Hypertension and cardiovascular risk assessment in dialysis patients

Francesco Locatelli1, Adrian Covic2, Charles Chazot3, Karel Leunissen4, José Luño5 and Mohammed Yaqoob6

1Department of Nephrology and Dialysis, Azienda Ospedale di Lecco, Ospedale A. Manzoni, Lecco, Italy, 2‘C. I. Parhon’ University Hospital, Dialysis and Transplantation Center, Iasi, Romania, 3Centre de Rein Artificiel, Tassin, France, 4University Hospital Maastricht, Department of Internal Medicine, Maastricht, Netherlands, 5Division of Nephrology-Dialysis, Hospital General Universitario Gregorio Marañón, Madrid, Spain and 6The Royal London Hospital, London, UK

Correspondence and offprint requests to: Professor Dr Francesco Locatelli, Department of Nephrology and Dialysis, Ospedale A. Manzoni, Via Dell’Eremo 11, 23900 Lecco, Italy. Email: nefrologia{at}ospedale.lecco.it



   Abstract
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
Introduction. Cardiovascular (CV) disease is the main cause of morbidity and mortality in dialysis patients. Hypertension in patients affected by chronic renal insufficiency (CRI) has been recognized as one of the major classical CV risk factors in CRI from the very beginning of the dialysis era. However, its treatment is still unsatisfactory.

Methods. A discussion is employed to achieve a consensus on key points relating to the epidemiological, pathophysiological and clinical characteristics of hypertension in renal patients, in the light of global CV risk assessment.

Results. CV disease is accelerated by CRI, in particular by uraemia-specific risk factors. This is reflected by the fact that general population-based equations for calculating CV risk underestimate the real CV risk in CRI and dialysis patients. Hypertension in dialysis patients is clearly a major CV risk factor. Isolated systolic hypertension with increased pulse pressure is the most prevalent blood pressure (BP) anomaly in dialysis patients, due to stiffening of the arterial tree. BP should be assessed by clinical measurements on a routine basis, leaving 24 h monitoring for selected cases. The targets of BP control should be those recommended by the present guidelines, i.e. <140/90 mmHg, or the lowest possible values that are well tolerated. The pathophysiological cornerstone of hypertension in dialysis patients is extra-cellular volume expansion, which is typically sodium-sensitive, given the loss of renal function. Therefore, the principles of hypertension treatment in dialysis are an achievement of dry body weight, proper dialysis prescription with respect to dialysis time and intra-dialytic sodium balance, and dietary sodium and water restriction. Pharmacological treatment should only be the second option, after the adequate and complete application of all other means. No comparative pharmacological trials have specifically addressed the issue of hypertension control in dialysis patients. Therefore, this workshop group had to rely largely on data obtained in the general population. Drugs interfering with the renin-angiotensin system were felt to be the first choice, as they have widely been shown to interfere significantly with CV remodelling. Despite long-standing concerns, ß-blockers are being used increasingly even in patients with congestive heart failure and ischaemic cardiomyopathy. Other drug classes may be used in association or as first-line agents according to clinical requirements.

Conclusions. Hypertension in renal patients has to be given particular and continued attention, and it should be adequately treated in light of the increased CV risk of this patient population. Research into the mechanisms of uraemic cardiomyopathy and cardiovascular remodelling should provide a precious new insight and lead to more precisely targeted and more effective therapies than in the past.

Keywords: antihypertensive drugs; arterial stiffness; cardiovascular disease; cardiovascular risk assessment; cardiovascular risk prevention; dialysis; dialysis duration; dry body weight; hypertension; left ventricular hypertrophy



   Introduction
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
Cardiovascular (CV) disease is the leading cause of morbidity and mortality in dialysis patients, accounting for ~50% of deaths [1] and chronic renal insufficiency (CRI) has been recently referred to as a vasculopathic state, given the accelerated atherosclerosis and arteriosclerosis observed in this patient population.

Many of the well documented risk factors for CV disease in the general population (age, smoking, hypertension, diabetes, dyslipidaemia, physical inactivity, etc.) are also present in end-stage renal disease (ESRD) patients and may have exerted noxious effects for many years before the beginning of renal replacement therapy. The number of new elderly, diabetic and hypertensive ESRD patients is continuously increasing and is reflected by the high proportion of patients starting renal replacement therapy with already established CV disease.

In addition to general CV risk factors, ESRD patients have uraemia-specific risk factors that can also be responsible for the onset or progression of CV disease: volume overload with consequent hypertension, anaemia, deranged calcium-phosphate metabolism, accumulation of specific uraemic toxins (advanced glycation end-products, asymmetric dimethyl arginine, homocysteine), and chronic inflammatory processes. All of these risk factors can finally lead to left ventricular impairment via myocardial hypertrophy and/or ischaemia, which may predispose to cardiac dilatation and pump dysfunction [1].

This report focuses on one ‘classical’ CV risk factor in dialysis patients, i.e. hypertension, pointing out the pathophysiological processes and clinical characteristics that are peculiar to renal patients, particularly in ESRD. Hypertension is discussed in the wider light of modern CV risk assessment.

