Division of Nephrology, Dialysis and Transplantation and CNR Centre of Clinical Physiology, Reggio Cal, Italy
Keywords: arterial stiffening; cardiovascular risk; end-stage renal disease; hypertension; left-ventricular hypertrophy; uraemia
Introduction
Hypertension is an established, strong trigger of cardiovascular events. However, the relative importance of its various components remains unclear. The prognostic value of hypertension in patients with end-stage renal disease (ESRD) has long been taken for granted and for this reason there is a paucity of high-quality studies in this area. There are very few prospective studies aimed at clarifying the impact of arterial pressure components on the incidence of cardiovascular complications in ESRD. Uncertainty enshrouds the optimal timing of blood-pressure (BP) measurement in relation to dialysis treatment, the threshold for treatment and the prognostic usefulness of 24-h ambulatory monitoring. In this brief review I will touch upon these important, unresolved arterial-pressure issues in ESRD.
Systolic, diastolic or pulse pressure?
Diastolic BP depends on peripheral vascular resistance and on central artery stiffness. High peripheral vascular resistance raises diastolic pressure while high arterial stiffness has an opposite influence on this component so that the relative contribution of these opposing factors determines the diastolic and eventually the pulse pressure. Pulse and systolic pressure are strongly interrelated because both rise with increases in vascular resistance and arterial stiffness. Pulse pressure seems to be a stronger predictor than systolic pressure because increases in pulse pressure at a given (fixed) systolic pressure are associated with a greater risk of ischaemic heart disease than are increases in systolic pressure at a given pulse pressure [1]. However, the high degree of correlation between systolic BP and pulse pressure (r=0.90) [2] virtually precludes establishing the relative contribution of these two components in determining cardiovascular risk. Arterial stiffness (i.e. reduced compliance) is the main, but not the only, factor explaining the increased risk of systolic hypertension and of high pulse pressure. Thus, it has been demonstrated that systolic and pulse pressures have an effect on cardiovascular outcomes on their own, even after taking into account arterial compliance [3]. Therefore, systolic pressure load and pulsatile stress also appear to play a role in cardiovascular damage independently of the physical properties of the arterial wall.
Ideally antihypertensive treatment, particularly in the elderly, should maximize systolic BP reduction and minimize diastolic BP reduction, thus diminishing pulse pressure.
Arterial rigidity and arterial pressure components in ESRD
In the early 1990s, an extensive meta-analysis of observational studies in the general population demonstrated that the risk of cardiovascular events is linearly related to diastolic pressure and that such a relationship holds true in the normotensive range as well. However, patients included in this meta-analysis had no cardiovascular complications at baseline [4]. On the other hand, the relationship between BP and risk was J shaped in a study by Cruikshank et al. [5], which included patients with cardiac ischaemia and in several other studies in high-risk populations. In retrospective cohort studies based on large haemodialysis databases, the risk of mortality is U shaped [6,7] being minimal at systolic BP values (measured post-dialysis) between 150 and 159 mmHg [6]. The characteristics of patients under study dictate the expected relationship between arterial pressure and risk. Given the high prevalence of cardiovascular co-morbidities in the dialysis population (42% of patients were reported to have congestive heart failure in a recent study [7]), low BP may be a proxy of compromised cardiovascular conditions. Although co-morbidities can be entered as co-variates in the survival analysis, it is difficult to control for this confounding factor by statistical methods alone. The only prospective observational study in dialysis patients that adequately controlled for cardiac function at baseline, by measuring left-ventricle (LV) mass and function by echocardiography, showed that a 10 mmHg increase in mean BP was associated with a 44% higher risk of developing congestive heart failure and that patients with left-ventricular hypertrophy or chronic heart failure were at a much higher risk of mortality than patients without these complications [8]. Heart failure lowers BP and the prevalence of heart failure is very high (40%) in both incident and prevalent haemodialysis patients. Thus, low BP is most often a marker of severe cardiac disease rather than a causal risk factor for cardiovascular mortality in these patients (reverse causality).
As to the cardiovascular risk associated with the arterial pressure components in ESRD, it should be considered that uraemia is a sort of catalyst of the ageing process and that there is a high prevalence of old people among patients on long-term dialysis treatment. Therefore, the systolic and the pulsatile components are expected to be stronger predictors of cardiovascular events than the diastolic component in ESRD. In ESRD anaemia, overhydration and arteriovenous fistula induce an adaptive increase in blood flow, thereby triggering active remodelling, i.e. re-arrangement of the cellular and extracellular components of the vascular wall, which ultimately leads to vascular hypertrophy and structural enlargement (vessel dilatation) [9]. Vascular remodelling eventually increases LV stress and thus causes LV hypertrophy. Furthermore, low diastolic pressure and compromised arterial cushioning in the coronary artery impair myocardial perfusion during diastole, particularly in the subendocardium. These considerations are important for the interpretation of the prognostic role of arterial pressure components in ESRD.
