1 Azienda Ospedale di Lecco, Ospedale A. Manzoni, Lecco, Italy, and 2 University Hospital, Heidelberg, Germany, 3 Hôpital Manhes, Ste Geneviève des Bois, France, 4 Hospital Reina Sofia, Córdoba, Spain, 5 University Hospital Würzburg, Germany, 6 The Royal London Hospital, London, UK, 7 Reggio Cal Hospital, Reggio Calabria, Italy
Abstract
Introduction. Cardiovascular disease (CVD), as the leading cause of morbidity and mortality in patients on renal replacement therapy (RRT), has a central role in everyday nephrological practice.
Methods. Consensus was reached on key points relating to the clinical approach and treatment of the main cardiovascular risk factors in RRT patients (hypertension, anaemia, hyperparathyroidism, dyslipidaemia, new emerging risk factors). In addition, the role of convective treatments on cardiovascular outcomes was examined.
Results. Hypertension should be managed by aiming at blood pressure values of 140/90 mmHg (
160/90 mmHg in the elderly), firstly by ensuring target dry body weight is achieved. No single class of drug has proved superior to others in RRT patients, provided that the blood pressure target is achieved, although ACE inhibitors have shown specific organ protection in high-risk patients (HOPE study) and are well tolerated. Anaemia should be managed by using erythropoietin and iron supplements, aiming at haemoglobin levels of 12 g/dl and keeping serum ferritin levels <500 ng/ml. The management of hyperparathyroidism is currently unsatisfactory, as calcium supplements have the potential to increase cardiovascular calcification. While awaiting new calcium- and aluminium-free phosphate binders, it is essential to ensure dialysis adequacy. Clinical studies are in progress to assess the real impact of lipid-lowering drugs in RRT. In the meantime, serum LDL-cholesterol <160 mg/dl and triglycerides <500 mg/dl may be desirable targets. The impact of new emerging risk factors (inflammation and chronic infection, hyperhomocysteinaemia, metabolic waste-product accumulation) and their proper management are still under research. Convective dialysis treatments may confer some degree of protection from dialysis-related amyloidosis and mortality, but clinical data on this important issue are still controversial and no definitive conclusions can be drawn at present.
Conclusion. CVD prevention and treatment is a great challenge for the nephrologist. Achieving evidence-based consensus can help in encouraging the implementation of best clinical practice in line with the progress of current knowledge.
Keywords: anaemia; cardiovascular disease; convective treatments; dyslipidaemia; hyperparathyroidism; hypertension
Introduction
Cardiovascular disease (CVD) is the main cause of morbidity and mortality in patients on renal replacement treatment (RRT), accounting for about 50% of the deaths. The risk of cardiac events such as myocardial infarction in patients on RRT is estimated by two of the largest end-stage renal disease (ESRD) registries, the United States Renal Data System (USRDS) and the European Registry of the patients on renal replacement therapy (EDTA), to be between 3.5 and 50 times higher than in the general population [1,2]. The determinants of CVD in the population on RRT are multiple and include the traditional risk factors identified in the general population, and additional risk factors specific to chronic renal failure (CRF) [3]. Cardiovascular risk factors for the general population (such as age, gender, family history of CVD, hypertension, smoking, diabetes mellitus, dyslipidaemia, obesity, and low physical activity) are also present, and often contemporary, in RRT patients. Moreover, they have often been having an effect since the onset of CRF or even before.
The uraemic state per se is associated with specific additional cardiovascular risk factors which can contribute to the development and progression of CVD: volume overload with consequent hypertension [4,5], anaemia [6], disturbance of Ca-P metabolism [7], and possibly accumulation of metabolic products (advanced glycation end-products (AGE), asymmetric dimethyl arginine (ADMA), homocysteine), chronic inflammation, and hypercatabolism.
Finally, dialysis treatment itself is linked to general and cardiovascular outcome. The importance of the adequacy of dialysis treatment, shown in the 1980s for haemodialysis (HD) and in the 1990s for peritoneal dialysis (PD), is now well acknowledged [8]. The importance of the duration of HD sessions was also demonstrated, independent of adequacy as determined by Kt/V [5]. The role of biocompatibility in influencing cardiovascular risk factors and outcome in HD patients is currently under debate.
