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Hemodialysis International 2006; 10:241–248 Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, The relationship of hypertension with adverse outcomes is uncertain in the hemodialysis population.
If hypertension is an etiologically significant cardiovascular risk factor in hemodialysis patients, thefirst step would be to assess the level of BP accurately. BP obtained at home over a week andaveraged using a validated oscillometric automatic device can prove valuable. To the extent BPlowering influences cardiovascular outcomes, home BP of 150/90mm Hg would warrant therapy,since it correlates with target organ damage and hypertension diagnosed by ambulatory BPmonitoring. To manage hypertension, limiting dietary sodium intake and individualizing dialysatesodium delivery would be first steps. The magnitude of reduction in BP with dietary sodiumrestriction and the whether dialysate sodium can be safely limited in those who are hypotension-prone is unclear. Antihypertensive drug therapies can effectively reduce BP and are needed by thevast majority of hemodialysis patients. Whether control of hypertension translates into betteroutcomes is not known, but collective evidence suggests that hypertension should be controlledin hemodialysis patients.
Keywords: hypertension, hemodialysis, end-stage renal disease, home BP monitoring, ambulatoryBP monitoring.
velop a rational approach to evaluation and managementof BP. Available evidence suggests that hypertension Guidelines on the management of hypertension in hemo- should be treated in hemodialysis patients.5 The purpose dialysis patients have been impeded because of cohort of this review is to develop a clinical approach to the studies that show ‘‘reverse epidemiology’’ of hypertension management of hypertension in hemodialysis patients.
in the hemodialysis population. In contrast to the clear In a survey of 2535 hemodialysis patients from 69 di- evidence of a continuous, graded, and etiologically sig- alysis units in the United States, the prevalence of hyper- nificant relationship of hypertension with cardiovascular tension was 86%.6 Although many patients received morbidity and mortality in the general population,1 stud- antihypertensive drugs, only 30% had well-controlled ies in hemodialysis patients show that those with the BP, 58% had poorly controlled BP, and 12% had untreat- highest blood pressure (BP) have the best survival.2–4 ed hypertension. These findings underscore the appro- There are numerous reasons why this may be so that I priate recognition of high BP in hemodialysis patients, have discussed elsewhere,5 but the question for those en- but poor control despite use of multiple medications.
trusted with the care of hemodialysis patients is to de- When ambulatory BP monitoring was used to assess hypertension control in a hemodialysis population, theprevalence of systolic hypertension was 73%.7 When an Correspondence to: R. Agarwal, MD, Associate Professor of unselected hemodialysis population from the same center Medicine, Indiana University and VAMC, 1481 West 10thStreet, Indianapolis, IN 46202, U.S.A.
was evaluated, the prevalence of systolic hypertension was 37%.8 These data suggest the possibility that hyper- r 2006 The Authors. Journal compilation r 2006 International Society for Hemodialysis tension may not be accurately assessed in the general In a systematic review,15 we have found that predialysis systolic BPs generally overestimated ambulatory BP by avariable amount. The heterogeneity between BP differ- ences between dialysis unit BP and ambulatory BP did notallow for pooling the estimates. The agreement limits be- tween the 2 BPs was wide (between 41.7 and There are 3 ways in which we can assess the level of BP in À 25.2 mmHg). Predialysis diastolic BP also generally a hemodialysis patient. Blood pressure can be obtained overestimated the ambulatory BP with wide agreement during, before, and after dialysis by the dialysis staff, at limits (23.7, À 18.9 mmHg). Postdialysis BPs underesti- home by the patient, or by an automatic ambulatory BP mated average ambulatory BP with wide agreement limits monitor. The value of each of these techniques has been for both postdialysis systolic (33.1, À 36.3 mmHg) and diastolic BPs (19.3, À 23.9 mmHg). Thus, dialysis unitBP measurements are imprecise estimates of ambulatory BPs. The recent National Kidney Foundation K/DOQIguidelines suggest that predialysis and postdialysis BPs Single recordings of BP either before or after dialysis are should be o140/90 and o130/80 mmHg, respectively.16 often used to make clinical decisions. Generally, these BP These results fail to provide solid data to back the K/ are not obtained using standard procedures.9 Both pre- DOQI guideline recommendations regarding BP goals in dialysis and postdialysis BP are useful in assessing BP.10 hemodialysis patients. Better methods are needed for the However, these BP need to be obtained over 2 weeks and assessment of BP in hemodialysis patients for clinical de- averaged. Even then, the data are useful only in a qual- itative sense and cannot be used to predict ambulatory BPwith any degree of accuracy.7 The correlation of such ‘‘routine’’ measurements of BP with ambulatory BP7,8 andmore importantly target organ damage11 is weak. As BP As BP tends to vary over the course of the week depend- falls with dialysis, it is little surprise that the threshold for ing in part on the intravascular volume status, several diagnosing hypertension using predialysis BP is higher measurements should be used to better assess hyperten- than postdialysis BP.7,8 Whether both BP can provide an sion in hemodialysis patients. This is possible readily with incremental value in diagnosing hypertension is less cer- home BP monitoring, which is a useful alternative to as- tain, although preliminary data suggest that both may be sess BP and has been incorporated into national guide- lines for the assessment of hypertension.13 This method is Owing to environmental hazards of mercury, mercury attractive as the peaks and valleys of BP that a typical sphygmomanometers are fast disappearing and will soon hemodialysis patient experiences are captured to obtain a be obsolete. Although there has been a reluctance in us- time-averaged value. Thus, the approximate barometric ing oscillometric devices in hemodialysis patients, the use load is better reflected by these measurements at home. In of validated, automatic, oscillometric sphygmomanome- a study of nearly 150 patients at one center, BP obtained 3 ters using standard methods13 is a good clinical practice.
