Haemodialysis acutely improves endothelium-independent vasomotor function without significantly influencing the endothelium-mediated abnormal response to a ß2-agonist

Adrian Covic1, David J. A. Goldsmith2, Paul Gusbeth-Tatomir1 and Maria Covic1

1Dialysis and Transplantation Center, ‘C. I. PARHON’ University Hospital, Iasi, Romania and 2Renal Unit, Guy's Hospital, London, UK

Correspondence and offprint requests to: Dr Adrian Covic, MD, PhD, Dialysis and Transplantation Center, ‘C. I. PARHON’ University Hospital, Iasi, 6600, Romania. Email: acovic{at}xnet.ro



   Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Increased aortic stiffness markers—aortic pulse wave velocity (PWV) and augmentation index (AIx)—have emerged as powerful predictors of survival in haemodialysis (HD). Various and often contradictory abnormalities of endothelium-dependent (ED) and endothelium-independent (EID) vasomotor function, have been described in dialysis subjects, pre- and post-dialysis, using methods that are difficult to export to the clinical setting or to large prospective trials assessing their relevance. Therefore, we determined the influence of a HD session on PWV and the ED and EID vascular reactivity, employing pulse wave analysis (PWA) of the aortic waveforms, combined with provocative pharmacological stimuli known to reduce wave reflection.

Methods. PWV and aortic AIx (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse wave height) were determined from PWA of arterial waveforms recorded by applanation tonometry using a SphygmoCorTM device in 41 HD (20 males, age 41.8 years) and in 20 controls with essential hypertension (10 males, age 43.6 years). ED and EID vascular reactivity were assessed by changes in AIx following inhaled salbutamol and sublingual nitroglycerin (GTN), respectively, pre- and post-dialysis session. Echocardiography was performed in all patients, pre-HD and before the PWV recordings.

Results. Pre-HD AIx (27.9±11.9%) was significantly higher compared with hypertensive patients with normal renal function (16.5±17%, P<0.05). Dialysis significantly reduced AIx to 18.2±18.3% (P<0.05 compared with pre-HD AIx), a level comparable with non-renal subjects (P = NS). Overall, PWV increased following HD to 7.89±2.09 m/s (P = 0.004 vs pre-HD, 6.34±1.32 m/s in essential hypertensive patients, P<0.05); however, a 19.1% increase was seen in 29 subjects and a 9.1% decrease in the remaining 12 subjects, both P<0.05. In HD patients, either pre- or post-HD, the EID vascular reactivity is significantly greater than the ED vasodilatation elicited by a ß2-agonist. Moreover, when compared with hypertensive patients with normal renal function, the dialysis session only improved the EID abnormality (post-HD GTN AIxHD = -20.8±22.9% vs post-GTN AIxhypertensive = -14.2±5.7%, P = NS), while it had a non-additive effect on the ED response. A smaller response to a GTN challenge was associated with a greater left ventricular mass: r =-0.42, P = 0.007. In contrast, a diminished response to a ß2-agonist did not represent a marker for cardiac abnormalities.

Conclusions. The HD session acutely restores EID but not ED vasomotor function comparable with essential hypertensive patients. Pulse-wave analysis methodology, combined with provocative pharmacological testing may be used to unveil subsets of patients with more severe cardiac structural abnormalities.

Keywords: arterial stiffness; augmentation index; endothelial vasomotor function; haemodialysis; pulse wave velocity; renal failure; vascular compliance



   Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients receiving dialysis treatment [end-stage renal disease (ESRD)] have greatly increased rates of cardiovascular morbidity and mortality. The strongest current predictors of cardiovascular mortality in HD patients relate to large artery structure and function, ascribed to long-standing hypertension and the effects of uraemia [1,2]. Rigid, stiff arteries are characterized by an increased pulse wave velocity (PWV), traveling from the heart to peripheral, resistance vessels. In these subjects, the energy of the reflected wave will combine at an earlier time-point with the antegrade pulse wave, thus increasing the augmentation index (AIx). In ESRD patients on dialysis, for each increase of 1 m/s in PWV the all-cause mortality-adjusted odds ratio is 1.39 (95% CI = 1.19 to 1.62); similarly, the AIx emerged as a powerful predictor of mortality—the risk ratio for each 10% increase in AIx, after adjustment for all confounding factors, is 1.51 (95% CI = 1.23 to 1.86) for all-cause mortality and 1.48 (95% CI = 1.16 to 1.90) for CV mortality [1,2]. Importantly, these associations could not be demonstrated for brachial artery blood pressure (BP).

It is important to study changes in AIx induced by different stimuli, to better understand the aethiopathogenesis of the arterial wall rigidity and to refine prognostic studies. Factors influencing the smooth muscle tone, such as the endothelium-dependent (ED) NO release or decreases in the volume/sodium/uraemic toxins load following a dialysis session, are important modulators of the reflected wave energy and therefore will have a major impact on basal AIx or on changes in AIx. In a previous series of studies [3] we described the direct effect of a haemodialysis (HD) session on AIx: a significant reduction in 43% of the patients, with no/a modest effect for the rest; more importantly, a persistently high AIx following HD emerged as a marker of abnormal cardiac structure—left ventricular chamber dilatation, suggesting that pulse wave analysis (PWA), performed before and after HD, can be used to highlight a particular subset of high-risk ESRD patients.

ESRD patients (on dialysis) are known to have abnormalities of ED and endothelium-independent (EID) vasomotor function [4]. However, their relative prognostic importance remains to be determined, since most analyses of endothelial vasomotor function based on intravascular drug infusion or reactive hyperaemia, are difficult/impractical to export from the vascular laboratory suite to the clinical setting or to large studies, and are frequently non-reproducible [5]. Recently, a simple, non-invasive and reproducible methodology, employing PWA combined with pharmacological stimuli known to reduce wave reflection endothelium, independently (nitrovasodilatation) or by activation of the L-arginine NO pathway (using a ß2-agonist [6]), has been validated in healthy individuals and hypercholestrolaemic patients [5,7].

Using this novel approach, we set out to synthesize the haemodynamic response to a single HD session by comparing aortic PWV, and ED and EID vasomotor function, in healthy HD patients. As a control group, we measured the same parameters in well matched essential hypertensive patients.



   Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study populations
HD group. N = 41, 20 males, age 41.8 years, on HD for > 3 months (mean duration = 42.1±38.6 months). Exclusion criteria were regular cardiovascular instability on dialysis (dialysis hypotension for >5% of dialysis sessions over the preceding 6 months), other major illnesses (e.g. malignancy), recent (last 3 months) myocardial infarction, unstable angina, congestive cardiac failure, peripheral vascular disease, recent (last 3 months) transient ischaemic attacks/cerebrovascular accidents, diabetes mellitus. All patients on the unit have been subjected to echocardiography; due to anatomical reasons, 20% had low quality echocardiograms, and were excluded. From the remaining 80%, patients who also fulfilled the other criteria were identified, and 41 were invited to participate. All 41 patients were able to complete the study successfully.

ESRD aetiology: 21 patients had chronic GN, 10 had unknown causes, four had ADPKD, six had interstitial nephritis. HD parameters: 5 h x 3/week, Kt/V>1.4, Fresenius F60 dialysers, conductivity 135 mS, dialysate Ca2+ = 1.75 mmol/l.

Pre-dialysis laboratory parameters: Hb = 11.9±1.5 g/dl (all patients stable for >3/12 on s.c. erythropoietin), plasma ionized Ca++ = 1.02±0.15 mmol/l, PO4 = 1.71±0.46mmol/l. Random pre-dialysis total cholesterol was 4.72 ±0.34 mmol/l and CRP was 2.3±1.4 mg/dl. All patients were normotensive; 30 without any antihypertensive medication, eight on one class (a calcium channel blocker, amlodipine), and three on three classes of antihypertensives. No ACE inhibitors were in use. Nine patients were chronic cigarette smokers. No patient received any lipid-lowering drug therapy.