We present here an analysis of the major unresolved issues concerning the determinants of CVD in RRT patients, particularly focusing on the influence of HD: hypertension, anaemia, hyperparathyroidism, dyslipidaemia, and new emerging risk factors, such as inflammation, infections and accumulation of metabolic waste products. This is followed by an analysis of the influence of convective treatments and dialysis membrane biocompatibility on cardiovascular stability and outcomes. The accord reached on key points is provided.
Hypertension
The relationship between hypertension and outcome in dialysis patients has been a controversial issue, in part because most ESRD patients are likely to be exposed to hypertension for several years, and long-term hypertension can cause cardiac failure with consequent reduction of blood pressure values (reverse causality). Therefore, if an observational study is based on cross-sectional evaluation of risk patterns, the categorization of the patients by blood pressure (BP) can be misleading. Not surprisingly, some studies show a negative effect of low BP and a positive effect, or no effect at all, of high BP [9]. However, a recent report on the Tassin experience showed a 2.2-fold increase in the risk of cardiovascular death in patients with a pre-dialysis mean BP 98 mmHg (equivalent to a blood pressure of 130/80 mmHg) as compared with patients having a mean BP of <98 mmHg [5]. In a Canadian cohort, Foley et al. [4] found that after adjusting for age, diabetes, ischaemic heart disease, haemoglobin, and serum albumin, each 10 mmHg rise in mean arterial BP was independently associated with a progressive increase of concentric left ventricular hypertrophy (LVH), and the development of de novo cardiac failure and de novo ischaemic heart disease.
These data suggest that hypertension plays a major role in determining cardiac damage in dialysis patientsas it does in the general populationvia LVH, which predisposes the patient to ischaemic cardiac damage by reducing coronary reserve and capillary density [10]. Impairment of coronary perfusion in a hypertrophic heart may be catastrophic, resulting not only in regional impairment of left ventricular contraction but also in left ventricular dilatation, thus perpetuating a vicious circle leading to progressively altered left ventricular geometry and systolic dysfunction [11].
In view of the fact that the issue of risk stratification is now fully incorporated into general hypertension guidelines [12] and that, if we look at these guidelines, dialysis patients are always (or almost always) in the high-risk group, these patients should be monitored and treated accordingly, keeping BP as low as possible.
From these premises the question arises as to the BP values to reach and maintain in RRT patients. BP targets can be set only on the basis of prospective studies. In the only prospective study performed to date in the dialysis population, a BP of 140/90 mmHg minimized the occurrence of LVH and death [4]. Therefore, a BP 140/90 mmHg can currently be considered a sensible goal in dialysis patients. However, in elderly patients, who are becoming the majority in the dialysis population, these values may be too low and put patients at risk of hypotensive/hypoperfusion episodes, so blood pressure values of
160/90 mmHg on average may be more appropriate.
Another issue under current debate is the correct way to assess blood pressure control in dialysis patients, particularly since 24-h ambulatory blood pressure monitoring (ABPM) has become available in many centres. There is no question that ABPM provides a far better estimate of the arterial pressure load on the cardiovascular system than a single or a short series of standard BP measurements in the clinic. The advantage of ABPM over clinic BP may be much more pronounced in ESRD because 55% of these patients do not show the physiological nocturnal decline: identical clinic BP in dialysis patients may therefore be associated with different 24-h BP loads. However, dialysis units are a data-rich environment, allowing the collection of several BP measurements, which can easily be averaged and used as an estimation of the risk of hypertension in the long term. Zoccali et al. [13] have recently compared the predictive power of ABPM for left ventricular mass with an average of 12 routine pre-dialysis measurements in 64 non-diabetic HD patients without heart failure. ABPM did add significant, but weak, information to the prediction of left ventricular internal dimension: it increased by 9% (P=0.01) the variance already explained by pre-dialysis diastolic BP and other significant covariates. However, ABPM did not provide any significant and independent explanatory information in addition to the corresponding pre-dialysis BP measurements with respect to posterior wall and interventricular septum thickness or left ventricular mass (-0.6 to +3.9%, average +1.1%). Thus ABPM is a valuable research tool, but the precision of this method as an estimate of the pressure load can be satisfactorily approached by using the average value of 12 pre-dialysis BP measurements over 1 month, which in most centres is already routine practice.