times daily at home for 1 week, and averaged, correlated We have evaluated one such oscillometric BP measure- better with ambulatory BP8 and target organ damage as ment device (HEM 907, Omron Healthcare, Bannock- assessed by left ventricular hypertrophy.11 This study burn, IL, U.S.A.) and have found it to perform well in demonstrated that home BP obtained in the morning, af- hemodialysis patients.14 Standardized measurements of ternoon, and evening for 1 week is feasible, even in a BP around dialysis correlate better with ambulatory BP8 relatively uneducated population.8 When these BP ob- tained at home over a week are averaged, a BP level of 4120 mmHg systolic obtained immediately following di- 150/90 mmHg or more was found to be the best deter- alysis using a standard technique and averaged over 2 minant of an awake ambulatory BP of 135/85 mmHg that weeks has a good sensitivity and specificity in making a is considered hypertensive in the general population.8 diagnosis of hypertension in these patients.8 The problem The diagnostic performance characteristics of home BP of obtaining such measurements due to time constraints monitoring are superior to BP obtained in the dialysis is self-evident. Even if BP were to be uniformly obtained unit in determining ambulatory BP and left ventricular using standard techniques, there is little relationship with hypertrophy.11 Thus, home BP monitoring can comple- echocardiographic left ventricular hypertrophy.11 ment the assessment of hypertension in hemodialysis Hemodialysis International 2006; 10:241–248 changes in BP with the administration of erythropoie- tin,24 ABPM was able to detect a rise in overall BP with just 13 patients.25 When ABPM was compared with home BP monitoring, again, ABPM was found to be more sen- sitive in detecting an increase in BP with erythropoietin.26 We have exploited the reproducibility and sensitivity of ABPM in detecting antihypertensive effects of water-sol- 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10 11 uble antihypertensive drugs administered to hemodialysis patients 3 times weekly using only a small number of Figure 1 Twenty four-hour ambulatory blood pressure (BP) recording in a patient with chronic kidney disease. Blood Ambulatory BP monitoring is required for the diagno- pressures are plotted against time over 24 hr. The gray shad- sis of the white coat effect. The white coat effect is the ed area between 22:00 PM and 06:00 AM represents the sleep elevation in BP due to alerting reactions in the office set- time. The dotted lines are placed at 135 and 85 mmHg, in- ting in patients who have preexisting hypertension. Mitra dicating the threshold over which the average ambulatory BPis considered high. It is obvious that the patient has systolic et al. have compared interdialytic ABPM with BP obtained hypertension. There is no decline during sleep in this pa- in hemodialysis patients at arrival to the dialysis unit, af- ter 10 min of rest in a quiet room and at other timepoints.29 The authors reported that BP on arrival to thehemodialysis unit was 420/10 mmHg higher than that in patients. Perhaps, shorter periods of home BP monitoring the previous 6 hr recorded by ABPM in 15 of 36 (41%) would provide valuable information as well, but will need patients. Even after resting for 10 min, BP was elevated in to be evaluated in prospective studies.
19% of the patients, suggesting a true white coat effect.
