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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 20  |  Issue : 2  |  Page : 91-97

Intradialytic changes in endothelin-1 level and its relation with intradialytic hypertension


1 Department of Medicine & Nephrology, Ain-Shams University, Cairo, Egypt
2 Department of Clinical Pathology, Ain-Shams University, Cairo, Egypt

Date of Submission01-Nov-2019
Date of Acceptance04-Dec-2019
Date of Web Publication27-Apr-2020

Correspondence Address:
Dr. Ahmed A Emara
Department of Medicine & Nephrology, Ain-Shams University Hospitals, Cairo 11591
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_37_19

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  Abstract 


Background Intradialytic hypertension (IDH) is a major problem affecting 5–15% of patients with end-stage renal disease on maintenance hemodialysis (HD). We evaluated the changes of endothelin-1 (ET-1) levels during HD and its relation to IDH.
Patients and methods We divided 48 stable HD patients into two groups: group I included 24 HD patients with IDH, and group II included 24 HD patients with well-controlled blood pressure (BP). Diabetic patients, patients taking angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs), and patients with severe infection, malignancy, or having decompensated liver cell failure were excluded from this study. For all patients, BP measurement was done before HD session and every half an hour throughout the sessions. ET-1 level was measured using enzyme-linked immunosorbent assay technique; three samples (before session, when BP rises during session, and at end of session) were taken from group I patients, and one sample was taken before the session in group II patients.
Results Group I had significantly lower dry weight than group II (59.9±16 vs.71.5±11 kg) but a significantly higher ultrafiltration volume (2 vs. 1.5 l). There was a significant positive correlation between basal ET-1 and diastolic blood pressure after dialysis (r=0.51, P<0.05). In this study, basal ET-1 level had a significant moderate diagnostic performance in prediction of IDH (P< 0.001). Basal ET-1 more than or equal to 100 pg/ml had 100% specificity, 75% sensitivity, and 87.5% diagnostic accuracy in prediction of IDH, leading to suggestion that ET-1 was a significant risk factor for having IDH (P<0.05).
Conclusion High ET-1 is a significant risk factor for having IDH, and basal ET-1 level had a significant moderate diagnostic performance in prediction of IDH.

Keywords: endothelin-1, hemodynamics, hypertension, intradialytic hypertension


How to cite this article:
ElSharkawy M, Zaghla HA, Emara AA, El-Emary Y, Hassan M. Intradialytic changes in endothelin-1 level and its relation with intradialytic hypertension. J Egypt Soc Nephrol Transplant 2020;20:91-7

How to cite this URL:
ElSharkawy M, Zaghla HA, Emara AA, El-Emary Y, Hassan M. Intradialytic changes in endothelin-1 level and its relation with intradialytic hypertension. J Egypt Soc Nephrol Transplant [serial online] 2020 [cited 2020 May 28];20:91-7. Available from: http://www.jesnt.eg.net/text.asp?2020/20/2/91/283245




  Introduction Top


Hemodialysis (HD) is a life-sustaining procedure for patients with end-stage kidney disease; nevertheless, a common consequence of HD is the tendency for blood pressure (BP) to change frequently both during and after HD treatments. Large variability in BP measurements during HD is considered a risk factor for increased mortality in patients with end-stage kidney disease [1].

Data demonstrate that the expected response to a HD treatment is a reduction in systolic blood pressure (SBP) of ∼10–15 mmHg with BP decreasing steeply during the first hour and then decreasing more slowly for the remaining duration of the treatment. However, there is a spectrum of BP responses, with a distinct subgroup even showing increases in BP during the treatment [1].

A paradoxical increase in BP during chronic HD sessions, also known as intradialytic hypertension (IDH), is a well-known complication. Various definitions of IDH exist, but, to date, there is no standard definition [2].

In some studies, IDH was defined as a rise in mean arterial pressure (MAP) more than 15 mmHg within or immediately after dialysis. In others, a lower threshold was applied (>10 mmHg increase in SBP), and in some, an inclusive definition was adopted (BP rise of any degree during the second or third intradialytic hour). Other definitions include increasing intradialytic BP that remains unresponsive to volume withdrawal and worsening of pre-existing hypertension or new-onset hypertension after administration of erythropoietin-stimulating agents [3].