The last question regarding hypertension in dialysis patients is whether certain classes of drugs are preferable to treat high BP values. First of all, one must always bear in mind that the most important and the safest therapeutic tool for treating hypertension in dialysis patients is to keep them at their target dry body weight. We provide an adaptation of the general WHO-ISH recommendations specifically for dialysis patients, taking into consideration the clinical condition of the patient, with consequent indications and contraindications (Table 1).
|
However, there is currently no proof that one class of drugs is superior to another in dialysis patients with respect to primary or secondary prevention of CVD.
Anaemia
Anaemia is an important determinant of cardiac hypertrophy, which is a frequent finding in uraemic patients. Diminished left-ventricular capillary supply in renal failure increases the critical oxygen diffusion distance in the hypertrophic myocardium, thus predisposing it to ischaemia and subsequent failure. In a Canadian cohort of 433 dialysis patients, anaemia predicted mortality independently of age, diabetes mellitus, cardiac failure, hypoalbuminaemia, serum creatinine, mean arterial pressure, or echocardiographic heart disease. The independent relative risk of mortality was 1.18 per 1.0 g/dl decrease in haemoglobin level [6]. Anaemia also independently predicted heart failure at the start of dialysis and the recurrence of heart failure at a later time.
Reducing anaemia increases oxygen transport and reduces cardiac output and pulse rate, consequently reducing cardiac work load, which is followed by a reduction in LVH. It is not yet proven whether reduced tolerance of ischaemia can be reversed by increasing the oxygen supply [15]. However, erythropoietin (Epo) therapy raised blood pressure in up to 30% of dialysis patients (improvement of anaemia may result in vasoconstriction, which is one explanation of the hypertensive effect of Epo) [16]. An untreated rise in BP may enhance cardiac work-load and exacerbate cardiovascular disease. Moreover, the correction of anaemia improves uraemic coagulopathy (e.g. better platelet function), increases blood viscosity, and reduces erythrocyte deformability: these effects may enhance thrombus formation [17]. In this respect it is of note that intensive ultrafiltration during HD may be followed by haemoconcentration, which can in turn have a pro-thrombotic effect, particularly on the vascular access. Such haemoconcentration can be documented by determining pre- and post-dialytic haematocrit, which should not increase by more than 15% over the pre-dialytic level.
Therefore, the haemoglobin/haematocrit safety ceiling and target levels of Epo therapy are under debate. In the large Amgen study [18], 1200 HD patients, aged over 65 years, with clinically evident congestive heart failure or coronary artery disease (high-risk patients), were randomized either to maintain a haematocrit of 30% or to increase the haematocrit to a target level of 42%, by increasing the Epo dose. Unfortunately, the trial was interrupted after an interim analysis because the number of deaths and non-fatal myocardial infarctions was higher in the group with a target haematocrit level of 42%. Although the difference was not statistically significant, the interim analysis suggested that continuing the study would not show a benefit from the improved correction of anaemia.
In a Canadian trial, normalization of haemoglobin with Epo prevented progressive LV dilatation in HD patients with a normal LV volume. However, in patients with pre-existing LV dilatation it did not induce regression of concentric LVH or of LV dilatation [19]. On the contrary, Hayashi et al. [20] obtained regression of LVH in nine patients in pre-dialysis after 12 months of Epo treatment aimed at normalizing haematocrit (40.4±0.6% in men, 37.6±0.8% in women), without renal function and 24-h BP control being negatively influenced. In the Spanish quality of life study, in 115 patients without very severe co-morbidity, the haematocrit level was increased from 3035% to a mean of 39±2.1%: the sickness impact profile decreased and physical and psychosociological function improved, in the absence of increased cardiovascular events in patients at higher haematocrit levels [21].
In conclusion, target haemoglobin levels of 12 g/dl seem to be appropriate and safe for all patients, provided that a rapid increase is avoided and blood pressure is very carefully controlled. There is still no agreement on the benefit/risk ratio in correcting anaemia above that ceiling. However, it is sensible to individualize the target haemoglobin and to avoid rapid correction of anaemia [22].