This study suggests that the white coat effect may be common in hemodialysis patients. By comparison, in apopulation of elderly patients with hypertension but Ambulatory BP monitoring involves wearing a small de- without kidney disease, white coat hypertension was seen vice usually hooked to the belt that is connected via a in 13%; these patients had a cardiovascular prognosis that hose to a BP cuff around the arm. The device automat- was similar to well-controlled hypertension.30 ically inflates at 20–30 min intervals while the patient Ambulatory BP has been used to predict cardiovascular goes about his usual activity, and records this in its mem- outcomes in hemodialysis patients in 2 studies. The first ory. The recordings can then be downloaded to a com- study of Amar et al. found a strong relationship of am- puter and analyzed. An ambulatory BP recording over bulatory pulse pressure with total mortality.31 The second 24 hr in a subject without dipping is shown in Figure 1.
study from Zocalli’s group found that the night/day Studies utilizing ABPM have demonstrated that hemo- systolic BP ratio, an index of dipping, was the sole BP dialysis patients do not experience lower BP at night, i.e., indicator associated with all-cause and cardiovascular have a high prevalence of ‘‘nondipping.’ 17–20 This phe- mortality.32 Echocardiographic left ventricular hypertro- nomenon of nondipping cannot be detected by other phy was similarly a predictor of these outcomes. These methods and provides a more accurate estimate of the BP results suggest that nondipping and left ventricular burden—also called ‘‘BP load’’—on the cardiovascular hypertrophy provide overlapping prognostic information system.21 Whereas in individuals with essential hyper- that is compatible with the hypothesis that they represent tension nondipping is associated with left ventricular common pathophysiological pathways for cardiovascular hypertrophy, strokes, and cardiovascular morbidity and mortality, in patients on hemodialysis, nondipping is as-sociated with reduced arterial distensibility22 and systolic hypertension to left ventricular hypertrophy.11 Because of numerous readings obtained by ABPM and Most patients on hemodialysis have systolic hypertension the lack of alerting reactions, there is excellent reproduc- that may or may not coexist with diastolic hyperten- ibility between days when duplicate readings are per- sion.33 In fact, isolated diastolic hypertension is rare.8 formed.23 Ambulatory BP monitoring is also more JNC 7 guidelines designate systolic BP as the primary sensitive to change with interventions. For example, treatment target in people above 50 years.34 Most dialysis whereas routine BP monitoring failed to demonstrate patients are elderly and even the younger ones have the Hemodialysis International 2006; 10:241–248 vascular age of healthy people who are older. A direct interdialytic weight gain (2.9 vs. 2.3 kg; po0.001), in- relationship between systolic BP and total mortality and terdialytic thirst scores, and episodes of intradialytic hy- systolic BP and cardiovascular events has emerged in the potension in the individualized Na period. Pre-HD BP hemodialysis population.35 An inverse relationship be- was lower by 15.6/6.5 mmHg in individualized Na HD in tween diastolic BP and these hard end-points is seen.35 As patients with uncontrolled BP at baseline. These data pulse pressure is the difference between systolic and di- suggest that lowering dialysate Na based on predialysis astolic BP, it is not surprising that pulse pressure is an plasma Na level may reduce interdialytic weight gain, excellent marker of total mortality in hemodialysis pa- tients.35,36 When pulse pressure and systolic BP are com-pared, Tozawa et al. found that systolic BP is a superior determinant of cardiovascular and total mortality.35 Thus,it appears reasonable to target systolic BP.
The majority of patients with end-stage renal disease(ESRD) on chronic dialysis undergoing standard three times a week treatment need antihypertensive drug therapy.6,38 Several classes of antihypertensive drugs areavailable and all except diuretics are effective in control- ling hypertension in hemodialysis patients. The selectionof these agents requires consideration of the comorbidi- Fluid restriction is often prescribed for hemodialysis pa- ties, pharmacokinetics, and hemodynamic effects of these tients, but is without physiologic rationale. Free water agents. For example, in patients with left ventricular restriction is a therapeutic option for hypo-osmolar states, hypertrophy, angiotensin converting enzyme (ACE) in- not volume overload. A more appropriate therapy for hibitors may be effective in causing regression, although these patients would be to restrict dietary sodium intake.
the trial sizes have been limited.39,40 Calcium-channel A 2-g sodium diet is commonly recommended. If the pa- blockers (CCBs) are the most widely prescribed class of tient follows the 2 g sodium diet, an interdialytic weight drugs in patients on hemodialysis.6,41 Calcium-channel gain of 1.25 kg would be expected over 2 days or 1.9 kg blockers appear to be more effective when the plasma over the weekend. Only rarely do dialysis patients achieve volume is expanded. As hypertension in hemodialysis such small interdialytic weight gains. Limiting weight patients is thought to be largely a result of volume ex- gain would mitigate the large swings in BP and may ease pansion, these agents may have a unique advantage in the intradialytic hypotensive symptoms.