The clinical significance of IDH lies in the fact that among hypertensive HD patients, those with IDH appear to have some of the worst outcomes. Prior observational analysis showed that compared with patients whose SBP decreased by at least 10 mmHg from pre-HD to post-HD, those with increases in BP of that magnitude had a higher odds ratio for hospitalization or mortality after 6 months [1].

In a cohort of more than 100 000 HD patients followed for more than 5 years, patients with either a 30-mmHg decrease or any increase in SBP had the highest mortality [1].

Among patients with IHT, studies have demonstrated that endothelin-1 (ET-1) levels rise during dialysis [4]. The aim of this study was to evaluate the role of ET-1 in hypertension in end-stage renal disease (ESRD) and the possible relation of changes in ET-1 level during dialysis with IDH.


  Patients and methods Top


This study was conducted on 48 patients with ESRD on regular HD for at least 6 months. Patients were recruited from Nephrology Department at Ain-Shams University Hospitals, from February 2015 to June 2015. This paper was extracted from a master thesis study approved at Ain shams university in July 2015 and based on ain shams university regulations at that time there was no ethical committee approval needed for this kind of observational studies. Only PhD thesis and Interventional studies need ethical committee approval at that time. Also, Patients consent were taken orally with full explanation and labs were withdrawn only after their agreement.

The patients were divided into two groups: group I included 24 patients with IDH (an increase in MAP ≥15 mm Hg during or immediately after HD) [5], and group II included 24 patients with well-controlled BP, and no history of IDH.

Patients with ongoing infections or inflammatory diseases, decompensated liver disease, and diabetes mellitus were excluded. Moreover, patients with IHD on nitrates or angiotensin-converting enzyme inhibitors (ACEIs) were not recruited as these medications could potentially effect the results.

All the patients were dialyzed using Fresenius 4008S (Fresenius Medical Care Renal Company, Germany) dialysis machines and a fully synthetic polyethersulfone dialyzer. Dialysate was composed of the following: Na+ 135 mEq/l, K+ 2 mEq/l, Ca++ 1.25 mmol/l, Mg+ 1.5 mEq/l, CL− 106 mEq/l, and HCO3− 35 mEq/l. Dialysate flow rate was 500 ml/min. During HD, all patients were anticoagulated with unfractionated heparin. Sodium modeling and cool dialysate were not used during the treatments. Diet was unrestricted during the HD. BP was monitored every 30 min. Blood samples were collected simultaneously at the beginning of dialysis, middle, and end of dialysis.

All patients were subjected to full detailed history, including age, cause of ESRD, duration of HD, and type of vascular access; thorough clinical examination, including BP measurement before HD session and every half an hour throughout the session; and also laboratory investigations including complete blood count, routine chemistry, parathyroid hormone, ferritin, total iron binding capacity, and transferrin saturation.

Endothelin-1 level assay

Peripheral venous blood samples were collected in tubes containing aprotinin (300 kallikrein in activation per milliliter of whole blood) and EDTA1Na (1 mg/ml whole blood) and centrifuged at 3000 rpm for 15 min at 4°C. Plasma ET-1 concentration was measured by enzyme-linked immunosorbent assay using kits manufactured by Gen Asia Biotech Co. Ltd (Shanghai China) [6]. This kit used enzyme-linked immunosorbent assay based on biotin double-antibody sandwich technology to assay human ET-1. Assay range was 2–600 ng/l with high sensitivity (1.01 ng/l) and excellent specificity for detection of ET-1. No significant cross-reactivity or interference between human ET-1 and analogs was observed. The intra-assay and interassay coefficient of variations were less than 10% and less than 12%, respectively.

In group I patients, samples were taken during the midweek HD session, just before start of session, at the end of the session (after 4 h), and another reading at the time when BP rises during the session.

In group II patients, only one sample was taken from before the midweek HD session.

