more severe podocyte injury leading to more resistance to steroid therapy.[15]


   Conclusion Top


In our study, suPAR level was significantly higher in nephrotic children than the control group. Moreover, its level differed significantly between the nephrotic groups according to their response to steroid therapy, regardless of the underlying histopathology. Furthermore, suPAR had significant correlations with proteinuria, serum albumin, and CRP. We suggest that suPAR levels act as a marker for steroid responsiveness in children with NS. Further cohort studies are needed to evaluate the clinical application of suPAR level for predicting steroid responsiveness.

Conflict of interest: None declared.

 
   References Top

1.
Nandi M, Mondal R. Nephrotic syndrome with atherosclerosis. Indian Pediatr 2011;48:907-8.  Back to cited text no. 1
[PUBMED]    
2.
Sureshkumar P, Hodson EM, Willis NS, Barzi F, Craig JC. Predictors of remission and relapse in idiopathic nephrotic syndrome: A prospective cohort study. Pediatr Nephrol 2014;29:1039-46.  Back to cited text no. 2
[PUBMED]    
3.
Backes Y, van der Sluijs KF, Tuip de Boer AM, et al. Soluble urokinase-type plasminogen activator receptor levels in patients with burn injuries and inhalation trauma requiring mechanical ventilation: An observational cohort study. Crit Care 2011;15:R270.  Back to cited text no. 3
[PUBMED]    
4.
Chang JW, Pardo V, Sageshima J, et al. Podocyte foot process effacement in postreperfusion allograft biopsies correlates with early recurrence of proteinuria in focal segmental glomerulosclerosis. Transplantation 2012;93:1238-44.  Back to cited text no. 4
[PUBMED]    
5.
Langkilde A, Hansen TW, Ladelund S, et al. Increased plasma soluble uPAR level is a risk marker of respiratory cancer in initially cancer-free individuals. Cancer Epidemiol Biomarkers Prev 2011;20:609-18.  Back to cited text no. 5
[PUBMED]    
6.
Huttunen R, Syrjänen J, Vuento R, et al. Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: A prospective cohort study. J Intern Med 2011;270:32-40.  Back to cited text no. 6
    
7.
Mardining Raras TY, Astuti T, Noor Chozin I. Soluble urokinase plasminogen activator receptor levels in tuberculosis patients at high risk for multidrug resistance. Tuberc Res Treat 2012;2012:240132.  Back to cited text no. 7
[PUBMED]    
8.
Berres ML, Schlosser B, Berg T, Trautwein C, Wasmuth HE. Soluble urokinase plasminogen activator receptor is associated with progressive liver fibrosis in hepatitis C infection. J Clin Gastroenterol 2012;46:334-8.  Back to cited text no. 8
[PUBMED]    
9.
Lönnkvist MH, Theodorsson E, Holst M, Ljung T, Hellström PM. Blood chemistry markers for evaluation of inflammatory activity in crohn's disease during infliximab therapy. Scand J Gastroenterol 2011;46:420-7.  Back to cited text no. 9
    
10.
Persson M, Engström G, Björkbacka H, Hedblad B. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the malmö diet and cancer study. Atherosclerosis 2012;220:502-5.  Back to cited text no. 10
    
11.
Savva A, Raftogiannis M, Baziaka F, et al. Soluble urokinase plasminogen activator receptor (suPAR) for assessment of disease severity in ventilator-associated pneumonia and sepsis. J Infect 2011;63:344-50.  Back to cited text no. 11
[PUBMED]    
12.
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2:139-274.  Back to cited text no. 12
    
13.
Okada SS, Grobmyer SR, Barnathan ES. Contrasting effects of plasminogen activators, urokinase receptor, and LDL receptor-related protein on smooth muscle cell migration and invasion. Arterioscler Thromb Vasc Biol 1996;16:1269-76.  Back to cited text no. 13
[PUBMED]    
14.
National Library of Medicine – National Institutes of Health; 2011. Available from: http://www.nlm.nih.gov/medlineplus/ency/article/003622.htm. (Last accessed Nov 15, 2016).  Back to cited text no. 14
    
15.
Peng Z, Mao J, Chen X, et al. Serum suPAR levels help differentiate steroid resistance from steroid-sensitive nephrotic syndrome in children. Pediatr Nephrol 2015;30:301-7.  Back to cited text no. 15
[PUBMED]    
16.
Wei C, Trachtman H, Li J, et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 2012;23:2051-9.  Back to cited text no. 16
[PUBMED]    
17.
Maas RJ, Wetzels JF, Deegens JK. Serum-soluble urokinase receptor concentration in primary FSGS. Kidney Int 2012;81:1043-4.  Back to cited text no. 17
[PUBMED]    
18.
Huang J, Liu G, Zhang YM, et al. Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int 2013;84:366-72.  Back to cited text no. 18
[PUBMED]    
19.
Wei C, Möller CC, Altintas MM, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008;14:55-63.  Back to cited text no. 19
    
20.
Kumagai T, Mouawad F, Takano T. Pathogenesis of common glomerular diseases – Role of the podocyte cytoskeleton. Cell Health Cytoskelet 2012;4:103-18.  Back to cited text no. 20
    
21.
Sinha A, Bajpai J, Saini S, et al. Serum-soluble urokinase receptor levels do not distinguish focal segmental glomerulosclerosis from other causes of nephrotic syndrome in children. Kidney Int 2014;85:649-58.  Back to cited text no. 21
[PUBMED]    
22.
Trachtman H, Wei C, Reiser J. Circulating factor in FSGS: A black sheep in the suPAR family? Pediatr Nephrol 2013;28:1151-2.  Back to cited text no. 22
[PUBMED]    
23.
Sever S, Trachtman H, Wei C, Reiser J. Is there clinical value in measuring suPAR levels in FSGS? Clin J Am Soc Nephrol 2013;8: 1273-5.  Back to cited text no. 23
[PUBMED]    
24.
Almroth G, Lönn J, Uhlin F, et al. Fibroblast growth factor 23, hepatocyte growth factor, interleukin-6, high-sensitivity C-reactive protein and soluble urokinase plasminogen activator receptor. Inflammation markers in chronic haemodialysis patients? Scand J Immunol 2013;78:285-90.  Back to cited text no. 24
    

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Correspondence Address:
Dr. Suzan O Mousa
Department of Pediatric, Faculty of Medicine, Children's University Hospital, Minia University, El-Minya
Egypt
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DOI: 10.4103/1319-2442.229266

PMID: 29657195

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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]

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