| Abstract|| |
Based on apparently conflicting epidemiological data there has recently been considerable uncertainty and controversy concerning optimal blood pressure (BP) levels in patients on maintenance hemodialysis. It has also become obvious that it is not only the mean arterial pressure, but also the arterial pulse pressure profile, which impacts on hemodynamic stress and outcome. Epidemiological surveys document that, in the pre-dialysis state, up to 53% of chronically dialyzed patients have systolic BP above 140 mm Hg, but only 17% have diastolic BP values above 90 mm Hg. In other words, the systolic BP tends to be elevated, while the diastolic BP remains within normal limits. This constellation reflects the reduced elasticity of central arteries leading to increased pulse wave velocity and larger BP amplitude. Recent retrospective surveys created much uncertainty: they indicated that short-term survival was optimal when predialysis systolic BP values were between 130 and 180 mm Hg, higher values conferring little additional risk. In contrast, the risk of death was increased dramatically for BP values below 120 mm Hg. According to epidemiological studies in the general population, patients with low systolic BP are characterised by poor cardiac function and high cardiac risk. It has been observed that after such high-risk patients have died, in the long run, a continuous positive relationship exists between BP and survival. These observations are in agreement with what has also been observed in dialysis patients by Charra (Tassin, France). We are of the opinion that, in general, a pre-dialysis systolic BP in the low normal range is optimal for survival. This goal may not be achieved in all patients and may cause side effects so that it is necessary to individualize the approach. Rapid ultrafiltration carries the risks of sympathetic activation and intradialytic hypotension, which must be avoided. Relatively simple measures are effective in lowering blood pressure, e.g. low salt intake, reduction of dialysate sodium concentration, long slow and possibly more frequent dialysis sessions.
Keywords: Blood pressure, Dialysis outcome, Cardiovascular mortality, Hypervolemia, Sympathetic activation.
|How to cite this article:|
Ritz E, Pablick-Deetjen J, Zeier M, Amann K. Blood Pressure on Dialysis: An Ongoing Controversy. Saudi J Kidney Dis Transpl 2002;13:1-13
|How to cite this URL:|
Ritz E, Pablick-Deetjen J, Zeier M, Amann K. Blood Pressure on Dialysis: An Ongoing Controversy. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2020 Jan 19];13:1-13. Available from: http://www.sjkdt.org/text.asp?2002/13/1/1/33195
| Introduction|| |
Controversial interpretation of retrospective observational surveys has recently caused considerable uncertainty about blood pressure in patients on maintenance hemodialysis, and particularly which blood pressure values are optimal for patient survival.
It is our opinion that there is a rational explanation for the apparent conflict of the data; such understanding of the underlying pathophysiology facilitates selection of appropriate interventions and provides a rationale for the changes in the current dialysis procedures that are advisable.
1. Historical notes on blood pressure in hemo dialyzed patients
Hypertension in the uremic patient has been known since the days of Richard Bright.  When maintenance hemodialysis was introduced as a therapeutic modality, the crucial importance of hypertension as a complication of uremia was recognized. After the first dialysis patient, Clyde Shields, had been on dialysis for no more than eight weeks, Belding Scribner commented with admirable insight on the elevated blood pressure and its control by the dialysis procedure.  "As in the case of nephrectomized dogs, hypertension appears to be influenced by the size of the extracellular space. A combination of dietary sodium restriction and ultrafiltration during dialysis permits regulation of extracellular volume".
It was initially thought that hypervolemia was fully under control once the patient had lost edema, but it was soon recognized that hypervolemia with its effect on blood pressure might still be present even when the patient had lost edema. These observations led to the introduction of the concept of "dry weight", which was defined in 1967  as "not merely the absence of edema, but that body sodium content and volume of body water (or critical component thereof) below which further reduction results in hypotension".
It is fair to say that the early efforts to achieve the optimal control of blood pressure and to maintain dialysis patients as close as possible to "dry weight" have been relaxed with time.  This led one nester of clinical nephrology to pose the bitter question "Volemia and blood pressure in renal failure: have old truths been forgotten?" 
2. Determinants of blood pressure in dialyzed patients
Mean pressure and pulse pressure
Static blood pressure (BP) in a circulatory system is given as the product of cardiac output (CO) and total peripheral resistance (TPR), i.e. BP=CO x TPR. This formula describes mean arterial pressure, which increases proportionally to the cardiac output and total peripheral resistance.