We feel that hypertension and its consequences in CRI patients deserve description and attention even at present, as the treatment of this detrimental condition is still largely unsatisfactory, despite considerable improvements in instrumental tools for assessing organ damage, dialysis devices and pharmacological drugs.

The Accord Group reached consensus on several key points, which is provided at the end of the text.



   CV risk assessment and prevention
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
Overall, dialysis patients have a 10–20-fold increase in risk of death, compared with the general population, which in the US corresponds to a yearly CV mortality rate of 9% [2].

CV disease in uraemia is mainly a combination of atherosclerosis (with its two principal consequences—coronary artery disease and cerebrovascular disease), arteriosclerosis and uraemic cardiomyopathy. Valvular disease, endocarditis and pericarditis may complicate the clinical picture.

In the general population, large epidemiological and interventional trials have identified several risk factors to be associated with an increased risk of CV morbidity and mortality. While some of them are present in both renal and non-renal individuals (‘traditional’ risk factors), others are more or less specific for chronic kidney disease (‘kidney disease-related’ risk factors) [3] (Table 1). Unfortunately, as convincing intervention data in ESRD patients is lacking, many of the existing guidelines for CV risk prevention (and assessment) in the general population have been extrapolated by nephrologists to the dialysis patient population.


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Table 1. CV risk factors in dialysis patients

 
Can the Framingham risk equation be applied to ESRD patients?
When applying the Framingham risk equation to approximately 1800 CRI patients, Sarnak et al. [4] found a weak negative correlation between the calculated risk and baseline renal function, concluding that Framingham risk factors increase in prevalence as renal function deteriorates. A first report in ESRD patients did not find any difference in the Framingham risk score compared with the general population of the same age [5]. In a very recent cross-sectional study [6], 1041 dialysis patients from the CHOICE cohort were compared with age-matched individuals from the NHANES III study. The calculated risk for de novo atherosclerotic CV disease was found to be two times greater in the dialysis population, the relative difference being greatest at younger ages (i.e. 40–49 years). However, the calculated risk was 5–15 times lower than effective de novo CV disease, as shown by the USRDS data. This underestimation disappears if the calculated risk for a uraemic patient is compared with non-renal subjects who are 10–15 years older. A dialysis patient aged 25–44 years is at a similar absolute risk of death from CV disease as an individual without renal disease, aged over 75 years. Therefore, we can safely conclude that the group of Framingham risk factors may account for some, but not all, of the impressive CV risk generally seen in present dialysis cohorts.

Hypertension as a risk factor in the present dialysis population
There is evidence from several studies, as from everyday clinical practice, that blood pressure (BP) control is rather poor in a significant number of dialysis patients, as compared with the targets advised by present guidelines [7]. The main cause has been identified as the difficulty in obtaining optimal dry weight, coupled with usually large inter-dialytic weight gain and unrestricted, often excessive dietary sodium intake.

Is BP an important predictor for CV morbidity and mortality in dialysis populations?Surprisingly, several studies failed to identify hypertension as having a major influence on CV risk in large cohorts of ESRD patients [8]. Very few observational studies have associated hypertension with shorter survival and excellent BP control with increased survival [9]. Most of the studies demonstrated an association between low BP and increased mortality, that is a ‘U / J’ shape relationship. Port et al. [10], analysing 4839 USRDS patients, found that a pre-dialysis systolic BP < 110 mmHg was significantly associated with a 4-fold increase in the risk of death. Similarly, in Iseki's study [11] (a cohort of 1243 patients followed for more than 5100 patient-years), the crude death rate was 40% for diastolic BP < 70 mmHg, 25% at 80–89 mmHg and 13% if the diastolic BP > 100 mmHg. Zager et al. [12], in over 5000 patients followed for a mean of 2.9 years, showed that the lowest mortality rate was recorded in patients with a pre-dialysis systolic BP between 150 and 159 mmHg. However, all this evidence is questionable because of the important problem of case-mix (significant systolic dysfunction and left ventricular dilatation among study populations). Therefore, we are left with the only consideration that a spontaneously low BP, as a consequence of major CV disease, is a negative prognostic marker. Moreover, low pre-dialysis BP values are predictive of death only in association with short observation periods. In contrast, long-term observation showed that patients with normal BP have reduced mortality, compared with those with higher BP [9,13]. In fact, the only prospective evidence in dialysis patients with an adequate control for cardiac parameters at baseline demonstrated that a 10 mmHg increase in mean arterial BP was, in fact, associated with a significant increase in risk (44%) of developing de novo cardiac failure [14].