Another unresolved issue in the management of anaemia in chronic renal failure is whether iron supplementation, which is necessary for Epo to be active, may create cardiovascular problems in the long term. The question arises from the following observations: deliberate iron depletion in non-renal patients increases resistance to low-density lipoprotein oxidation and is associated with an increase in serum concentration of high-density lipoproteins; volunteer blood donation is associated with a large and significant decrease in arteriosclerosis and vascular events; experimental data show increasing resistance to oxygen radical-mediated injury in iron-depleted subjects; finally, myocardial dysfunction is found in patients with haemochromatosis.
It is not possible to assign a minimum cut-off value for stored iron or serum ferritin [23] and recommendations can only be made by extrapolating data from non-ESRD patients. However, if the immunosuppressive effects of high iron load are taken into account, it seems reasonable not to exceed ferritin levels of 500 ng/ml until the risk/benefit ratio of higher ferritin levels is clearly documented.
Hyperparathyroidism
Disturbances of calcium and phosphate metabolism may play a role in the CVD of RRT patients. Factors implicated include elevated serum calcium and phosphate, secondary hyperparathyroidism, administration of phosphate-chelating agents, and supplementation of vitamin D. However, the effect of these different factors on the cardiovascular system is still incompletely understood because of the discrepancies which exist between the results of laboratory studies and the clinical impact of alterations observed in experimental animals and in in vitro experiments. This is particularly the case for parathyroid hormone (PTH) excess and its effects on the heart and the vessels. Myocardial and vascular cells are a target for PTH and PTH-related peptide, via specific receptors on their membranes. Experimental studies have shown that PTH produces positive inotropic and chronotropic effects on isolated cardiomyocytes, which occur in association with increased intracellular calcium and cAMP activity. These effects mimic the action of calcium ionophores, and can be blocked by verapamil. In vitro experiments on isolated mitochondria have demonstrated that PTH uncoupled oxidative phosphorylation, inhibited energy production, reduced cellular ATP concentrations, and impaired the activity of creatine kinase. Impaired calcium extrusion, resulting from impairment of Ca2+-ATPase, Na+-Ca2+ exchange and Na+-K+ ATPase, also contributes to intramyocytic calcium overload. In animal models, PTH has been shown to activate fibroblasts and to promote the development of intramyocardial fibrosis, which is a hallmark of left ventricular hypertrophy in chronic uraemia.
In humans, primary and secondary hyperparathyroidism have also been associated with increased myocardial calcium content [7], but the clinical consequences of secondary hyperparathyroidism as such are less clear. A high degree of fibrosis and myocardial calcium content may be responsible for the development of high stress, inadequate myocardial hypertrophy, and diastolic dysfunction of the left ventricle [24]. However, the effects of parathyroidectomy (PTX) on left ventricular structure and function in dialysis patients have been extremely variable. In some studies a significant improvement in cardiac function was observed after parathyroidectomy [25], but the majority of authors did not observe significant changes in left ventricular structure and function [26,27]. Moreover, no data are available linking increased PTH concentration to strong end-points such as survival or cardiovascular morbidity.
Secondary hyperparathyroidism and increased calciumxphosphate product have been linked to the calcification of cardiac valves [28] and of coronary arteries [29]. Recent data indicate that cardiac valve calcification is mainly linked with hyperphosphataemia, and that it is most frequently observed in patients with low PTH and adynamic bone disease [30].
There is also uncertainty concerning the clinical importance of the direct role of PTH on the vasculature. Excessive plasma PTH is probably directly linked to calcaemic arteriolopathy (calciphylaxis), but its association with arterial metastatic calcification is less obvious. While PTX can prevent vascular calcification in animals, in humans the role of PTH is not clear. An excess of PTH probably plays a prominent role in diffuse media calcification, whereas it is only one factor among many others in the pathogenesis of patchy intima and subintima calcification. Arterial calcification is directly correlated with hyperphosphataemia and is more frequently observed in older subjects and in the presence of adynamic bone disease [31]. The latter results in a decreased capacity by bone to buffer the calcium and phosphorus input. Consequently, hyperphosphataemia frequently develops, contributing to the elevation of the calciumxphosphate product. This mechanism also increases the risk of hypercalcaemia and thereby contributes to metastatic calcium deposition.