However, blood pressure is not static. During the cardiac cycle there are pulsatile changes of pressure which were underestimated in the past. The instantaneous changes of pressure during the cardiac cycle are to a large extent determined by (i) the elasticity of central arteries as well as (ii) the superimposition of outgoing pulse wave and reflected pulse wave (augmentation) respectively; for further details the reader is referred to recent reviews.  '  In brief, the stiffer the aorta, the greater the peak systolic pressure and the more pronounced the decrease in diastolic blood pressure [Figure - 1]. Furthermore, during the cardiac cycle the outgoing pulse wave is reflected in the periphery. The returning wave normally arrives in the aortic root during diastole, thus increasing diastolic pressure and augmenting coronary perfusion during diastole. When the aorta is stiff, however, the returning wave arrives earlier, i.e. during systole thus augmenting the peak systolic pressure as well as the wall stress and myocardial oxygen consumption. The large blood pressure amplitude (pulse pressure) is a simple clinical sign that indicates the increased stiffness of the aorta, i.e. diminished aortic compliance. Furthermore, the large blood pressure amplitude is an independent predictor of cardiovascular risk and death. There is a striking analogy between uremia and ageing, both of which are associated with increased aortic stiffness, increased aortic pulse wave velocity and increased blood pressure amplitude. Some authors even have considered uremia as a state of "accelerated ageing".
3. Blood pressure in uremia:
Guyton was the first to point to the overriding role of hypervolemia in the genesis of hypertension of renal failure. In the patient with renal disease, retention of sodium and water increases venous return and cardiac output. This tends to raise the mean arterial pressure (unless it is acutely compensated by the counter-regulatory vasodilatation with reduction of peripheral resistance). The increase in the cardiac output will cause hyperperfusion of tissues.
To prevent the hyperperfusion, vasoconstriction ultimately ensues after days to weeks. This process is poorly understood and is called "autoregulation". It normalizes tissue perfusion, but at the price of elevated mean arterial pressure [Figure - 2]. The delayed occurrence of this reaction is important, since it may explain why changes of volemia in dialyzed patients take considerable time (lag phenomenon) to translate into increases or decreases of blood pressure. Although these patients no longer have peripheral edema, hypervolemia is a major determinant of blood pressure in dialyzed patients as demonstrated for instance by Katzarski. He compared the normotensive patients in the French dialysis center, Tassin, with normotensive and hypertensive Swedish patients in Stockholm. The indices of blood volume and extracellular volume were comparable in the patients of Tassin and the normotensive patients of Stockholm, whilst these indices were clearly elevated in the hypertensive patients of Stockholm. In the center of Tassin, particular efforts are made to avoid hypervolemia (see below). It is remarkable that the prevalence of hypertension in dialyzed patients in Tassin is even lower than in the French general population. This presumably indicates that patients are in a state of slight salt depletion. It is remarkable that despite increased norepinephrine and angiotensin II concentrations the total peripheral resistance is low. This is reminiscent of what is seen in Bartter's syndrome or the hypertensive patients treated with diuretics.
Hypervolemia is necessary, but not sufficient to explain the increase of the blood pressure in renal patients, since normotension despite hypervolemia is seen in some hyper circulatory states, e.g. pregnancy or anemia.
Clearly, the total peripheral resistance in the renal patients must be inappropriate to the volume state and the level of blood pressure. Several mechanisms may cause such increase in the vascular resistance, both functional and structural [Table - 1].
In many renal patients, the plasma renin activity is inappropriately high  and there is a good experimental evidence  that the local renin system in the vessel wall is activated in renal failure as well.
Studies using microneurography clearly documented sympathetic overactivity in the dialyzed patients unless they had undergone bi-nephrectomy.  Sympathetic overactivity is triggered by the afferent arterial signals emanating from the diseased kidney, but there is also interaction between the renin angiotensin system and the sympathetic nerve systems. 
Furthermore, there is convincing recent evidence that in uremic patients vasodilatation is inappropriate, particularly in response to acetylcholine. This finding reflects diminished release or action of nitric oxide (NO); , this may or may not be related to the accumulation of circulating inhibitors of NO synthetase, particularly asymmetric dimethyl-L-arginine (ADMA). ,,,,
The central elastic arteries and the peripheral arterioles (resistance vessels) show striking structural abnormalities in renal failure [Figure - 3] as discussed in detail elsewhere.  Whilst the former is responsible for the impaired elasticity, the latter may contribute to the maintenance of elevated vascular resistance and interfere with the vasodilatory reserve of the heart in response to the increased oxygen demand.