Most dialysis patients have isolated systolic hypertension and increased pulse pressure (PP) as a consequence of stiff large arteries due to diffuse arteriosclerosis. The pathological changes in vascular compliance are similar to those seen in non-renal, high-age populations, but they occur 15–20 years earlier in ESRD patients. Tozawa et al. [15], following a cohort of 1243 dialysis patients for 9 years, demonstrated that PP was a better predictor of total mortality than systolic or diastolic BP. Klassen et al. [16] calculated that each incremental elevation of 10 mmHg in post-dialysis PP was associated with a 12% increase in the risk of death. In the USRDS Waves 3 and 4 Study—including 11 412 haemodialysis (HD) patients treated between 1993 and 2000—the most significant prognostic discriminator as a mortality predictor was wide PP [17].

In contrast to the still controversial interpretation of the BP–CV risk relationship, it appears beyond doubt that hypertension before dialysis initiation is predictive for mortality in dialysis patients. In a recent retrospective study of 184 non-diabetic patients with CRI [18], uncontrolled hypertension (>140/90 mmHg) was an independent risk factor for all-cause mortality (RR = 1.79, P = 0.01, 95% CI = 1.15–2.8.) and the main risk factor for CV mortality (RR 2.93, P = 0.0000, 95% CI = 1.69–5.12). Since regression of left ventricular abnormalities in patients on dialysis is difficult to obtain and generally only partial, whatever the strategies employed, it is clearly preferable to tackle the major promoters of left ventricular hypertrophy (LVH) already in the pre-ESRD period. The available evidence clearly points to the need for early and aggressive BP control in patients with chronic renal disease. This strategy is also important for LVH prevention.

What BP targets are important to achieve?
In the absence of level A trials with hard end-points, two different opinions are currently expressed: (i) a differentiated approach, recommending for the minority of dialysis patients with ‘classic systolic-diastolic hypertension’ an optimum pre-HD BP set at <140/90 mmHg, while for the majority of HD patients with isolated systolic BP and wide pulse PP the pre-dialysis BP should be kept at 150–160/85–90 mmHg [19]; (ii) a similar approach as in the general population [7], where systolic BP values well below 140 mmHg are optimal for long-term survival. In other words, the optimal BP would be the lowest tolerable BP consistent with an acceptable degree of well-being and no episodes of intra-HD hypotension. Evidence supporting this second opinion has been convincingly reviewed by the Heidelberg group [20]. Recent data from the ongoing CREED study suggested that the risk for CV events increased from a systolic BP of 125 mmHg onwards, even after adjusting for age, sex, previous CV complications, diastolic BP, diabetes, left ventricular mass and ejection fraction [21].

Is ambulatory blood pressure monitoring (ABPM) better than office BP?
Mean 24 h systolic BP determined by ABPM has been shown in several investigations to be a more reliable tool in predicting end-organ damage than office (casual) BP. Moreover, ABPM—not casual BP assessment—can differentiate between those who have a nocturnal fall of BP and those who have not; the latter condition, called ‘non-dipping’ (which has a multi-factorial aetiology, but where autonomic dysfunction plays a central role), is associated with more severe adverse CV and general outcome.

Recently, some investigators have questioned the rather dominant opinion that ABPM is superior to office BP in predicting end-organ damage. Besides concerns about reproducibility [22], ABPM-derived BP levels failed to better predict outcomes, compared with office BP measured by a nurse. The investigators of the SILVHIA study, examining the impact of angiotensin-receptor antagonists vs ß-blocker therapy on LVH regression in dialysis patients, did not find a better prediction of therapy-induced changes in left ventricular mass when ABPM-derived levels were compared with casual BP [23]. Furthermore, Zoccali [24] have shown that the average of 12 routine measurements of pre-dialysis BP is a similar predictor of left ventricular mass as ABPM. Therefore, ABPM should only be performed to highlight non-dippers and especially the inverted dippers—a high-risk subset of patients [24].

Nocturnal hypertension is seen in one-third of the dialysis patients, possibly due to overhydration, obstructive sleep apnoea, or autonomic neuropathy. It is an independent CV risk factor. Although intervention studies are lacking and therefore urgently needed, one may assume that treating nocturnal hypertension (by administering anti-hypertensive medication at night, using {alpha}-blockers, reducing dry body weight, correcting sleep apnoea or reverting to long-duration HD) may reduce CV mortality [2224,25].

Should other aspects of BP-related parameters be assessed on a routine basis in dialysis patients?
Recent relevant data suggest that in dialysis patients, as in the non-renal population, we should move beyond the simple measurement of BP levels. First, the well conducted prospective investigations from Gerard London's group demonstrate that: (i) pulse wave velocity (PWV) and augmentation index (AGI) are major independent predictors of survival [26]; (ii) using ACE-inhibitors (ACE-I) [27] and dialysis treatment [28], it is possible to ameliorate the aortic stiffness markers PWV and AGI; and (iii) changes in PWV in response to decreases in BP predict mortality in ESRD patients [29]. Most important, PWV and AGI can easily and accurately be measured at bedside, using aplanation tonometry, and the results obtained are reproducible. Secondly, an abnormal circadian BP and PP variability status also emerged as a powerful independent predictor of survival and cardiac structural damage in ESRD [30]. Therefore, we should implement on a routine basis a ‘package’ of BP and vascular evaluation in ESRD patients including: mean pre-dialysis BP levels, PP, nocturnal BP dipping and PWV.