Statistical analysis

The collected data were coded, tabulated, and statistically analyzed using IBM SPSS statistics (statistical package for social sciences) software, version 22.0 (2013; IBM Corp., Chicago, Illinois, USA). Descriptive statistics were done for quantitative data as minimum and maximum of the range as well as mean±SD for quantitative normally distributed data, whereas it was done for qualitative data as number and percentage. Inferential analyses were done for quantitative variables using independent t test in cases of two independent groups with normally distributed data and paired t test in cases of two dependent groups with normally distributed data. In qualitative data, inferential analyses for independent variables were done using χ2 test for differences between proportions. However, correlations were done using Pearson correlation for numerical normally distributed data. Logistic regression model was used to find out independent factors affecting IDH. Receiver operating characteristic curve was used to evaluate the diagnostic performance of ET-1 in diagnosis IDH. The level of significance at P value less than 0.05 was considered significant, otherwise nonsignificant.


  Results Top


The mean age of the patients was 43.6±6.8 years. There were 31 males and 17 females. Etiology of ESRD was hypertension in 34 patients, obstructive uropathy in eight patients, and unknown in six patients. Dry weight was significantly higher in group II. However, ultrafiltration (UF) volume was lower in group II ([Table 1]) and was comparable in the two groups. A total of 45 patients had arteriovenous fistula as an access for HD, whereas the remaining three patients had tunneled cuffed catheters.
Table 1 Demographic and basic clinical characteristics and laboratory data among study and control groups

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Hemodynamic profile

As shown in [Table 2] and [Table 3], at the start of HD, there was no significant difference in SBP between the two groups, whereas during and after the session, the study group had higher SBP ([Figure 1]). In the study group, SBP significantly increased during dialysis, then remained stationary after dialysis with higher level than predialysis level. However, in control group, SBP significantly decreased during and continued to decrease after dialysis. Regarding diastolic blood pressure (DBP), before HD, there was no significant difference in DBP between groups, whereas during and after session DBP, it was higher in the study group ([Figure 2]). In the study group, DBP increased during dialysis then decreased after dialysis but was still significantly higher than baseline level. In control group, DBP significantly decreased during and continued to decrease after dialysis. Regarding MAP, there was no significant difference before dialysis between groups, whereas it was higher in study group during and after session. Moreover, in the study group, MAP increased during dialysis then decreased after dialysis but still significantly higher than baseline level. In control group, MAP significantly decreased during and continued to decrease after dialysis ([Figure 3]).
Table 2 Blood pressure changes in the study population

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Table 3 Endothelin-1 among study and control groups

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Figure 1 SBP among study and control groups. SBP, systolic blood pressure.

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Figure 2 DBP among study and control groups. DBP, diastolic blood pressure.

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Figure 3 MAP among study and control groups. MAP, mean arterial blood pressure.

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Endothelin-1 profile

Baseline ET-1 was significantly higher in study group than control group ([Figure 4]). In study group, ET-1 significantly increased during dialysis, then decreased after dialysis, but still was higher than baseline level, though without statistical significance.
Figure 4 Endothelin-1 among study and control groups.

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Correlation between ET-1 and demographic, basic clinical characteristics, laboratory data, and BP changes in the study population revealed significant positive correlation between basal ET-1 and K (r=0.404, P=0.049). Moreover, there was a significant positive correlation between basal ET-1 and DBP after dialysis in study group (r=0.510, P=0.011, [Figure 5]). Moreover, there was a positive correlation (with trend of significance) between the change in ET-1 level after the session and baseline and the same changes in DBP and MAP (r=0.345, P=0.099, and r=0.358, P=0.086 for DBP; [Figure 6] and MAP, respectively).
Figure 5 Correlation between basal endothelin-1 and DBP after dialysis among the study groups. DBP, diastolic blood pressure.

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Figure 6 Correlation between changes (after-basal) in endothelin-1 and changes in DBP among study group. DBP, diastolic blood pressure.