There are additional problems, which may impact on the control of blood pressure (BP), such as erythropoietin (EPO) therapy with exhypoxic vasoconstriction,  hyperparathyroidism,  or hypercalcemia.  Recently attention has also been drawn to the marked seasonal variation of blood pressure in the dialyzed patients; blood pressure tends to be higher during winter and lower during summer. 
There are also marked abnormalities of the circadian blood pressure profile, which have become apparent after the introduction of the technique of ambulatory blood pressure measurement (ABPM). Even in the early phase of renal disease, there is attenuation of the decrease or even an increase of blood pressure during night-time.  The frequency of the sleep apnoea syndrome is also higher in the dialyzed patients; this is associated with a nocturnal increase in blood pressure. 
ABPM data show that BP in the interdialytic interval is more closely related to post-dialysis BP; it tends to increase during dialysis sessions independent of the acute interdialytic volume increase and to rise particularly in the hours preceding the next dialysis session. 
4. Blood pressure response to volume subtraction
Volume subtraction tends to decrease plasma volume, a tendency that is counteracted by "refilling", i.e. translocation of volume from the extracellular to the intravascular space. The rate of the latter process shows considerable inter-individual variation and is markedly dependent on the patient's volume state: the more hypervolemic the patient is, the more rapid is the rate of refilling. When patients come close to dry weight, the refilling rate decreases and the patients are more prone to develop hypotension.
Hypovolemia induces counter-regulatory mechanisms; presumably, sympathetic activation is the most important. Sympathetic activation causes an increase in cardiac output thus creating a new steady state. If compensation cannot be reached there will be progressive sympathetic activation until vasovagal syncope sets in.  This is a reflex response (Betzold Jarisch reflex), which occurs when the left ventricle is "pumping empty".
Another important determinant of intradialytic hypotension is left ventricular (LV) hypertrophy and left ventricular fibrosis. Stiff hypertrophied and fibrotic left ventricles require higher diastolic filling pressures. As a result, when left atrial pressure decreases during ultrafiltration, patients with LV hypertrophy and reduced LV compliance are prone to develop intra-dialytic hypotension. This explains the observation of Ruffmann  who found a correlation between diastolic transmitral filling velocity (an index of LV compliance) and the frequency of intradialytic hypotensive episodes. Such hypotensive episodes are a potential predictor of cardiac death. 
There are other factors that modulate ultrafiltration tolerance, particularly dialysate temperature, as reviewed in detail elsewhere. 
Of particular importance is the fact that ultrafiltration tolerance is strikingly diminished when patients are on antihypertensive medication. One of the secrets how "dry weight" can be reached is to gradually wean patients from antihypertensive medication (see below).
5. Epidemiological surveys on blood pressure
According to the United States Renal Data System (USRDS),  pre-dialysis blood pressure is above 150 mm Hg systolic in 53% and above 90 mm Hg diastolic in 17% of the patients. As in the elderly, the most frequently encountered type of hypertension is isolated systolic hypertension. The underlying pathomechanism are explained above.
In the ongoing Deutsche Diabetes Studies,  the effect of statines is studied in type 2 diabetic patients on dialysis. The blood pressure values of patients in this study are given in [Table - 2]. If the strict new criteria of the ISH (International Society of Hypertension)/WHO (World Health Organisation) for optimal blood pressure are applied,  i.e. BP 130/85 mm Hg, less than 25% of these dialysed type 2 diabetic patients are strictly normotensive.
Such worldwide data on blood pressure in dialysis patients are in striking contrast to what has been reported from Tassin,  where less than 5% of the patients required antihypertensive medication and the median of the mean arterial blood pressure (MAP) was 97 mm Hg. Similar findings have been reported from Manchester, another center that adopted long slow dialysis sessions, where the average blood pressure was 117/68 mm Hg by ABPM and only 7.4% of the patients required antihypertensive medication. 
6. Correlation between blood pressure on dialysis and outcome
In a retrospective multicenter analysis on 5,433 patients dialyzed in several centers in the USA, Zager  found that pre-dialytic blood pressure values in the range of 130180 mm Hg, i.e. high BP values, had little power to predict all cause mortality or cardiovascular mortality during a 2-3 year follow-up. Based on the USRDS data, this finding was confirmed by Port et al  and others. 