   Dialysis strategies to achieve normalization of BP values: dry body weight, dialysis duration
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
Hypertension is a frequently unresolved issue in dialysis patients. BP control is one of the clinical criteria of dialysis adequacy. However, a large number of HD patients are reported as having high pre-dialysis BP.

Extracellular volume (ECV) overload is the major cause of hypertension in dialysis patients. Describing the pressure–natriuresis relationship, Guyton et al. [31] have established the major role of the kidney in the homeostasis of sodium and ECV. Progressively, as renal failure worsens, the capacity of the kidney to excrete sodium is reduced and the incidence of hypertension increases, so that ~90% of ESRD patients are hypertensive at the start of dialysis treatment. For the same degree of renal failure, the exchangeable sodium is higher in hypertensive than in normotensive patients. In the early days of HD treatment, hypertension control was achieved in a large majority of patients by ultrafiltration (UF) and low salt diet [32]. Controlling BP by reducing the ECV was termed by Thomson et al. [33] as ‘dry weight’. The importance of a low salt diet as an adjunct to UF was also recognised early on [34]. In Tassin, where, like in the 1960s, long-hour dialysis is still in use, dry body weight is the post-dialysis body weight that allows the pre-dialysis BP to remain normal, without the need for anti-hypertensive drugs, despite the inter-dialysis weight gain. At her/his dry weight, the patient has no clinical signs of fluid overload or dehydration [35]. This definition of dry body weight points to BP as the key indicator of ECV. Hence, normal BP is not only the goal, but it is also the best indicator of its single most determinant factor—ECV. The only published prospective trial of clinical ECV evaluation vs ‘objective’ assessment, using both bio-impedance and inferior vena cava diameter measurements [36], demonstrated a very poor sensitivity of a merely clinical evaluation. In clinical practice, assimilating ECV evaluation to BP monitoring is nevertheless the standard method. Only a normal BP allows one to state that a patient has achieved his/her dry weight. The post-dialysis target body weight is decreased at each dialysis session until normalization of BP. Usually, some weeks or months are necessary between the correction of ECV overload by dialysis and the normalization of BP (so-called ‘lag-phenomenon’) [37]. The precise meaning of this lag time may be the occurrence of vascular and cardiac remodelling, which may take many months. It has been shown in a group of 61 patients that 6 months were necessary for pre-dialysis mean BP to reach a plateau of normal values after the dry weight method and tapering of anti-hypertensive drugs were applied [38]. Moreover, the occurrence of a paradoxical rise in BP during the dialysis session has been shown to be responsive to the reduction of ECV via strict low salt diet and the reduction of the prescribed post-dialysis target weight [39]. One of the drawbacks of this method is the possible induction of a decrease in residual renal function. This may be the price to pay for an adequate control of ECV. Anyway, the respective importance of this, with respect to the survival of HD patients, still remains to be studied. One also has to take into consideration the anabolic state occurring after starting dialysis or after the recovery from a concomitant event, such as surgery or severe sepsis, which are variables that can interfere with the assessment of dry body weight. In such circumstances, fat and lean body mass recovery may lead to a quick increase in body weight. If such changes are underestimated, excessive fluid removal and severe intra-dialytic side effects may occur [38]. This requires frequent evaluation of ECV and day-to-day adjustments of dry body weight in order to ensure adequate ECV control and normal BP, because dry body weight is a dynamic variable.

Large UF rates (as a result of excessive inter-dialysis weight gain and/or too short treatment times) may confound the dry weight quest, increasing the frequency of BP drops during HD. Reducing the time of each dialysis session leads to a loss of ECV control. The increased UF rate needed to compensate for shortened dialysis treatment times reduces the possibility of vascular refilling and therefore favours side effects like intra-HD BP drops. This indicates that dialysis time is not long enough to achieve target dry weight. Repeated saline infusions and an increase of dry weight and dialysate sodium content to improve dialysis tolerance will worsen ECV overload and hypertension. This sequence of events has been described as the ‘vicious circle of short dialysis’ [40]. Also, because hypertension is frequent in this setting, a large number of anti-hypertensive medications are needed. These medications are considered by many authors as inefficient or possibly even harmful. They may increase intra-dialytic morbidity, making it difficult to reach the prescribed dry weight. However, the beneficial effects of ACE-I in patients with coronary heart disease, LVH and/or left ventricular diastolic dysfunction must always be balanced against the possible interference with the assessment and achievement of dry weight.