In contrast to the absence of a direct link between PTH and vital prognosis, data in the literature have shown that hyperphosphataemia as such is linked to mortality in dialysed ESRD patients [32]. Therefore, as far as cardiovascular risk and calciumphosphate homeostasis are concerned, hyperphosphataemia appears to be the principal culprit, and efficient control of phosphataemia is mandatory.
Presently, the use of calcium-based chelators is the most widely used therapy for this purpose. Unfortunately, phosphate control is usually obtained only with high doses, and frequent episodes of hypercalcaemia are observed, especially in patients with adynamic bone disease, which contributes further to the pathogenesis of metastatic calcification. Alternative approaches to controlling hyperphosphataemia should be proposed, such as a reappraisal of the real impact of moderate use of aluminium-based chelators, the use of sevelamer andcertainly the most efficient measure an increase in dialysis efficiency, whether obtained by prolonging dialysis time or by using convective techniques.
Dyslipidaemia
The prevalence of dyslipidaemia in chronic renal disease is higher than in the general population. It varies according to the cause of renal disease, the level of renal function, and dietary habits [33]. The prevalence of increased total serum cholesterol and LDL cholesterol (LDL-C) is relatively high in patients with chronic renal insufficiency and the nephrotic syndrome, and in patients treated by peritoneal dialysis (70100%), but it is lower in patients undergoing chronic haemodialysis. The prevalence of increased serum triglycerides, usually with a low HDL cholesterol (HDL-C), is high in all of these subgroups of patients (3050%).
In Germany, 196 diabetic patients were followed for 45 months from the start of dialysis. Diabetics subsequently dying from myocardial infarction had significantly higher median serum total cholesterol levels than survivors, higher LDL, higher LDL/HDL ratios, and higher apolipoprotein B levels [34].
Chronic uraemia is also associated with higher levels of serum lipoprotein (a) as compared to healthy controls, as was shown by Kronenberg et al. [35] both in haemodialysis and peritoneal dialysis patients. Interestingly, the higher lipoprotein (a) levels in these patients were not explained by differences in isoform frequencies, but were apolipoprotein (a) specific: only patients with high-molecular weight apolipoprotein (a) isoforms showed a significant elevation in lipoprotein (a) levels [35]. The increased plasma concentrations of lipoprotein (a) may contribute to the high risk of atherosclerosis in CRF, as indicated by a longitudinal study showing that a high lipoprotein (a) level is a risk factor for future cardiac events [36].
The European Joint Task Force and the National Cholesterol Education Program (NCEP) expert panel have issued guidelines for the general population to lower the cardiovascular risk in hyper- and dyslipidaemias. These guidelines should in general also be applied to dialysis patients, but with minor modifications. Physical activity is strongly encouraged. Specific diet protocols for lipid lowering should be avoided. Consensus has been achieved to aim at LDL-C serum levels of less than 160 mg/dl and serum triglyceride levels of less than 500 mg/dl. A high-risk strategy approach, aiming at lower lipid serum levels, has not been recommended at present. However, there is a case for treatment in individual borderline patients. Data indicate that the genesis of atherosclerosis in the dialysis population is different from that in the general population and that an actual benefit from using lipid-lowering drugs has not yet been demonstrated in this population. Therefore the results from several ongoing clinical trials (4D-study, UK HARP trial and CHORUS study) should be awaited before pharmacological lipid lowering is recommended in HD patients.
New emerging risk factors
Besides classical cardiovascular risk factors, new risk factors for atherosclerosis have come to the fore in the general population in the last decade, and are currently also under investigation in dialysis patients. However, the actual impact of these factors in causing cardiovascular disease and the benefits deriving from therapeutic approaches remain to be assessed by prospective studies.
