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Year : 2019  |  Volume : 32  |  Issue : 4  |  Page : 1217-1222

The role of endothelin-1 in intradialytic hypertension

1 Department of Internal Medicine, Faculty of Medicine and Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine and Menoufia University, Menoufia, Egypt
3 Department of Nephrology, Al Ahrar Hospital, Zagazig, Egypt

Date of Submission12-Jan-2019
Date of Decision28-Mar-2019
Date of Acceptance30-Mar-2019
Date of Web Publication31-Dec-2019

Correspondence Address:
Amal M Abdelraouf Baghdadi
Borg Elradwan, El Lewaa Abd El-Aziz Ali Street, Zagazig 44511
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_7_19

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To evaluate the role of endothelin-1 (ET-1) in intradialytic hypertension (IDH).
The etiology and pathogenesis of hemodialysis (HD)-induced hypertension remains complex and speculative. There is mounting evidence that ET-1 may play a vital role in IDH.
Patients and methods
This is a case–control study on 84 individuals including 56 end-stage renal disease patients on regular HD and 28 normal individuals. The patients were divided into three groups. Group I (cases group): 28 patients with IDH, group II (HD control group): 28 patients with well-controlled blood pressure and no history of IDH throughout HD, and group III (healthy control group): 28 healthy volunteers.
The mean age in this study was 50.1 years in group I, 57.1 years in group II, and 34.7 years in group III. Mean arterial pressure (MAP) significantly increased during dialysis in group I and significantly decreased in group II. Delta MAP started to increase more than or equal to 15 mmHg, that is IDH, 2 h after the start of HD session. Mean ET-1 level in group I was 281.8 pg/dl and in group II it was 250.5 pg/dl. There was significant positive correlation between ET-1 level after 2 h of starting of HD session and MAP and delta MAP.
ET-1 is a significant risk factor for having IDH.

Keywords: endothelin-1, end-stage renal disease, hemodialysis, intradialytic hypertension

How to cite this article:
Kora MA, Mohammed YS, Elzorkany KM, Tawfeek GA, Baghdadi AM. The role of endothelin-1 in intradialytic hypertension. Menoufia Med J 2019;32:1217-22

How to cite this URL:
Kora MA, Mohammed YS, Elzorkany KM, Tawfeek GA, Baghdadi AM. The role of endothelin-1 in intradialytic hypertension. Menoufia Med J [serial online] 2019 [cited 2020 Aug 7];32:1217-22. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1217/274281

  Introduction Top

Hemodialysis (HD) is a lifelong procedure for patients with end-stage renal disease (ESRD). Commonly, blood pressure (BP) tends to change frequently as a consequence to HD both during and after HD sessions. Large changes in BP during HD have high risks for increased morbidity and mortality in ESRD patients [1],[2].

The expected response to an HD treatment is a decrease in systolic blood pressure (SBP) of about 10–15 mmHg with BP decreasing sharply during the first hour and then decreasing more slowly for the rest of the treatment. However, there is a spectrum of BP responses, with a notable subgroup even demonstrating increases in BP during the treatment [2],[3],[4].

A paradoxical increase in BP during chronic HD sessions, also known as intradialytic hypertension (IDH), is a well-known but uncommon complication. Various definitions of IDH exist, but, up to date, there is no standard definition. As a result, the prevalence ranges from 5 to 15%, depending on the definition used [5]. Inrig et al. [6] defined IDH as a SBP increase of more than or equal to 10 mmHg from pre-HD to post-HD in at least four of six treatments. IDH can also be defined as an increase in mean arterial pressure (MAP) more than or equal to 15 mmHg during or immediately after HD, as defined by Chazot and Jean [7].

The exact pathogenesis of IDH is unknown. Several factors may be involved in the pathogenesis of IDH, including extracellular fluid volume overload, increased cardiac output, activation of the sympathetic nervous system, activation of the renin–angiotensin–aldosterone system, endothelial cell dysfunction, circulating vasoactive substances, removal of antihypertensive medications by HD, fluctuations in electrolyte levels during dialysis, and the use of erythropoiesis-stimulating agents [8],[9].

Vascular endothelial cells play an important role in BP regulation, as they release variable vasoactive substances which are involved in the regulation of vasomotor activity. Endothelin-1 (ET-1) is a vasoactive peptide which is believed to play a role in vascular abnormalities, such as hypertension, atherosclerosis, hypertrophy, and restenosis [10],[11]. ET-1 produces its biological effects by the activation of two receptor subtypes: ETA and ETB that belong to the family of transmembrane guanine nucleotide-binding protein-coupled receptors [12],[13].