Various dialysis strategies may influence the velocity and efficacy of achieving dry body weight and BP normalization in HD patients. Sequential long-hour dialysis has been reported to be effective in 90% or more of the patients, since the early days of dialysis treatment [32,33], but also more recently in different places [38]. Both long and short daily dialysis schedules are also effective. The interpretation of the success of these strategies is that increased time and/or frequency of dialysis treatment improve dialysis tolerance and make it easier to achieve dry body weight. Luik et al. [41] have shown in a limited number of patients that time alone (possibly related to dialysis dose) plays a role in improving BP control. Sequential short dialysis treatment frequently fails to achieve normal BP. However, the dry weight quest and normalization of BP equivalent to long-hour HD treatment may be obtained with short sequential HD treatment (3 x 4 hours/week) associated with low salt diet, stopping anti-hypertensive drugs and an aggressive UF policy [42]. This interesting experience demonstrates that the doctor's will is as important as the dialysis strategy in applying the dry weight method, to convince the patient to be compliant with dietary sodium and water restriction and succeed in BP normalization.



   Arterial wall properties in patients with renal insufficiency
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
Abnormalities of the arterial system, represented by both a high prevalence of atherosclerotic disease and a reduced wall distensibility of the large arteries, are common in dialysis patients and are related to CV morbidity and mortality [26]. The relationship between reduced arterial wall distensibility and mortality in dialysis patients might be explained by the fact that a reduction in the buffering capacity (compliance) of the arterial system leads to increased systolic stress and therefore to LVH, an important predictor of mortality in this population [43].

Although abnormalities in large arterial wall properties were examined in HD patients in various studies, few of them have addressed the relationship between the existence of arterial wall abnormalities and the level of renal function in CRI before ESRD. Although the fact that overt CV disease is often present already at the start of dialysis therapy, suggesting that the development of vascular abnormalities occurs early in the course of CRI, only a few studies have provided corroborative data on arterial wall properties in CRI patients before the stage of dialysis. Moreover, little data exist as yet on arterial wall properties in peritoneal dialysis (PD) patients. Recently, it has become possible to detect sub-clinical atherosclerotic lesions with the use of echographic assessment of the intima-media thickness (IMT) of the carotid artery, and the distensibility of the large arteries can also be assessed directly by ultrasound techniques. Alternatively, arterial stiffening can be evaluated by PWV, as shown by London and co-workers [26]. Several studies demonstrated a clear-cut relationship between echographic IMT assessment and the arterial thickness at histological examination [43]. Moreover, in transversal studies, IMT was found to correlate not only with atherosclerotic lesions in the coronary, carotid and femoral beds in symptomatic patients, but also with atherogenic risk factors in asymptomatic patients [44]. Therefore, these data suggest that increased IMT can be used as an early marker for atherosclerosis.

It is highly probable that both atherosclerosis, characterized by an increase in IMT, and arterial stiffening, characterized by a reduction in arterial compliance and distensibility, develop early in the course of CRI and are more pronounced in patients with ESRD, be they treated with PD or HD. This assumption is supported by the findings of a recent study, which showed that the distensibility coefficient of the common carotid artery was significantly reduced in HD and CRI patients compared with controls. This points to an increased stiffening of the large arteries over the entire spectrum of renal insufficiency [45]. Furthermore, the distensibility coefficient of the common carotid artery was significantly correlated with the degree of renal insufficiency in CRI patients. The reason for the reduced common carotid artery distensibility in renal patients is probably multi-factorial. Part of the difference with regard to arterial distensibility between healthy control subjects and renal patients is explained by higher BP levels in all patient groups than in controls despite antihypertensive treatment. However, the influence of factors other than BP per se on arterial wall distensibility is suggested by the observation that arterial distensibility was also reduced in long-term normotensive HD patients in the Tassin population [46] and by the fact that the level of renal insufficiency was significantly related to common carotid artery distensibility, regardless of age and BP control [45]. The level of renal function per se appeared to be more significantly associated with reduced arterial distensibility than secondary factors, such as calcium and phosphate metabolism. It is worth noting that age is also an independent determinant of both carotid artery distensibility and IMT in renal patients, which is in agreement with data from Blacher et al. [48]. This emphasizes that patient groups should be completely age-matched when arterial wall properties are compared.

Surprisingly, the study by Konings et al. [46] failed to find a difference in IMT, as a surrogate marker of atherosclerosis, among several groups of CRI patients and controls, in agreement with Savage et al. [49], but in disagreement with other investigators. In one study, London et al. [49] found significantly greater IMT in dialysis patients compared with controls. However, in this study, the mean difference in IMT between patients with ESRD and controls was small (0.8 vs 0.7 mm). Also, these values were still well below IMT values associated with clinical disease in non-renal populations (0.9–1.0 mm). However, Kato et al. [51] recently reported, in a cohort of 219 patients, that a relatively high IMT value in HD patients is a useful predictor of long-term CV and all-cause mortality over a 5 year follow-up.

From these data it is possible to extrapolate that increased arterial stiffness, as detected by reduced carotid artery distensibility, is the prevalent change in arterial wall properties in patients affected by renal disease. This is in line with recent findings of increased vascular calcification in dialysis patients. It could be hypothesized that arterial damage in renal patients is different from that of other populations and more closely related to deposits of calcified products in the arterial wall, possibly mediated in part through disturbances in calcium and phosphate homeostasis. IMT measurement is a useful tool in the risk stratification of dialysis patients, given its recently proven prognostic value regarding CV and overall mortality [50].