Control group. N = 20 essential hypertensive patients, 10 males, age 43.6 years. All patients were normotensive (<140/90 mmHg) after treatment with a calcium channel blocker. No ACE inhibitors or statins were in use. Cholesterol values were 5.1±0.4 mmol/l and CRP 1.1 ±0.9 mg/dl (both P<0.05 compared with dialysis patients). There were six chronic smokers.

Tests of endothelial vasomotor function
ED and EID vascular reactivity were assessed by the maximum changes in AIx following challenges with inhaled salbutamol (SAL) and sublingual nitroglycerin (GTN), respectively, as described by Wilkinson et al. [5] and Chowienczyk et al. [6]. In these previous studies, the ß2-agonist and GTN both significantly and consistently reduced AIx. Inhalation of a ß2-agonist was consistent with an ED activation of the L-arginine NO pathway, since it was substantially inhibited by L-NMMA and correlated to that of intra-arterial acetylcholine [5].

AIx calculation. Radial arterial waveforms (40 cardiac cycles) were recorded by applanation tonometry (Millar arterial pressure tonometer, SphygmoCorTM machine). BP was also measured at the non-fistula brachial artery by sphygmomanometry (mean of three readings taken after 10 min semi-recumbency). An averaged composite radial waveform was calculated from which specially designed software (SphygmoCorTM; PWV Inc., Westmead, Sydney, Australia) derived an aortic BP waveform, in real time, using a validated [8] transfer function algorithm. The validity of the method was confirmed prospectively by Pauca et al. [9]. Although, presently, there is no evidence validating the generalized transfer function in CRF, this technique has been used, with excellent reproducibility, in renal cohorts [3,7,10].

From the derived aortic BP waveform, the first and second systolic pressure peak and AIx were calculated (Figure 1). Three measurements were performed by a single trained technician, in the dialysis unit, with an ambient controlled air temperature of 22–24°C, before the second standard HD session of the week (the pre-dialysis baseline AIx). A second series of measurements was obtained following pharmacological stimuli (similar to Wilkinson et al. [5]). Recordings were made 3, 5, 7, 10 and 15 min following 500 µg of sublingual GTN spray administration and the lowest value was considered as post-GTN AIx (Figure 1). As demonstrated also by Wilkinson et al. [5], 30 min were sufficient for the haemodynamic changes after GTN administration to completely return to baseline. SAL was then given by inhalation with a spacer-inhaler device (after careful patient instruction). Recordings were obtained starting 15, 20 and 25 min following administration, and the lowest obtained value was considered as post-SAL AIx. Since heart rate is an important factor affecting arterial rigidity and wave reflection and hence a possible confounder, the post-dialysis baseline AIx was recorded 30 min following dialysis in order to minimize the impact of the post-dialysis tacchycardia. The heart rate pre-dialysis was 77.4±12.0 beats/min, significantly lower than the heart rate recorded at the end of the dialysis session (90.8±14.7 beats/min, P<0.05), but similar to that recorded at the time of the AIx measurement (80.1±14.5 beats/min, P = NS). Thereafter, the same interventions were applied. Data on the excellent AIx measurement reproducibility obtained by our group, in a similar setting, are reported elsewhere [3,11]. We also explored in five patients the possibility that a different sequence, i.e. administering SAL before GTN, may affect the response to SAL or to GTN. In this control group, a longer period (50 min) was required to return to baseline (pre-SAL) AIx values; however, with the exception of this difference, the changes in AIx induced by SAL and by GTN were similar to those obtained initially during the GTN–SAL sequence, in the same patients. Therefore, using the drugs in reverse order does not significantly affect the results, and the GTN–SAL sequence was applied and used for analysis in all patients.