In contrast, when the pre-dialysis blood pressure values were below 120 mm Hg systolic, a dramatic increase of short-term mortality was noted [Figure - 4].
These observations have caused considerable uncertainty and have led to concern that aggressive lowering of BP may paradoxically increase cardiovascular mortality and thus be counterproductive. This argument requires careful analysis and discussion.
In a retrospective single center analysis, Charra  showed that a progressive difference in patient survival became apparent in patients treated with long slow dialysis sessions and average pre-dialytic blood pressure values in the normotensive range [Figure - 5]: when patients with average predialysis mean arterial pressure (MAP) values above and below the median of 97 mm Hg (e.g. approximately 130/70 mm Hg) were compared, progressive survival benefit was seen in patients who had low blood pressures. It is also of note that it took 5-years before the difference in survival was demonstrable. In this population, antihypertensive treatment was required in less than 5% of patients after three months of dialysis, i.e. hypertension was less frequent than in the background population. 
The reported survival rates  were considerably better than those of major registries and this may well be related to the procedure of long slow dialysis, since similar results have also been reported from centers in Manchester  and Auckland-New Zealand, which adopted a similar treatment strategy.
Is low normal blood pressure good or bad?
In discussing these apparent discrepancies ,, several points have to be considered. In the general population, many studies showed that mortality was consistently higher in patients who had low blood pressure values at baseline. This was mainly interpreted as evidence of impaired cardiac function, but it is also noticeable that higher mortality was associated with lower blood pressure values even in patients with Alzheimer's disease. Of particular interest is the time course. In the HDFP study, excess mortality in patients with low blood pressure was found in the first three years of observation. Subsequently, however, presumably after cardiac patients at high risk had died, a monotonous continuous positive relationship between blood pressure and mortality was noted.
Second, the Framingham study showed that in the general population the beneficial effect of lowering blood pressure does not become apparent before the 10 th year of observation. Conversely, in patients with essential hypertension, particularly in the younger individuals, it takes several decades before increased mortality becomes apparent, as documented by the data of the Metropolitan Life Insurance Company. This is definitely of relevance in view of the observation of Charra , that the survival benefit in patients with lower blood pressure is demonstrable only after the 51 year of dialysis. Apparently the reversal of blood pressure dependent cardiovascular excess mortality takes longer than reversal of hyperlipidemia by statines, where a benefit of lipid lowering is apparent much more rapidly.
We propose the hypothesis that high mortality in patients with low predialysis blood pressure represents a case of reverse causality. Once cardiac function of the patients with a history of uremia has been markedly compromised by hypertension and coronary heart disease, a sufficiently high blood pressure can no longer be generated secondary to the impaired pumping function.
Accordingly, a paradoxical inverse relation will be observed: the lower the blood pressure, the higher the mortality; although in the remote past hypertension was an active player contributing to the cardiac damage. This interpretation has gained support by some recent preliminary observations. In Uruguay,  low blood pressure was indicative of higher mortality in patients starting dialysis, but only during the 1st year of observation. Subsequently, a continuous positive correlation between blood pressure and mortality was seen. The same was indicated by the preliminary results of a multicenter prospective incipient cohort study.  Initially, a negative correlation was observed between systolic blood pressure and mortality, subsequently a monotonous positive correlation was noted between systolic blood pressure and mortality.
Having said this, one must acknowledge some specific aspects of hemodialysis, which may render low blood pressure undesirable and potentially injurious, e.g. impaired fistula flow and fistula thrombosis.
Furthermore, patients who continue dialysis with low blood pressure are frequently intolerant to ultrafiltration. With higher rates of ultrafiltration, the rate of loss of plasma volume exceeds the rate of refilling and intense sympathetic activation occurs, which is obviously particularly undesirable in the presence of impaired cardiac function.  Such intense activation of the counter-regulatory presser systems may explain the paradoxical hypertensive crisis that may occur during ultrafiltration, as long as patients continue to be hypervolemic. 