In the last decade, evidence has been growing that inflammation of the vessel wall plays an essential role in the initiation and progression of atherosclerosis and in plaque erosion, fissure, and rupture, which has led to the definition of atherosclerosis as an inflammatory disease [37]. In CRF patients, chronic systemic inflammation, as evidenced by high C-reactive protein (CRP) levels, was associated with malnutrition and increased cardiovascular risk and mortality [38,39]. In these studies, it is difficult to distinguish which is the chicken and which the egg: in other words, it is difficult to unravel causeconsequence relationships based on mere statistical associations. However, attention is being given, in research and clinical practice, to factors that can trigger and maintain inflammation in CRF patients. The role of dialysis technique biocompatibility is under intensive debate, as will be illustrated in detail below. The possible role of infections such as Chlamydia, previously advanced for the general population, has not been confirmed by recent studies and is still open to debate [40].
Hyperhomocysteinaemia, a well-assessed independent risk factor for atherosclerosis in the general population, is present in CRF patients. It is inversely related to renal function. The clinical impact of lowering homocysteine levels in CRF patients, by means of folate or vitamin B6 and B12 supplementation [41], has still to be assessed.
Metabolic waste products accumulating in CRF patients may contribute to elevated cardiovascular risk. ADMA is an endogenous competitive inhibitor of nitric oxide (NO) synthase. It has been hypothesized that ADMA accumulation in renal failure inhibits NO-induced vasodilatation, thereby contributing to hypertension and cardiovascular disease [42]. A causal role for atherosclerosis and organ damage in non-diabetic dialysis patients has been suggested for AGE. Accumulation of AGE, an expression of high oxidative stress, can be treated by vitamin E administration. Intervention studies are needed before final recommendations can be made.
Convective treatments
Membrane choice and haemocompatibility
Recent reports suggest that the dialysis membrane may have an effect on the cardiovascular risk of dialysis patients [4345]. The beneficial effect of the membrane may be due to its characteristics of biocompatibility, which affect the production or release of pro-inflammatory cytokines, or its properties of permeability, including the removal of high-molecular-weight solutes. It has recently been suggested that permeability and biocompatibility properties may prevent acute side-effects and reduce long-term complications [46]. In a study based on a large number of patients treated with different membrane types, Hakim et al. [43] reported a lower relative mortality risk with modified cellulosic and synthetic membranes than with unsubstituted cellulosic membranes, which was maintained after adjusting for dialysis dose and co-morbid conditions. In a retrospective and uncontrolled study, Koda et al. [45] observed that high-flux membranes reduced not only the risk of ß2-microglobulin (ß2-M) amyloidosis morbidity, as detected by low carpal-tunnel syndrome surgery, but also mortality, even after adjustment for demographic and co-morbid conditions. A 44% reduced relative risk for carpal-tunnel syndrome surgery was also observed by Locatelli et al. [47] in 6440 patients treated in Lombardy between 1983 and 1995 by haemodiafiltration or haemofiltration, as compared to those treated by standard HD. This supports the importance of convective treatments in reducing morbidity from ß2-M deposition, which is clinically relevant because ß2-M deposition can also affect the heart, as demonstrated in an autopsy series [48], and contribute to uraemic cardiomyopathy.
In a recent report Bloembergen et al. [44], evaluating data from the USRDS, analysed the causes of death of HD patients treated with synthetic or cellulosic membranes. This observational study showed that the risk of death from infections and coronary artery disease was lower among patients treated with synthetic membrane dialysers. However, other studies that compared synthetic and cellulosic membranes have not been able to find significant differences in cardiovascular risk [49].
Recent reports have shown that inflammation, as detected by high serum CRP levels, enhances the cardiovascular risk of mortality in HD patients [38,39]. These results strongly suggest that successful treatment of the inflammatory condition may improve long-term survival in these patients. Furthermore, during the HD procedure marked cytokine secretion or production can occur. The ability of monocyte-derived macrophages to secrete cytokines (IL-1, IL-6 and TNF), chemokines (MPC-1), and growth factors may lead to activation and proliferation of smooth-muscle cells and the progression of vascular lesions, suggesting a link between CRP, cytokines, inflammation, and coronary artery disease [50].