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Fig. 1. Pulse waveforms from a dialysis patient before (left, ‘stiff’ pattern) and after (right, ‘normal’ pattern) GTN inhalation. AIx improved from 24 to –11%. The augmentation (AG) is defined as the difference between the first and the second systolic peak. The AIx is calculated by dividing the AG by the pulse pressure (PP) x 100.

 
In hypertensive patients, three sets of recordings were made during a 45 min period of supine rest, and the last was taken as a baseline. Recordings were made 3, 5, 7, 10, 15 and 20 min after GTN administration and 10, 15 and 20 min after SAL administration.

Haemodynamic changes induced by inhaled SAL were small, involving a maximum increase in heart rate of 6±7 beats/min (range 2–20 beats/min). Mean BP fell by 1±2 mmHg. After GTN administration, the change in heart rate was 3±5 beats/min (range -1 to 14 beats/min) and the mean BP fell by 4±4 mmHg.

PWV calculation. Fifteen minutes before the first baseline AIx determination (see above), a carotid and a femoral artery waveform were obtained consecutively using the SphygmoCor apparatus and customized software. Using an ECG gated signal, and anthropometrical distances, the PWV was derived using methodology previously described and validated [12]. This was repeated after the HD session.

Echocardiography for left ventricular mass
As per previous studies, all studied patients underwent 2-D and M-Mode echocardiography on the same day as the measurements of endothelial vasomotor function and PWV were undertaken. Detailed methods are provided in previous publications [3]. Left ventricular wall thickness and cavity dimensions were measured and the left ventricular mass index was derived.

Data analysis
The response to SAL or GTN was defined as the maximum change in each parameter after drug administration. Data were analysed by SPSS software (version 9.0). For inter-group comparisons, a t-test was used with Bonferroni correction and Fisher's exact test for the analysis of variance. All values represent mean (SD), and a P-value <0.05 was considered significant.



   Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Pre-dialysis AIx was 27.9±11.9%, significantly higher compared with hypertensive patients with normal renal function (16.5±17%, P<0.05). Following dialysis, AIx was significantly reduced to 18.2±18.3% (P<0.05 compared with pre-HD AIx but P = NS compared with non-renal subjects). Overall, PWV increased following a HD session, from 7.19±1.88 to 7.89±2.09 m/s (P = 0.004). In fact, PWV increased following HD in 29 subjects from 7.04±1.66 to 8.37±2.07 m/s (P<0.05) (a +19.1% increase), and decreased following HD in the other 12 subjects, from 7.57±2.36 to 6.75±1.74 m/s (P<0.05) (but with only a -9.1% decrease). The control group of essential hypertensive patients had a PWV of 6.34±1.32 m/s.

AIx values according to the type of NO-related intervention
A comparison of changes in AIx values recorded following the pharmacological stimuli (see Materials and methods), administered either pre- or post-HD, is presented in Table 1. In HD patients, consistently the EID vasodilatation induced by GTN was significantly greater than the ED vasodilatation elicited by a ß2-agonist. A HD session improves the ED-dependent response to a modest degree, in contrast with its more marked effect on the EID response. Moreover, when compared with hypertensive patients with normal renal function, it is evident that dialysis only restores the response to GTN (EID abnormality): post-HD GTN AIxHD = -20.8±22.9% vs post-GTN AIxhypertensive =–14.2±5.7% (P = NS) (Table 1).


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Table 1. Comparison of changes from baseline (i.e. pre-intervention) AIx induced by GTN and SAL administration, in dialysis and essential hypertensive patients

 
The HD-induced enhancement of the decrease in AIx following GTN administration was independent of the ultrafiltration volume or the change in BP, electrolytes. In fact, the AIx recorded following GTN or SAL administration, is only related to baseline AIx (Figure 2) (r = 0.69 and 0.87, respectively, P<0.001). Finally, the effect of GTN or SAL administration on AIx was independent of the baseline PWV. There is a clear dissociation between the effect exercised by a single HD session on AIx and PWV, since the same drop in AIx is recorded following dialysis regardless of the direction of changes (i.e. increase or decrease, see above) in PWV (Table 2).