ET-1 is formed by cleaving preproendothelin by the enzyme furin convertase into a smaller 38 amino acid peptide, big-ET-1. Mature ET-1 is then formed by the action of another enzyme, the endothelin-converting enzyme to produce the active 21-amino-acid peptide. ET-1 is a very powerful vasoconstrictor and is also known to be involved in vascular remodeling [13],[14].

Hence, we aimed to evaluate the role of endogenous ET-1 as a vasoactive substance in the occurrence of IDH in patients during maintenance HD.

  Patients and Methods Top

The study was approved from the ethics committee of Faculty of Medicine, Menoufia University and the patients gave an informed consent. The study was conducted on 84 individuals, including 56 chronic renal failure patients who were undergoing chronic HD for more than 6 months in HD units of Zagazig University Hospitals and Al Ahrar Teaching Hospital, Zagazig, Egypt; and 28 normal individuals, during the period from May 2017 to February 2018.

The patients were classified into three groups: group I (the cases group), 28 patients with ESRD on regular HD with IDH; group II (HD control group), 28 patients with ESRD on regular HD with well-controlled BP, and no history of IDH throughout HD sessions; group III (healthy control group) included 28 healthy participants who were clinically free and volunteered to participate in the study.

Adult patients aged equal to or more than 18 years with ESRD on maintenance HD of more than 6 months, and MAP equal to or more than 15 mmHg during or immediately after HD were included in this study after exclusion of ESRD patients on maintenance HD who suffer from hypotension during an HD session, evidence of severe infection, diabetes mellitus, severe hypoalbuminemia, severe anemia (hemoglobin <7 g/dl), those on medications (as angiotensin-converting enzyme inhibitor (ACEIs) or an angiotensin receptor blocker (ARBs)) or the medications were discontinued for 2 weeks prior to the study, patients with poor left ventricular function and ischemic heart disease requiring nitrates for coronary vasodilatation or ACEIs, large interdialytic weight gain (>5 kg), multiple organ dysfunctions, and inability to give informed consent.

All individuals underwent full personal history, present history specifically stressing (for individuals on HD) on the duration of HD treatment, type of dialysis, vascular access, dry body weight, and average weight gain between dialysis sessions, other organ dysfunctions and drug history with special emphasis on antihypertensive drugs and erythropoietin therapy. Patients also underwent complete general and local examination with special emphasis on arterial BP which were monitored before, during (every half hour), and after the HD session. MAP and delta MAP (D MAP) were also calculated as well as pulse rate, BMI, dry weight measurement, and cardiac examination.

All groups were subjected to complete blood count, blood urea (predialysis and postdialysis), serum creatinine, calcium, potassium, sodium, phosphorus, serum albumin; PTH were investigated, and also calculation of Kt/V was done in group I and group II only. Transthoracic echocardiography was done to all groups, and finally measure of ET-1 level was by enzyme-linked immunosorbent assay technique.

Blood collected by venipuncture was allowed to coagulate at room temperature for 10–20 min, and then was centrifuged at a speed of 2000–3000 rpm for 20 min to collect the supernatant. Specimens were held for a longer frozen time only once at − 20°C before the assay. The assay is based on the horseradish peroxidase enzymatic reaction with anti-ET-1 antibody. The level of detection range was 10–150 ng/l.

A commercially available kit was used (ET-1 enzyme-linked immunosorbent assay kit, BYEK1310; Chongqing Biospes Co. Ltd, Chongqing, China).

Statistical analysis

The Statistical Package for the Social Sciences (SPSS, version 18.0, SPSS Inc., Chicago, Illinois, USA) software computer program was used for analysis of our data. Data were expressed as mean value and SD for quantitative data, and frequency and percentage for qualitative data.

Analytical statistics were done as follows: t test for comparison of two independent quantitative variables normally distributed, U test (Mann–Whitney test) for comparison of more than two independent quantitative variables not normally distributed, F test (analysis of variance test) for the calculation of difference between quantitative variables in more than two groups in normally distributed data, two-way F test for calculation differences between more than two values of qualitative variables within the groups, χ2 test for comparison between two or more independent qualitative variables normally distributed, and Pearson's correlation coefficient (r) for comparison between two dependent quantitative normally distributed variables.

The significance level (P) was expressed as follows: P value greater than or equal to 0.05 was insignificant; P value less than 0.05 was significant; and a P value less than 0.001 was highly significant. Finally, cutoff values for sensitivity and specificity were calculated.