ESRD.42 Both dihydropyridine43–45 and nondihydropri- Another, perhaps less recognized, source of sodium dine calcium channel blockers have unaltered pharmaco- excess is the dialysate sodium prescription. In a patient kinetics in patients with ESRD on hemodialysis and have who weighs 72 kg, the total body water is estimated as little dialyzability,46,47 and therefore require no dose 43 L. If predialysis sodium concentration is 135 mEq/L modifications. Sustained-release verapamil could control and the patient is dialyzed against 145 mEq/L, an esti- BP in 21 of 28 hypertensive ESRD patients.48 Futher- mated 10 mEq/L Â 43 L or 430 mEq Na will be delivered.
more, a single dose of 40 mg oral verapamil given before This will be roughly equivalent to a 3 kg interdialytic hemodialysis to 10 patients with left ventricular hyper- weight gain. Individualizing sodium prescription in such trophy did not aggravate intradialytic hypotension.49 Pre- patients may be useful and data point to the usefulness of liminary studies with verapamil have even suggested a such a strategy in lowering BP in hypertensive subjects.
reduction in intradialytic hypotension.50 To evaluate the hypothesis that individualizing dialy- Angiotensin converting enzyme inhibitors and beta- sate sodium prescription limits interdialytic hyperten- blockers appear to be attractive agents due to their inde- sion, de Paula et al. performed a cross-over study in 27 pendent cardiovascular benefits. I have tested the utility nondiabetic, nonhypotension-prone hemodialysis pa- of an antihypertensive agent from each class administered tients.37 In a cross-over design, subjects underwent 9 after dialysis in a supervised manner 3 times weekly consecutive HD sessions with the dialysate Na concen- to assess the safety and efficacy of these drugs. Atenolol, tration set to 138 mEq/L, followed by 9 sessions wherein a water-soluble, renally excreted beta-blocker, was pres- the dialysate Na was individualized. To individualize di- cribed in 8 hemodialysis patients not receiving any alysate Na, patients average pre-HD plasma Na was meas- antihypertensive drugs.27 The half-life of atenolol is pro- ured 3 times during the standard Na phase and longed in ESRD; therefore, I reasoned that 3 times weekly multiplied by 0.95. There was a significant decrease in administration would suffice. Furthermore, atenolol is Hemodialysis International 2006; 10:241–248 removed by hemodialysis; intradialytic hypotension hemodialysis patients.55 A multicenter, open-label, 6- would be mitigated during the time of hemodynamic month study was performed in 406 patients to test the stress. After confirming hypertension by ABPM, patients tolerability and efficacy of losartan in patients on hemo- were administered atenolol 25 mg following hemodialysis dialysis.56 Fifteen patients discontinued the study owing and the dose of the drug was escalated at weekly intervals to adverse reactions related to losartan, and in 7 of them to 50 mg and finally 100 mg 3 times a week. The efficacy the adverse reaction was hypotension. In 2 patients, a of therapy was judged by ambulatory BP monitoring 3 possible anaphylactoid reaction was reported after dialy- weeks after instituting atenolol therapy. The mean 44-hr sis with an AN69 membrane, necessitating termination of ambulatory BP reduced from 144/80 to 127/69 mmHg dialysis and losartan in one patient. In contrast, 9 patients (po0.001). The systolic and diastolic BP loads were re- with a history of previous anaphylactoid reaction with ACE inhibitor and AN69 did not show this complication (po0.001). There was a persistent antihypertensive ef- with losartan and AN69. Thus, losartan is a well-tolerated fect over 44 hr. The BP reduction was achieved without antihypertensive in hemodialysis patients, with a very low any increase in intradialytic symptomatic or asymptomat- incidence of adverse reactions, and a lower incidence of ic hypotensive episodes, reduction in delivered dialysis, anaphylactoid reactions than those detected with ACE or statistically significant changes in serum potassium or Several other options are available to control hyperten- I have also assessed the antihypertensive effects of lis- sion. For example, transdermal clonidine applied at inopril, a renally excreted ACE inhibitor administered 3 weekly intervals can improve hypertension control.57 In times weekly following dialysis.28 Lisinopril was titrated addition, minoxidil, a potent vasodilator, is effective for at biweekly intervals at 10, 20, or 40 mg doses. If this was hypertension control.58 However, it should be used with not effective after full titration (lisinopril to 40 mg 3 times beta-blockers to maintain efficacy. The side-effects of hir- weekly), ultrafiltration was added to reduce dry weight.
suitism, pericardial effusion, and edema should be care- The primary outcome variable was the change in BP from the end of the run-in period to the end of the study.