The role of pulse pressure in cardiovascular risk in ESRD patients has been firmly established in a recent analysis of a very large dialysis database in the USA [10]. Interestingly, in this dialysis cohort each incremental elevation of 10 mmHg in post-dialysis pulse pressure was associated with a 12% increase in the risk of death. As in previous studies [6,7], low (unadjusted) systolic and diastolic pressure was associated with shorter survival. The study cohort included over 40% diabetics and high-risk patients but co-morbidities at baseline were not reported. One important result of this study is that it shows that pulse pressure is strongly and directly related to survival in ESRD and that this relationship emerges also in a high-risk scenario.
Pre-dialysis and post-dialysis arterial pressure and 24-h ambulatory monitoring
The definition of hypertension in dialysis patients is not straightforward because pre-dialysis measurements depend on the degree of volume expansion whereas post-dialysis measurements are influenced by the speed of volume subtraction and by the counter-regulatory response of the sympathetic system. The problem is also confounded by the fact that, in part due to nocturnal hypoxaemia [11], there is a paradoxical BP increase during the night, which increases the integrated pressure load on the cardiovascular system, a phenomenon that is not captured by day-time measurements. Due to these problems, it is felt that 24-h ambulatory BP measurement (ABPM) is the only reliable means for estimating arterial pressure load in dialysis patients. Therefore, the value of pre-dialytic, post-dialytic and interdialytic arterial pressure has generally been assessed in relation to 24-h ABPM (assumed as the gold standard) [12]. We should bear in mind, nevertheless, that the claim that 24-h ABPM in dialysis patients is a prognostic marker superior to other types of arterial pressure measurements is still unproven. In a recent study in hypertensive patients with left-ventricular hypertrophy, 24-h ABPM was not superior to nurse-recorded seated BP in terms of associations with treatment-induced changes in LV mass [13]. This is important mostly because two surveys in dialysis patients have shown that 24-h ambulatory monitoring and average pre-dialysis BP, namely the mean monthly value, explain to a similar degree the variance in LV mass [14,15]. The superiority of 24-h ABPM over repeated pre-dialysis measurements cannot, therefore, be taken for granted. In other words, the average of the 12 routine pre-dialysis measurements taken over 1 month, which is a costless and universally available measurement, may be as representative of the true BP, that is the integrated BP load, as is 24-h ABPM.
These considerations in no way detract from the utility of 24-h ABPM in ESRD patients, because this method is a valuable tool for the study of the complex BP alterations in such patients. The point at issue is that as an indicator of cardiovascular risk a single 24-h ABPM recording may not be superior to several measurements (e.g. the average of 1 month) taken in routine conditions before dialysis [16]. The relative importance of pre- and post-dialysis measurements as risk indicators can be estimated by comparing the strength of the relationship between these measurements and LV mass in patients without heart failure.
As shown in Table 1, in a group of 65 non-diabetic patients without heart failure pre-dialysis systolic pressure measured by the nurses was strongly and independently related to LV mass index (LVMI) and the strength of this relationship was higher than that between post-dialysis systolic pressure and LVMI both on univariate and multivariate analysis. Thus, adopting a solid surrogate end-point like LV mass as an indicator of the pressure load effect on the cardiovascular system, pre-dialysis BP seems superior to post-dialysis BP and equally as informative as 24-h ABPM about the effects of integrated pressure load on the heart.
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Is there any threshold for treatment in ESRD?
To understand the nature and the shape of the relationship between BP and risk, absolute risk can be related to systolic, diastolic or pulse pressure. As stated before, in ESRD patients the relationship between mortality and arterial pressure is either U shaped [6] or almost linear-inverse [7,10]. Thresholds for treatment and treatment goals in dialysis patients can only be established on the basis of prospective studies appropriately controlling for cardiovascular co-morbidities and cardiac function, an approach which until now has been adopted only in one study [8].
To further analyse the problem, we have recently examined the relationship between arterial pressure components and cardiovascular events (fatal and non-fatal) in haemodialysis patients (n=201) who took part in the CREED study, an ongoing prospective evaluation of traditional and non-traditional risk factors in ESRD patients without heart failure at baseline. A strength of this study is that each participant underwent echocardiography at baseline. The average age in this cohort was 60 years. As shown in Figure 1
, the relationship between (pre-dialysis) systolic pressure and cardiovascular events, adjusted for age, sex, previous cardiovascular complications, diastolic pressure, diabetes, ejection fraction and LV mass, increased from 125 mmHg onwards (P=0.02), while there was a non-significant risk increase (P=0.26) in patients with systolic pressure <100 mmHg. This may suggest that very low BP should be avoided. The association between pulse pressure and cardiovascular events is linear and patients in the top pulse-pressure group (>70 mmHg) display a >2-fold higher risk than those in the bottom group [16]. These data do not allow conclusive statements on this problem because the number of events (89 fatal or non-fatal cardiovascular complications) was relatively low. It is also important to stress that we need similar prospective observations in ESRD patients, well characterized for both cardiac ischaemia and cardiac function, to analyse more closely (e.g. in 5-mmHg intervals) the risk conveyed by hypertension in dialysis patients.
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Notes
Correspondence and offprint requests to: Carmine Zoccali, CNR Centro Fisiologia Clinica, Ospedali Riuniti, 89124 Reggio Cal, Italy. Email: carmine.zoccali{at}tin.it
References
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