   Pharmacological treatment of hypertension in dialysis patients
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
In HD patients, anti-hypertensive drugs are only indicated after control of dry body weight and adequate blood purification have been achieved. Dietary sodium restriction (5 g/day) should be prescribed. It is also important not to exceed with use of high sodium-dialysis in order to prevent dialysis-related iatrogenic hypertension. Two studies have shown a significant reduction of BP with less use of anti-hypertensive medication after reducing progressively the dialysate sodium concentration to 135 mmol/l in conjunction with a low salt diet [51,52]. All drugs that can aggravate hypertension, such as non-steroidal anti-inflammatory drugs, oestrogens, bronchodilators, etc., need to be avoided (as much as the clinical conditions of the single patients permit this). A cautious use of erythropoietin is recommended, particularly avoiding a rapid increase in haemoglobin concentration within short time periods (as widely recommended by the present guidelines on anaemia management in CRI). In patients with long-standing, severe hypertension, it is necessary to discard a secondary cause of hypertension, such as renal artery stenosis.

It is important to stress again that anti-hypertensive drugs in dialysis patients are indicated only after ensuring ECV normalization and an adequate dialysis prescription.

What are the best types of anti-hypertensive drugs?
The key issue is that they should be well tolerated, aiming at adequate BP control. Moreover, it is important to ensure that anti-hypertensive drugs do not interfere with the dialysis prescription. In other words, it is important to ascertain that anti-hypertensive drugs do not cause, by themselves, intra-HD hypotension. The latter may: (i) favour the use of hypertonic saline or of increased dialysate sodium, with the risk of a positive sodium balance, stimulation of thirst and high inter-HD weight gain, or (ii) interfere with the dialysis prescription delivery, particularly regarding reduced UF or dialysis time. Either option carries the risk of not achieving dry body weight.

The indication of a given class of anti-hypertensive drugs may be dependent on associated pathology (Table 2). No specific class of anti-hypertensive drug has proved to be more beneficial than others in dialysis patients, especially when considering that no ad hoc designed trials were ever performed in this population. Therefore, we are currently extrapolating data for a general high-risk population and CRI patients. Drugs interfering with the renin–angiotensin system, i.e. ACE-I and the new angiotensin 1 receptor antagonists (AT1RA), could be a valid choice. In fact, the renin–angiotensin system appears to be clearly implicated in the pathogenesis of hypertension in ESRD patients, as well as target organ damage. ACE-I are effective and well tolerated and are particularly indicated in patients with LVH and/or cardiomyopathy, as shown by the HOPE study in high-risk patients [54]. A further positive effect, possibly related to ACE-I therapy, is the inhibitory effect on thirst, due to a reduction of circulating angiotensin II, which is a potent stimulator of thirst. This may help in the maintenance of dry body weight. Apart from the adverse effects of ACE-inhibition therapy described in the general population (cough and hypersensitivity reactions, including angioneurotic oedema), the most significant adverse effect are bradykinin-mediated anaphylactic reactions in patients dialysed with an AN-69 polyacrylonitrile membrane. A negative effect on anaemia has also been described in ESRD patients treated with ACE-I. Therefore, ACE-I should always be considered as a possible cause of resistance to erythropoietin therapy.


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Table 2. Anti-hypertensive drugs in dialysis patients

 
AT1RA have also demonstrated efficacy and safety in dialysis patients. At least two studies have shown the anti-hypertensive efficacy of the AT1RA losartan with a few adverse effects in dialysis patients [54,55]. One possible advantage of AT1RA over ACE-I therapy is the good tolerability profile. AT1RA do not inhibit kinin degradation and AT1RA therapy is not associated with bradykinin-mediated anaphylactic reactions. Some recently published, controlled studies have shown a similar effect of AT1RA and ACE-I in heart failure with systolic dysfunction. In type-2 diabetic patients with CRI, AT1RA have been demonstrated to exert a beneficial effect, as shown by a reduction in the incidence of the primary composite end-point (progression of CRI/death) [56,57].

In large controlled trials in non-renal populations, ß-blockers proved to exert beneficial effects in patients with congestive heart failure and ischaemic cardiomyopathy. Therefore, they are prescribed more and more frequently by cardiologists. Moreover, they may be particularly suited as anti-hypertensive drugs in dialysis patients, since sympathetic overactivity is an important determinant of hypertension in ESRD. A recent epidemiological study which analysed BP and long-term mortality in the USA (USRDS data), concluded that ß-blocker use in dialysis patients is robustly associated with survival and may be CV-protective [17]. These observations favour the use of this class of anti-hypertensive drugs, particularly in dialysis patients with evidence of CV risk. Their adverse effects, such as bradycardia, bronchoconstriction, interference with peripheral artery vasodilation and a reduced response to hypoglycaemia, have been reduced in frequency and magnitude by the advent of selective ß1-blockers and ß-blockers with nitric oxide-mediated vasodilator action (nebivolol). However, the possible adverse effects related with ß-blocker use should always be considered, given the characteristics of the present dialysis population (old age, high frequency of diabetics, high frequency of chronic obstructive peripheral artery disease, high frequency of myocardial conduction defects and chronic lung disease), and the risk–benefit of such a drug class use has to be evaluated for each patient individually.