Another important aspect deserves comment. As discussed above, systolic blood pressure tends to be higher than diastolic blood pressure so that the blood pressure amplitude is increased. Lower diastolic blood pressure is by no means a benign condition, but may reflect increased aortic stiffness or atherosclerosis of the aorta. In the general population, low diastolic pressure is a predictor of cardiac death.  Blacher et al , have recently documented that the pulse wave velocity, an index of reduced vascular elasticity and frequently associated with high blood pressure amplitude, is a powerful predictor of death in hemodialysis patients; interestingly, the systolic blood pressure was not predictive in contrast to other  observations. Because of the time lag of several years before the beneficial effect of low blood pressure on survival becomes apparent [Figure - 5], the two observations are not necessarily in conflict. The observation of Blacher emphasizes, however, that mean arterial blood pressure alone does not provide a completely comprehensive index of the risk that results from altered hemodynamics. It is hoped that the indices of the central hemodynamics, e.g. the pulse pressure profile or measurements of vascular stiffness, will become available to the clinician and prove useful to identify high-risk patients.
7. Some practical points on patient management
Medicine is a science of probability and an art of uncertainty (Sir William Osier).
The need for the meticulous control of blood pressure that was emphasized by the pioneers of hemodialysis is currently no longer sufficiently appreciated. Today's dialysis strategies, particularly short dialysis sessions, deviate markedly from the procedures used by the pioneers; blood pressure control has become much more difficult than in the early days of dialysis. Logistics and economic pressures make it impossible to go back to the roots and adopt the old techniques. However, there is sufficient evidence that some relatively simple procedures, particularly induction of a negative sodium balance  permit effective lowering of blood pressure, even when the original gold standard of long slow dialyses  '  is not adopted.
What are the most important points?
First, it is obvious that hypervolemia must be avoided. The single most frequent omission is the failure to instruct the patient to reduce his sodium chloride intake. Not many dialysis physicians realize that ingestion of nine grams of sodium chloride per day will force the anuric patient to drink one litre of water per day; there is no way to resist the thirst provoked by the increased osmotic pressure that results from high salt intake. The patient will be forced to drink water until the dietary salt has been "diluted" to produce isotonic saline. The average sodium chloride intake in the region of Heidelberg is 14 g/day. The conclusion is obvious.
Second, the dialysate sodium concentration should be somewhat lower than the plasma sodium concentration to account for the Donnan effect. Because of the presence in the plasma of polyanionic plasma proteins, a protein-free fluid with lower sodium concentration is in thermodynamic equilibrium with protein-containing plasma in which the sodium concentration is higher by several millimoles. It has also been shown that slow step-wise lowering of dialysate sodium concentration by approximately 1 mmol/3 weeks  is well tolerated and permits gradual lowering of blood pressure in the majority of patients without major side effects. ,
Third, it is absolutely indispensable that antihypertensive agents are gradually withdrawn because dry weight cannot be attained by ultrafiltration as long as the patient is on antihypertensive agents. This tenet, of course, does not preclude the use of antihypertensive medication for reasons other than blood pressure lowering, e.g. beta blockers for prevention of cardiac arrhythmia  or ACE inhibitors for reversal of left ventricular hypertrophy. 
One should adopt the strategy of gradually increasing the intensity of ultrafiltration until "dry weight" is reached. Recognition whether the point of "dry weight" has been reached or not is difficult, because there are no easily available clinical indicators. Consequently, one has to resort to the somewhat unsatisfactory process of trial and error. The secret is patience. One should aim for this goal in the course of weeks and months and not days. For patients with poor ultrafiltration tolerance, ancillary measures, e.g. lowering of dialysate temperature or, if logistics permit, prolongation of the duration of dialysis sessions or additional sessions, e.g. 4 times per week, may be helpful. As shown in [Table - 3], the lowering of blood pressure with daily hemodialysis is particularly impressive.  A recent direct comparison shows that longer dialysis sessions lower blood pressure, independent of changes in the volume state.  Removal of pressor agents or, more likely, endogenous inhibitors of vasodilatation1 ,, would be a plausible mechanism.
There are patients who do not tolerate aggressive ultrafiltration. In our opinion, although every effort should be made to attain the dry weight, episodes of intradialytic hypotension must not be accepted.
In our prospective study  the risk of cardiovascular death was higher by a factor of 2.8 if hypotensive episodes occurred in dialyzed type 2 diabetic patients. Needless to say that medical causes explaining ultrafiltration intolerance, e.g. cardiac failure, liver failure, valvular heart disease, arrhythmia, etc., should be looked for, diagnosed and managed appropriately. If this is not sufficient, compromises will have to be made on an individual basis.
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Department of Internal Medicine, University of Heidelberg Bergheimer Str. 56a D- 69115 Heidelberg
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]
[Table - 1], [Table - 2], [Table - 3]