  Results Top

Group I, the IDH group, had 28 individuals (12 men and 16 women) with a mean age of 50.14 years, while group II, the non-IDH group, had 28 individuals (18 men and 10 women) with a mean age of 57.11 years. Group III, the healthy volunteers, had 28 individuals (16 men and 12 women) with a mean age of 34.68 years. There was no significant difference between BMI of the three groups [Table 1].
Table 1: Comparison of demographic data of the three studied groups

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There was no significant difference as regards the duration and cause of dialysis between groups I and II. There were also no significant differences between groups I and II in dialysis characteristics including dry weight, ultrafiltration, and Kt/V [Table 2].
Table 2: Comparison of dialysis data among the two hemodialysis groups

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There were no statistically significant differences between groups I and II in laboratory parameters except serum K and creatinine. We also investigated ejection fraction (EF) and left ventricular mass index (LVMI) and found that EF was significantly lower in groups I and II (HD groups) in comparison to group III (healthy individuals), and LVMI was significantly higher in group I compared with both groups II and III [Table 3].
Table 3: Comparison of laboratory, echocardiographic, and hemodynamic data of the three studied groups

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Regarding the hemodynamic profile in our study, there was statistically significant increase in the baseline pulse rate and MAP, recorded at the start of an HD session, in groups I and II compared with group III. Nevertheless, there were no significant differences in the baseline pulse rate and MAP between groups I and II.

As regards the changes in BP, group II showed a statistically significant decrease in MAP throughout an HD session with mean D MAP ranging from − 2.65 mmHg after first half hour to − 7.21 mmHg at the end of an HD session, which is the expected response to HD. On the other hand, MAP in group I significantly increased during and continued to increase throughout the HD session. MAP showed a mild increase in the first 1.5 h of HD session with mean D MAP ranging from 1.75 mmHg after half hour to 8.30 mmHg after 1.5 h of HD. After 2 h of an HD session, MAP showed a sharp increase, where the mean D MAP was 16.44 mmHg and remained increased more than or equal to 15 mmHg till the end of HD [Figure 1].
Figure 1: Comparison of D MAP of the three studied groups at different times. D MAP, delta mean arterial pressure.

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The ET-1 level in group I was 281.79 pg/dl, in group II it was 250.54 pg/dl, and in group III it was 26.82 pg/dl. ET-1 was significantly higher in groups I and II (HD groups) compared with group III (healthy volunteers) (P < 0.001) [Figure 2]. Also, group I had statistically significantly higher ET-1 level than group II (P = 0.04). This study showed that there was significant positive correlation between ET-1 level after 2 h of starting an HD session and MAP (r = 0.41, P = 0.02) and D MAP (r = 0.45, P = 0.01) in patients with IDH during this period [Figure 3].
Figure 2: Comparison of ET-1 of the three studied groups. ET-1, endothelin-1.

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Figure 3: Correlation between ET-1 and D MAP at 4th half hour among group I. ET-1, endothelin-1; D MAP, delta mean arterial pressure.

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The sensitivity of ET-1 in the differentiation between HD groups and healthy individuals at a cutoff of more than or equal to 95 was 100%, specificity was 100%, and the accuracy was 100%, while the sensitivity of ET-1 in differentiation between groups I and II at a cutoff of more than or equal to 237.5 was 71.4%; specificity was 67.9%; and the accuracy was 69.6%.

  Discussion Top

IDH, defined as an increased MAP more than or equal to 15 mmHg during or immediately after HD [7], is a well-known but uncommon complication that affects more than 15% of HD patients. IDH increases the incidence of cardiovascular morbidity and mortality [15],[16].

Although the problem has been known for decades, the pathogenetic mechanism is not yet clarified. It is agreed that IDH is multifactorial, for example volume overload, increased activity of the sympathetic nervous system and the renin–angiotensin–aldosterone system, imbalance of electrolytes, particularly sodium and calcium, endothelial dysfunction, and removal of antihypertensive drugs in dialysis. The dialysis-related increase in ET-1 concentrations has been documented in several studies [5]. Thus, we aimed in this study to evaluate the role of ET-1 in IDH in ESRD patients during maintenance HD.

There were no significant differences between groups in our study as regards baseline demographic, clinical, and dialysis characteristics other than age, while Inrig [17] found that IDH appears to occur more commonly in patients with a lower body weight, and found patients with IDH had lower interdialytic weight gains (lower UF volume). There were statistically significant differences between the three studied groups in all laboratory parameters except serum calcium and sodium. EF and LVMI also showed significant differences among the three groups.