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Fig. 2. The effects of GTN and SAL administration on AIx are related to baseline AIx, in dialysis subjects.

 

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Table 2. Dissociation between the effect exercised by a single HD session on AIx and PWV

 
Significance of the EID/ED changes in AIx in dialysis subjects
A smaller response to a GTN challenge was a marker of more abnormal heart structure: the greater the patients’ left ventricular mass, the smaller was the magnitude of changes in AIx elicited by GTN administration: r = -0.42, P = 0.007 (Figure 3). Also, in support of this observation, patients with thicker left ventricular walls had a significantly higher post-GTN AIx (Figure 4). In contrast, a diminished response to a ß2-agonist did not represent a marker for cardiac abnormalities.



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Fig. 3. Relationship between left ventricular mass and the effect of GTN challenge on pre-HD AIx.

 


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Fig. 4. Relationship between pre-HD post-GTN AIx and left ventricular parietal wall thickness (PWT, posterior wall thickness; IVST, interventricular septum wall thickness).

 
Further to support the above significance of a GTN challenge, we compared patients in whom sublingual GTN administration caused a negative AIx (group A) with patients in which post-GTN AIx remained positive (group B). Group B patients also had stiffer arteries (structural damage), as demonstrated by a significantly greater PWV (7.66±1.97 m/s), and a significantly greater left ventricular mass index (LVMI) (201.8±42.3 g/m2), compared with group A subjects (PWV = 6.29±1.31 m/s, LVMI = 155.9±31.2 g/m2, respectively) (P<0.05).



   Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our study examined in detail endothelial vasomotor dysfunction in uraemic patients and the acute effects of a single HD session on several key haemodynamic factors associated with long-term survival of HD patients. Using the simple, reproducible and non-invasive [3,5,7,11] pulse-wave analysis methodology, combined with provocative pharmacological testing, recently validated both in normal subjects and in subjects with endothelial dysfunction [5], we were able to demonstrate, in a population of well dialysed patients, marked abnormalities of ED and, to a lesser extent, of EID vasomotor function, compared with a control group of hypertensive patients with normal renal function. Most importantly, we showed that a HD session led to a non-significant improvement in ED vasomotor function, while correcting the EID dysfunction to a comparable level to essential hypertensive patients. The present findings augment and extend those first reported in 2000 [3]. In that previous study, we reported a clear association between increased aortic stiffness and left ventricular mass, and also demonstrated that subjects in which arterial characteristics improved least after HD, tended to have the greatest LVMI. Similar results were obtained by Joannides et al. [4] using a different technique (post-ischaemic hyperaemia) to assess the effect of endogenous NO release: they were able to show that the flow-dependent vasodilatation of peripheral conduit arteries is profoundly altered in HD patients while there is only a small but significant decrease in the vasodilating response to exogenous NO (GTN). The fact that the response to flow is altered more than that to exogenous NO argues for a decreased availability of endothelial NO in HD patients.

An abnormal endothelial vasomotor function has been typically described in patients with chronic renal failure [13], on HD [1417], on peritoneal dialysis [18], or after successful renal transplantation [11]. Factors such as dialysable inhibitors of endothelial nitric oxide synthase (e.g. ADMA [14]), oxidative stress [13,1617], hyperhomocysteinaemia [13], erythropoietin and cyclosporin A have all been implicated.