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To illustrate the predictive value, we performed a receiver operating characteristic plot for ET-1 in prediction of IDH; it showed a significant moderate diagnostic performance in prediction of IDH (area under the curve=0.802, P≤0.001, 95% confidence interval=0.644–0.954). [Table 4] and [Figure 7] show the diagnostic characteristic of the cutoff more than or equal to 100.0 pg/ml of ET-1 (sensitivity, specificity, predictive values, and likelihood ratios).
Table 4 Diagnostic characteristics of basal endothelin-1 more than or equal to 100.0 pg/ml in prediction of intradialysis hypertension

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Figure 7 ROC curve for basal endothelin-1 in prediction of IDH. IDH, intradialytic hypertension. ROC, receiver operating characteristic.

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  Discussion Top


The clinical spectrum of intradialytic complications has changed over time with the ongoing advances in HD machine technology, dialyzers, and dialysate water purification [7]. Nevertheless, acute hemodynamic changes during HD are still the most frequent complications encountered during HD treatment. Major advances have been made over the past decade toward the illustration of the molecular mechanisms beyond endothelium-dependent regulation of vascular tone and blood flow. ET-1 has been found to play a significant role in the complex regulation of local and systemic vascular resistance, blood flow distribution and oxygen delivery, sodium balance, and arterial pressure [8],[9],[10].

ET-1 is a potent vasoconstrictor and has inotropic and mitogenic properties [11]. The pathogenesis of dialysis-induced hypotension and hypertension remains unclear, and there is growing evidence supporting the possible role of ET-1 in these hemodynamic changes [12].

In our study, we have found that baseline (before HD session) ET-1 was significantly higher in the study group (IDH group) than that of the control group. Moreover, within the study group, ET-1 is significantly increased during dialysis, then decreased after dialysis, but still higher than baseline level but without statistical significance. This may indicate a prognostic value for ET-1 and it being a possible predictor to the development of IDH.

There was no difference between the groups regarding baseline demographic and clinical characteristics, except that group I (cases) had significantly lower dry weight but a significantly higher UF volume than group II. This agreed partially with the findings of Inrig [5], who found that IDH appears to occur more commonly in patients with lower body weight, but in contrast to our study, he found that patients with IDH had lower interdialytic weight gains (lower UF volume) [5].

Regarding higher UF volume in our study group, this agreed with the data by Teng et al. [13] who found that absolute and relative intradialytic weight gain, and the absolute and relative UF volumes, as well as the UF rates, were higher in IDH dialysis patients than those in the control patients [13].

There was no difference between groups regarding laboratory data except for higher predialysis serum K in the study group.

In the study of Rubinger et al. [14], postdialysis plasma potassium level was lower in patients with hypertensive episodes. The lower plasma potassium in these patients could indeed have resulted from intradialytic activation of the renin–angiotensin system, leading to increased circulating angiotensin and aldosterone levels, with further activation of central nervous system mineralocorticoid and angiotensin type I receptors and enhanced sympathetic outflow, so an acute decrease in serum potassium was shown to be associated with increased BP, presumably mediated by arteriolar constriction via sympathetic stimulation [14]. In our study, we did not measure serum K after dialysis.

Regarding ET-1 level, group I (cases) had significantly higher ET-1 than group II. It was significantly increased during dialysis then decreased after dialysis but was still higher than predialysis level but without statistical significance. This agrees with the results of Raj et al. [15], who found increased ET-1 level during HD in patients with IDH as ET-1 levels increased before to after dialysis in the nine patients with IDH in a study including 27 patients (nine with IDH, nine with IDH, and nine with stable intradialytic BP) [15].

Our results also are consistent with results of Chou et al. [16], who found that patients with IDH showed a significant increase in ET-1 levels before to after dialysis compared with patients without IDH in a study including 60 patients with and without IDH [16].

These results are also consistent with Gutiérrez-Adrianzén et al. [17], who found ET level after dialysis was higher than predialysis level in 10 patients with IDH in comparison with 11 patients without IDH [17].