Calcium channel blockers (CCB) have long been used and are effective and well tolerated in dialysis patients. Some adverse effects, such as tachycardia, flushing, headache and oedema, are associated with their use, particularly with the short acting dihydropyridine CCB. Non-dihydropyridine CCB, such as verapamil and diltiazem, are negative inotropic and should be used with caution in patients with congestive heart failure. In particular, the combination with ß-blockers may produce an additive effect on the negative inotropic and chronotropic actions. Non-dihydropyridine CCB may be useful in the prevention and therapy of cardiac arrhythmia and in patients with diastolic dysfunction.

Other classes of anti-hypertensive drugs, such as vasodilators and centrally acting sympathetic inhibitors, may be useful drugs to be used in association. Moreover, considering the fact that the association of more than one anti-hypertensive drug is frequently required in hypertension secondary to renal disease, the different classes of drugs should not be regarded as competitors, but rather as complementary tools to treat a complex condition at different levels.



   Emerging mechanisms of LVH in uraemia: lessons from experimental models
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
Uraemia has long been associated with a high incidence of CV mortality [1] that is frequently preceded by LVH, which in turn is recognized as an independent risk factor for survival. Little is known of the mechanisms by which uraemia induces LVH. Hypertension, anaemia, the arteriovenous shunt, and the retention of sodium and water are all thought to be important clinical factors. Recently, new insight on the molecular mechanisms of LVH in uraemia has been provided by experimental models. Here we review only some issues regarding the role of two putative emerging mediators of LVH, calpain and ouabain, and of altered vascular reactivity. Calpain is a Ca2+ requiring cysteine protease that has been previously characterized as a mediator of cell death. Long-term studies have revealed that Ca2+ homeostasis is altered in myocytes from uraemic rats compared with pair-fed sham-operated controls [58]. There is also evidence indicating that intracellular calcium is increased in the hearts of uraemic patients compared with healthy subjects. A likely outcome of raised intracellular calcium concentration in the uraemic myocardium is the activation of calpain which may, in turn, lead to cell death. Calpain activation has been identified in numerous injurious states where intracellular calcium is known to be elevated, including traumatic brain injury, Alzheimer's disease and ischaemic stroke.

Calpain has many protein substrates that are closely associated with the structural integrity of the cell. It is feasible that the activation of calpain may help facilitate the cellular structural remodelling that leads to the development of LVH. Indeed, some evidence of a role for calpain in experimentally induced cardiac hypertrophy does exist [59]. Furthermore, CCB have been shown to be effective in reversing LVH, independently of anti-hypertensive effects, in patients with essential hypertension [60].

Recent efforts have focused on the activity of calpain in the hearts of sham-operated control rats, spontaneously hypertensive rats, and rats rendered uraemic by 5/6th nephrectomy. The effect of uraemic serum on human-derived myoblasts in the presence and absence of calpain inhibitors has also been studied. Mean calpain activity was found to be 3.4-fold higher in the uraemic group of animals, compared with both the control and spontaneously hypertensive rats groups. Calpain activity was significantly higher in the myoblasts treated with media enriched with uraemic serum than those treated with media enriched with serum from healthy human volunteers. Uraemic serum treatment caused a 4-fold rise in DNA fragmentation in the myoblasts, which could be significantly attenuated with three distinct calpain inhibitors. It was concluded that calpain is a likely mediator of uraemia-induced myocardial injury [61]. This observation was recently extended by showing that calpain activity can be stimulated by nanomolar concentrations of ouabain due to an influx of extracellular calcium [62]. As circulating ouabain is a cardiac glycoside which is known to be elevated in uraemia [63] and strongly associated with LVH remodelling in essential hypertension [64], it has been hypothesized that endogenous ouabain might be one of the factors that facilitates the remodelling of the left ventricle in patients with renal failure.

Recently, there is a growing body of evidence to suggest that altered bio-mechanical (reduced vessel compliance) properties of conduit vessels in uraemia cause an increase in pulsatile work load on the heart due to early arterial wave reflections. This contributes to LVH in dialysis patients. In experimental uraemia, it has been possible to extend this observation by showing that altered vascular reactivity precedes morphological changes of IMT. This is due to oxidative consumption of nitric oxide in the vessel wall, resulting in the generation of a potent oxidant, peroxynitrite. Functional nitric oxide deficiency and generation of peroxynitrite have implications for the causation of accelerated atherosclerosis/arteriosclerosis seen in uraemia [65].



   Final accord
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 
After intensive discussion, the panel reached consensus on the following key points.

CV risk assessment and prevention by measuring BP
Predicting CV risk in current dialysis populations using Framingham-based equations, for the same age category, underestimates the effective risk since uraemia-specific factors are not accounted for.