The release of pro-inflammatory cytokines may act as an underlying pathophysiological event in the HD-related acute phase response. Due to the lack of markers reflecting clinically relevant biocompatibility phenomena, prospective clinical trials are needed to demonstrate that regulation of cytokine transcription induced by a specific membrane is able to modify the long-term effects of the HD procedure. Inappropriate cytokine generation and activity during HD can be related to contaminated dialysate, direct contact of peripheral mononuclear blood cells with the dialysis membrane or activated complement fractions [51]. Dialysate contamination is a relevant factor, triggering monocyte/macrophage activation. Therefore, the assumption can be made that it is crucial to improve water and dialysate purity. Bioincompatible membranes may induce inappropriate monocyte activation and cytokine production [52]. It is noteworthy that Bologa et al. [53] have recently found that TNF- and IL-6 predicted the degree of hypoalbuminaemia and dyslipoproteinaemia, and that IL-6 might predict the risk of mortality in HD subjects. In a recent paper, Kimmel et al. [54] similarly reported that increased IL-1, TNF
, IL-6, and IL-13 levels were significantly associated with a higher relative mortality in HD patients.
Even though almost all available studies support the hypothesis that high-flux, biocompatible membranes are associated with reduced cardiovascular risk, to date there is no absolute proof showing a causeeffect relationship between the type of membrane used and the outcome of HD patients. This lack of evidence is due in all probability to the absence of long-term randomized clinical trials. Fortunately, two such studies are in progress, one in the USA (HEMO study [55]) and another in Europe (MPO study [56]). Both trials have been designed to evaluate prospectively the long-term effect of the dialysis membrane on mortality in a large population of subjects. We therefore hope that the real impact of dialysis membranes on the outcome of HD patients will soon be known.
Cardiovascular stability
In the last two decades many clinical studies have been conducted to investigate the impact of convective transport on cardiovascular instability in HD patients. In a randomized crossover study, Teo et al. [57] showed that higher convective transport obtained by haemodiafiltration (HDF) was associated with improved myocardial function in both the short and the long term. However, cardiovascular stability was similar with both procedures. In a prospective, randomized, multi-centre study Locatelli et al. [49] evaluated the effect of different dialysis membranes and techniques on intradialytic tolerance, as well as on nutritional aspects and serum ß2-M levels. The authors compared different levels of convection using membranes with the same degree of biocompatibility. They found that the overall incidence of intradialytic hypotension was low, and suggested that the lack of positive results might be due to a bias in patient selection. In a long-term longitudinal study, Kerr et al. [58] compared HD with HDF over a period of 18 months. In this trial, episodic hypotension was rare and there was no significant difference between the two dialysis procedures. Randomized studies were performed to assess the hypothesis that subjects dialysed with high-flux membranes had less intradialytic hypotension than patients treated with low-flux membranes. No significant differences were found between the two membrane types [59,60].
There is no clinical evidence for the potential benefit of high convective transport for improved blood pressure control in HD patients. In the previously mentioned trial by Kerr et al. [58] there was no change in systolic and diastolic blood pressure, either pre- or post-dialysis, during the study. Similar results were reported in other studies, with no significant difference in mean arterial pressure between conventional HD and HDF [47,48,57].
Final accord
After intensive discussion, the panel reached a consensus on the following key points:
Hypertension
Anaemia
Hyperparathyroidism
Dyslipidaemia
New emerging risk factors
Convective treatment modalities
Membrane choice and haemocompatibility
Cardiovascular stability
Contributors
Francesco Locatelli wrote the Introduction and, as chairman, co-ordinated both the expert panel discussion and the preparation of the manuscript.
Jürgen Bommer prepared the Anaemia section; Gérard Michel London the Hyperparathyroidism section; Alejandro Martin-Malo the Convective treatment section; Christoph Wanner the Dyslipidaemia section; Mohammed Yaqoob the New emerging risk factor section; and Carmine Zoccali the Hypertension section.
Acknowledgments
This report comes from the second Accord Workshop which took place in Malta in January 2000. 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.)
We would like to thank Thorsten Brandt, Helen Wright, Marco D'Amico, Lucia Del Vecchio, Fanny Dell'Oro, and Daniela Ravasio for their help in editing the manuscript.
Notes
Correspondence and offprint requests to: Prof. Dr Francesco Locatelli, Department of Nephrology and Dialysis, Ospedale A. Manzoni, Via Dell'Eremo 11, 23900 Lecco, Italy.
References