On the contrary, in another study done by Tomić et al. [18], including 30 chronic HD patients and 20 healthy participants as controls, ET was higher in HD patients than control, but there was a significant decrease in ET-1 plasma concentration in HD patients after HD treatment in comparison with its values before HD. This difference may be due that their study group did not include only patients with IDH but various dialysis populations [18].

Regarding changes in BP, in group I (cases), SBP significantly increased during and continued to increase after dialysis, DBP increased during dialysis then decreased after dialysis but still significantly higher than before level. MAP increased during dialysis then decreased after dialysis but still was significantly higher than before level. This is consistent with the results of the study done by Raj et al. [15], which showed that MAP increased significantly from the initial value in the group of patients who had IDH together with ET-1 levels which increased in same group of patients with hypertension, suggesting a cause and effect relationship [15].

However, in group II (control), SBP significantly decreased during and continued to decrease after dialysis, DBP significantly decreased during and continued to decrease after dialysis, and MAP significantly decreased during and continued to decrease after dialysis.

In our study, 50% (12 patients) of the study group (cases) had IDH according to provided definition (an increase in MAP more than or equal to 15 mmHg during or immediately after HD) [5], but if we used other definitions of IDH (increase in SBP>10 mmHg) [19], ∼95.8% (23 patients) will be diagnosed to have IDH.

Regarding the correlations of ET-1, there was no significant correlation between ET-1 level and age of study group; this is against findings of Inrig [5], who found IDH common in older patients.

In our study, there was significant positive correlation between basal ET-1 and DBP after dialysis in patients with IDH, and also there was borderline statistical significance between ET level after dialysis and DBP at end of session (P=0.07). However, there was no correlation between ET and SBP neither before nor after dialysis; this may be owing to small sample size.

This agreed with Gutiérrez-Adrianzén et al. [17], who found that after HD, analysis of the mean plasma concentrations of ET-1 showed that there had been a significant increase in the group that had an increase in SBP, DBP, and MAP (group having IDH), suggesting that the higher elevation of ET-1 level may have an important role in the genesis of IDH [17].

In a previous study by Tomić et al. [18], a positive correlation existed between ET-1 plasma concentration and DBP, but was in patients taking ACE inhibitors (which were excluded in our study), whereas in patients not taking ACE inhibitors (as our study), there was a negative correlation between ET-1 plasma concentration and SBP [18].

Lastly, there was a significant positive correlation between basal ET-1 and K in group I (cases) patients and a borderline statistically significant (P=0.064) negative correlation between basal ET-1 and Na in group I.

Effect of sodium on ET-1 and IDH level was discussed in the study by Inrig et al. [20], which found that lower serum Na level (predialysis) is related to occurrence of IDH [20]. This may be owing to that IDH is associated significantly with higher dialysate-to-serum sodium gradients [21], but they did not find a correlation between predialysis Na and ET level [20].

Regarding diagnostic performance of ET in prediction of IDH, we found basal ET-1 to have significant moderate diagnostic performance in prediction of IDH, with area under the curve of 0.802, with sensitivity of 75.0% and diagnostic accuracy of 87.5%. We found that basal ET-1 more than or equal to 100 pg/ml had high specificity (100%) and high positive predictive value (100%) in prediction of IDH.


  Conclusion Top


IDH is a common complication in ESRD (50% in our study). ET-1 may be a significant risk factor for having IDH, and basal ET-1 level had a significant moderate diagnostic performance in prediction of IDH. Further studies are needed on a larger sample size, with measurement of Na and K after dialysis and also to measure dialysate Na to identify more risk factors of having IDH.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Van Buren PN, Inrig JK. Mechanisms and treatment of intradialytic hypertension. Blood Purif 2016; 41:188–193.  Back to cited text no. 1
    
2.
Sebastian S, Filmalter C, Harvey J, Chothia MY. Intradialytic hypertension during chronic haemodialysis and subclinical fluid overload assessed by bioimpedance spectroscopy. Clin Kidney J 2016; 9:636–643.  Back to cited text no. 2
    
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Georgianos PI, Sarafidis PA, Zoccali C. Intradialysis hypertension in end-stage renal disease patients. Hypertension 2015; 66:456–463.  Back to cited text no. 3
    