At the start of HD, the baseline hemodynamic profiles of patients in both groups I and II had no significant differences. This is partially consistent with the findings of Chou et al. [18], who found that both IDH-prone patients and control patients had no significant difference in their baseline pulse rate but MAP was higher in the IDH-prone patients.

The changes in BP in our study are consistent with the definition of IDH by Chazot and Jean [7], that is MAP increased by more than or equal to 15 mmHg starting 2 h after the start of an HD session.

Many factors have been proposed to be the cause of hypertension in HD patients. Hypervolemia is assumed to be the most common. In the presence of IDH, an increase in UF rate and decrease of dry weight were the usual strategies that had been adopted and were proposed to be effective [1]. However, most patients present with even higher BP during HD after increases in UF rates. This suggests that factors other than hypervolemia may participate in the pathogenesis of acute increase of BP during HD.

We measured ET-1 level, as a vasoactive substance, 2 h after the start of HD in line with the occurrence of IDH. Our results showed a highly significant increase in ET-1 in HD groups compared with healthy volunteers, which is consistent with the results of study done by Tomic et al. [19], including 30 chronic HD patients and 20 healthy participants as controls, where endothelin was higher in HD patients than controls.

Comparing both HD groups in our study, group I had a statistically significant higher ET-1 level than group II. These results are in agreement with Teng et al. [10], who demonstrated increased plasma ET-1 levels in hypertensive ESRD patients during HD possibly stimulated by volume depletion with sympathetic activation, which may attenuate hypertensive HD effects, thus contributing to intradialytic and IDH.

Our results are also consistent with the results of Chou et al. [18], who found that patients with IDH showed a significant increase in ET-1 levels compared with patients without IDH in a study including 60 patients with and without IDH.

HD is known to have dual effects on endothelial function. On one hand, HD therapy can improve endothelial function by eliminating uremic toxins, inflammatory factors, and other NOS inhibitors. On the other hand, due to the high turbulence of blood at the needle site, lack of biocompatibility of dialysis membranes, and dialysate problems, as well as hemodynamic changes, HD itself may directly or indirectly damage the vascular endothelium and thus weaken the beneficial effect of HD on endothelial functions, resulting in abnormalities of the release of ET-1 [10].

The positive correlation in our study between ET-1 level after 2 h of starting an HD session and MAP and D MAP in patients with IDH during this period is consistent with the findings of Gutierrez-Adrianzen et al. [20], who found that in 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, diastolic BP, and MAP (group having IDH), suggesting that the higher elevation of ET-1 level may have an important role in the genesis of IDH.

The diagnostic performance of plasma ET-1 level in the prediction of IDH in our study had good sensitivity and specificity.

  Conclusion Top

IDH is a common complication in ESRD. Our results suggest that besides the volume status and vasodilation–contraction balance, ET-1 is a significant risk factor for having IDH and may be ET-1 level had a significant diagnostic performance in the prediction of IDH; however, larger studies are required to confirm this in the future.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Yorkgitis BK, Cooper ZR. Renal replacement therapy. In: Luchette FA, Yelon JA, eds. Geriatric trauma and critical care. 2nd ed. Cham, Switzerland: Springer International Publishing; 2017. 383–394.  Back to cited text no. 3
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Inrig JK, Oddone EZ, Hasselblad V, Gillespie B, Patel UD, Reddan D, et al. Association of intradialytic blood pressure changes with hospitalization and mortality rates in prevalent ESRD patients. Kidney Int 2007; 71:454–461.  Back to cited text no. 6
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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. Hemodial Int 2015; 19:279–286.  Back to cited text no. 10
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Valero-Munoz M, Li S, Wilson RM, Boldbaatar B, Iglarz M, Sam F. Dual endothelin-a/endothelin-b receptor blockade and cardiac remodeling in heart failure with preserved ejection fraction. Circ Heart Fail 2016; 9:1–9.  Back to cited text no. 12
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Chester AH, Yacoub MH. The role of endothelin-1 in pulmonary arterial hypertension. Glob Cardiol Sci Pract 2014; 2014:62–78.  Back to cited text no. 14
Eftimovska-Otovic N, Grozdanovski R, Taneva B, Stojceva-Taneva O. Clinical characteristics of patients with intradialytic hypertension. Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2015; 36:187–193.  Back to cited text no. 15
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Tomic M, Galesic K, Markota I. Endothelin-1 and nitric oxide in patients on chronic hemodialysis. Ren Fail 2008; 30:836–842.  Back to cited text no. 19
Gutierrez-Adrianzen 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 Hum Hypertens 2015; 29:366–372.  Back to cited text no. 20


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]


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