Pre- to post-HD studies comparable with our work are very few in number, and often conflicting in their findings, such that whether the dialysis procedure per se causes a significant change of endothelial function is still a matter of debate, as well as the precise nature of these changes: improvement vs impairment of the endothelial function. Hand et al. [14], using brachial artery cannulation and forearm plethysmography, showed that HD acutely improves vascular reactivity to L-arginine, consistent with the removal of uraemic inhibitor(s) of NO synthesis. Cross et al. [15] also showed (using brachial artery studies based on flow-mediated vasodilatation/hyperaemia) that dialysis improves ED vascular reactivity, whereas the EID responses remained unchanged. At the same time, reductions in plasma concentrations of ADMA and homocysteine were recorded. In contrast, Miyazaki et al. [16] and more recently Kosch et al. [17], demonstrated an acute worsening of the brachial artery ED vasoreactivity, following dialysis with a cellulosic membrane. This was related to a significant increase in the oxidative stress [16,17] caused by a bio-incompatible membrane, and was abrogated by using a vitamin E-coated HD membrane [16] or a polysulphone membrane [17].

We confirm that using a high-flux polysulphone biocompatible membrane prevents a further deterioration of the ED vasodilatation, which, however, remains highly abnormal when compared with matched hypertensive subjects with normal renal function. Our data suggest for the first time that dialysis improves the EID vasomotor function. When analysing previous studies [17] it is evident that the NO-donor GTN induces greater vasodilatation (by ~30%) compared with ED, NO-releasing manoeuvres (flow-mediated vasodilatation). Whether our novel findings owe more to the use of sophisticated methodology (applanation tonometry derived PWA), the use of specific dialysis membranes, or patient characteristics is difficult to determine. A study should be performed comparing the different available techniques addressing ED and EID vasomotor function. The exact consequences of these abnormalities have yet to be determined. Although cross-sectional in nature and therefore clearly not a cause–effect relationship, our preliminary data nevertheless suggest that EID-impaired vasodilatation may contribute to LVH. We consider that a lack of GTN-induced vasodilatation may be a marker of more abnormal structural abnormalities, with a strong impact on afterload.

A second important finding in this present study is that for the majority of subjects, a HD session leads to an increase in aortic PWV. At all times PWV remained significantly greater than that recorded in well matched essential hypertensive subjects. The reasons for the increased arterial stiffening seen in uraemia are a mixture of acquired functional and structural alterations. Our studies also showed that there is a clear dissociation between the behaviour of one measure of aortic stiffness, AIx, which tended to fall after a HD session, compared with aortic PWV, which rose (Table 2). AIx is a composite parameter, and besides being an assay of aortic stiffness is also significantly influenced by arterial wave energy reflections. In contrast, aortic PWV is related more closely and directly with aortic compliance. This dissociation between the behaviour of AIx and PWV has been noted before in hypertensive patients with normal renal function, following the administration of vasomotor drugs [1216], but has not yet been described in ESRD populations.

Again, other studies examining acute alterations in aortic PWV following dialysis are few. Cohen and Townsend [19], using a different methodology (the Jay Cohn model) to measure arterial characteristics, reported that HD is associated with a reduction in small artery compliance (i.e. increase in arterial stiffness), dependent on a rise in plasma calcium across the HD session. Tycho Vuurmans et al. [20], using a very similar methodology to that employed in our study, also found no overall significant change/improvement in aortic PWV while the aortic AIx decreased. However, treating patients with ACE inhibitors for 1 week produced a significant improvement in basal pre-HD aortic PWV up to normal levels, 24 h after HD.

In conclusion, we have shown important and complex short-term alterations in aortic stiffness/compliance caused by a HD session with biocompatible membranes: improvement in EID vasomotor function without significantly influencing the endothelium-mediated abnormal response to a ß2-agonist. These changes relate directly to left ventricular weight. We feel that profiling dialysis sessions using these haemodynamic parameters, rather than crude measures of brachial artery BP, may offer a better approach to the long-term avoidance of the progressive and highly destructive arterial and cardiac remodelling that is a feature of dialysis patients.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received for publication: 18. 7.03
Accepted in revised form: 24. 9.03