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Assimon MM, Flythe JE. Intradialytic blood pressure abnormalities: the highs, the lows and all that lies between. Am J Nephrol 2015; 42:337–350.  Back to cited text no. 4
    
5.
Inrig JK. Intradialytic hypertension: a less-recognized cardiovascular complication of hemodialysis. Am J Kidney Dis 2010; 55:580–589.  Back to cited text no. 5
    
6.
Gen Asia Biotech Co.Ltd. Human endothelin 1(ET-1) ELISA kit. Available at: www.genasiabio.cn/product/elisa/Human/18316.html. [Accessed 12 April 2018].  Back to cited text no. 6
    
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Davenport A. Intradialytic complications during hemodialysis. Hemodial Int 2006; 10:162–167.  Back to cited text no. 7
    
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Busse R, Fleming I. Vascular endothelium and blood flow. Handb Exp Phamacol 2006; Part 2:43–78.  Back to cited text no. 8
    
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Moncada S, Higgs A. The L-Arginine-nitric oxide pathway. N Engl J Med 1993; 329:2002–2012.  Back to cited text no. 9
    
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Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332:411.  Back to cited text no. 10
    
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Taddei S, Virdis A, Ghiadoni L, Salvetti A. Vascular effects of endothelin-1 in essential hypertension: relationship with cyclooxygenase derived endothelium-dependent contracting factors and nitric oxide. J Cardiovasc Pharmacol 2000; 35:S37–S40.  Back to cited text no. 11
    
12.
Daughirdas JT. Pathophysiology of dialysis hypotension: an update. Am J Kidney Dis 2001; 38:S11–S17.  Back to cited text no. 12
    
13.
Teng J, Tian J, Lv WL, Zhang XY, Zou JZ, Fang Y et al. Inappropriately elevated endothelin-1 plays a role in the pathogenesis of intradialytic hypertension. Hemodialysis Int 2015; 19:279–286.  Back to cited text no. 13
    
14.
Rubinger D, Backenroth R, Sapoznikov D. Sympathetic activation and baroreflex function during intradialytic hypertensive episodes. PLoS One 2012; 7:e36943.  Back to cited text no. 14
    
15.
Raj DS, Vincent B, Simpson K, Sato E, Jones KL, Welbourne TC et al. Hemodynamic changes during hemodialysis: role of nitric oxide and endothelin. Kidney Int 2002; 61:697–704.  Back to cited text no. 15
    
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Chou KJ, Lee PT, Chen CL, Chiou CW, Hsu CY, Chung HM et al. Physiological changes during hemodialysis in patients with intradialysis hypertension. Kidney Int 2006; 69:1833–1838.  Back to cited text no. 16
    
17.
Gutiérrez-Adrianzén OA, Moraes ME, Almeida AP, Lima JW, Marinho MF, Marques AL et al. Pathophysiological, cardiovascular and neuroendocrine changes in hypertensive patients during the hemodialysis session. J Human Hypertens 2015; 29:366–372.  Back to cited text no. 17
    
18.
Tomić M, Galešić K, Markota I. Endothelin-1 and nitric oxide in patients on chronic hemodialysis. Renal Fail 2008; 30:836–842.  Back to cited text no. 18
    
19.
Van Buren PN, Kim C, Toto RD, Inrig JK. The prevalence of persistent intradialytic hypertension in a hemodialysis population with extended follow-up. Int J Artif Organs 2012; 35:1031–1038.  Back to cited text no. 19
    
20.
Inrig JK, Molina C, D’Silva K. Effect of low versus high dialysate sodium concentration on blood pressure and endothelial-derived vasoregulators during hemodialysis: a randomized crossover study. Am J Kidney Dis 2015; 65:464–473.  Back to cited text no. 20
    
21.
Movilli E, Camerini C, Gaggia P, Zubani R, Feller P, Poiatti P et al. Role of dialysis sodium gradient on intradialytic hypertension: an observational study. Am J Nephrol 2013; 38:413–419.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
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