No change in mean ambulatory BP was noted during a 2-week run-in period. However, the average 44-hr am-bulatory BP declined from 149/84 to 127/73 mmHg, a To what level BP should be lowered and how is not decline of 22/11 mmHg (po0.001) at final evaluation.
known. The National Kidney Foundation K/DOQI guide- Four patients received 10 mg, five 20 mg, and two 40 mg lines suggest that predialysis and postdialysis BPs should lisinopril, of which only one required ultrafiltration ther- be o140/90 and o130/80 mmHg, respectively.16 How- apy. There was a persistent antihypertensive effect over ever, these guidelines are opinion based. Although obser- 44 hr. Blood pressure reduction was achieved without vational studies suggest a mean arterial pressure of any increase in intradialytic symptomatic or asymptomat- o99 mmHg to be associated with best survival, these pa- ic hypotensive episodes. Therefore, supervised lisinopril tients have long-hours hemodialysis unlike most patients therapy was effective in controlling hypertension in in North America. Lowering BP too much may make fluid chronic HD patients. Some studies have shown that removal during dialysis difficult and may increase the ACE inhibitors induce erythropoietin resistance.51,52 A discomfort associated with dialysis. On the other hand, small peptide, n-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), by reducing BP to a lower level, a cardiovascular benefit is a physiological inhibitor of hematopoiesis and is degraded may be realized. The balance between risks and benefits by ACE. Accumulation of AcSDKP occurs in ESRD patients, will need to be addressed in randomized-controlled trials.
and particularly in those treated by ACE inhibitors and may Operationally, an ideal BP in a hemodialysis patient partly explain erythropoietin hyporesponsiveness in ESRD would be associated with hemodynamic stability during patients.53 In patients treated with ACE inhibitors, a high dialysis, orthostatic tolerance after dialysis, the best car- incidence of anaphylactoid reactions has been reported dur- diovascular survival, and optimal health-related quality of ing dialysis with AN69 membranes due to bradykinin gen- life. Although some of these goals can be achieved by di- eration.54 Thus, ACE inhibitors should not be used in etary and dialysate sodium restriction to reduce the am- plitude of BP fluctuations, additional factors must be Angiotensin II receptor blockers are also effective in considered. For example, the amplitude of fluctuations hemodialysis patients. The pharmacokinetics of losartan in BP for a given level of volume expansion would depend have been carefully examined and remain unaltered in on the vascular compliance. The tolerance to hemodial- Hemodialysis International 2006; 10:241–248 Table 1 Guidelines on assessment and treatment of hypertension in hemodialysis patients Assessment of hypertensionUse standardized measurements where possibleUse standard equipment. Oscillometric technique may work wellAverage several readings: 2 weeks preferableBoth predialysis and postdialysis BP are usefulHome BP is an excellent alternative to assess BP. It correlates best with ABPM and LVHTreatment of hypertensionDialysate and dietary sodium restriction is usefulAssess dry weight accuratelyDrug therapies: lisinopril or atenolol has the advantage of long half-lives and can be administered 3 times weekly after dialysis ABPM = ambulatory BP monitoring; BP = blood pressure; LVH = left ventricular hypertrophy.
ysis would then not only depend on the extent of volume (left ventricular hypertrophy) and hypertension diag- excess (sodium intake) but also the cardiovascular state.
nosed by ambulatory BP monitoring. To manage hyper- Thus, a patient with diastolic dysfunction and left ven- tension, limiting dietary intake, and individualizing tricular hypertrophy who requires larger filling pressures dialysate sodium delivery would be the first steps. The to maintain an adequate cardiac output may become magnitude of reduction in BP with dietary sodium re- hypotensive despite minimal fluid shifts. As left ventricu- striction and whether dialysate Na can be limited in those lar hypertrophy is associated with arterial stiffness, intra- who are hypotension prone is unclear. Antihypertensive drug therapies can effectively reduce BP and are needed interdialytic hypertension. Accordingly, it is likely that by the vast majority of hemodialysis patients. Whether tolerance to BP goals will vary by cardiovascular comor- control of hypertension translates into better outcomes is bidities. If there is a true association between hyperten- not known, but collective evidence suggests that hyper- sion and cardiovascular disease in hemodialysis patients, tension should be controlled in hemodialysis patients.
then the lowest possible home BP that is associated withleast symptoms on dialysis and best quality of life may be a prudent goal. This BP goal would need to be individ-ualized. As a home BP of 4150/90 mmHg correlates with This work was supported by grant number 5RO1-NI- hypertension detected by ABPM, BP targeted to o150/ DDK062030-03 from National Institutes of Health.
Manuscript received April 2006; revised April 2006.
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