The risk factor paradox described for BP in ESRD (spontaneous low-normal BP = negative prognostic marker) is mainly due to case-mix. Long(er)-term observations and prospective evidence with an adequate control for baseline cardiac parameters, demonstrate that patients with normal BP have reduced CV mortality, compared to those with high BP.

Isolated systolic hypertension is most prevalent in dialysis patients, as a consequence of increased arterial stiffness, due to early onset arteriosclerosis. PP has recently emerged as a powerful predictor of CV mortality.

BP should be assessed by average pre-dialysis casual BP levels, while ABPM should only be used to investigate patients with highly abnormal circadian variability (nocturnal hypertension—inverted dippers) and patients with suspected white-coat hypertension, as well as for research purposes.

For the management of hypertension in dialysis patients, a similar approach to that of the general population (where systolic BP values below 140 mmHg and diastolic BP below 90 mmHg are optimal for long-term survival) is recommended: the optimal BP should be the lowest well tolerated BP values consistent with an acceptable well-being and no episodes of intra-HD hypotension.

Dialysis strategies to achieve normalization of BP values: dry body weight, dialysis duration
The major determinant of hypertension in dialysis patients is an expansion of the ECV.

ECV homeostasis in dialysis patients is sodium sensitive. ECV, and, ultimately, BP depend on sodium input (via diet and possibly also from dialysate), and sodium output via adequate UF (dry weight prescription) and dialysate composition.

BP is the most reliable tool to identify if dry body weight is achieved. Decreasing progressively the post-dialysis body weight until normal pre- and post-dialysis BP is obtained, is the basis of the ‘dry weight’ method. It must be understood that there is a lag-time between the moment when true dry body weight is reached and the normalization of BP.

The failure to reach normal BP (that is normal ECV) must be analysed, looking for the usual limits of current HD practice, such as large inter-dialytic fluid intake favoured by high-sodium diet or hypertonic dialysate, short treatment time and/or the use of anti-hypertensive drugs, jeopardizing the haemodynamic tolerance for UF.

The dry body weight method is recommended to stop anti-hypertensive drugs, thereby minimizing intra-dialytic side effects of ECV correction. However, the indication for CV protection with ACE-I and AT1RA remain to be discussed and studied in this setting.

Arterial wall properties in patients with renal insufficiency
The two facets of arterial wall disease are atherosclerosis and reduced arterial compliance (stiffening of the arterial wall). The latter is common in dialysis patients and has been correlated with development of LVH and CV mortality.

Arterial stiffening can be evaluated by means of PWV or by direct echographic assessment. Early atherosclerosis can be evaluated by means of IMT by echographic examination of the carotid artery.

Arterial stiffening develops early in the course of CRI and is correlated with the degree of renal insufficiency itself. It seems to be more precocious and prevalent in CRI patients than the genesis of atherosclerosis, as evaluated by IMT.

IMT measurement has a prognostic value with respect to CV and overall mortality in dialysis patients.

Pharmacological treatment of hypertension in dialysis patients
Pharmacological antihypertensive treatment should be the last-choice option, after ensuring dry body weight achievement and proper dialysis duration, an optimal sodium balance (dietary sodium restriction and proper prescription of dialysate sodium concentration) and blood purification adequacy.

No specific class of anti-hypertensive drugs has proved to be more beneficial than others in dialysis patients. Ad hoc designed trials have not been performed.

ACE-I and AT1RA may be agents of first choice, as they have the most favourable CV protection profile in the general population, particularly in patients at high CV risk. One possible advantage of AT1RA over ACE-I is their better tolerability.

Beneficial effects of ß-blockers have also been demonstrated in controlled trials in patients with congestive heart failure and ischaemic cardiomyopathy.



   Acknowledgments
 
This report comes from the sixth ‘Accord Workshop‘, which took place in Malaga in April 2003. The Accord Programme is an independent initiative supported by Membrana GmbH, seeking to bring about European consensus on important treatment and management issues in nephrology and dialysis, to help optimize clinical outcomes for patients (more information can be found at the Accord website: www.accord-online.com). Francesco Locatelli, as chairman of the Accord programme, wrote the Introduction and oversaw the consistency of the manuscript edition of the Accord workshop. Contributions in other sections were made by the following participants: Adrian Covic: Cardiovascular risk assessment and prevention; Charles Chazot: Dialysis strategies to achieve normalization of BP values: dry body weight, dialysis duration; Karel Leunissen: Arterial wall properties in patients with renal insufficiency; José Luño: Pharmacological treatment of hypertension in dialysis patients; Mohammed Yaqoob: Emerging mechanisms of LVH in uraemia: lessons from experimental models. We would like to thank Marco D’Amico and Robin Wright for their help in editing the manuscript.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 CV risk assessment and...
 Dialysis strategies to achieve...
 Arterial wall properties in...
 Pharmacological treatment of...
 Emerging mechanisms of LVH...
 Final accord
 References
 

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