295

Address correspondence to

: Dominic S. C. Raj, MD, DM,Division of Nephrology, 5th Floor — ACC, 2211 Lomas Blvd.NE, Albuquerque, NM 87131-5271, or e-mail:draj@salud.unm.edu.

Seminars in Dialysis

—Vol 17, No 4 (July–August) 2004pp. 295–298

HYPERTENSION IN HEMODIALYSIS PATIENTS

Blackwell Publishing, Ltd.

Hypertension Control with Daily Dialysis

Ehab Saad,* Bernard Charra,† and Dominic S. C. Raj*

*Division of Nephrology, University of New Mexico, Albuquerque, New Mexico, and †Center de Rein Artificiel, Tassin, France

ABSTRACT

Hypertension is present in 60–90% of patients on maintenancehemodialysis (HD) and it is an important cause of cardiovascu-lar (CV) mortality and morbidity. Frequent and prolonged HDhas been uniformly shown to control hypertension in end-stagerenal disease (ESRD) patients more effectively than conven-tional HD. The etiology of hypertension is predominantlyvolume dependent, but in a subset of patients increased renin,sympathetic overactivity, and endothelial dysfunction may playa role. Intradialytic hypotension precludes attainment of dryweight and hence optimal control of hypertension in conven-

tional HD is challenging. Frequent and prolonged dialysis withgentle and persistent ultrafiltration allows time for refilling ofthe intravascular compartment and permits normalization ofextracellular volume. It is also possible that intensive dialysisenables removal of pressor molecules and improves endothelialfunction. Improved blood pressure control translates intoregression of left ventricular hypertrophy in patients on dailyHD. Thus prolonged and frequent dialysis permits better controlof hypertension via volume and volume-independent mechanismsand also improves cardiac geometry.

Address correspondence to: Dominic S. C. Raj, MD, DM, Division of Nephrology, 5th Floor – ACC, 2211 Lomas Blvd. NE, Albuquerque, NM 87131-5271, or e-mail: draj@salud.unm.edu.

The introduction of bicarbonate buffer, biocompatible,high-flux membranes, and computerized ultrafiltration(UF) profiling have enabled delivery of adequate

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within a short time. There is an inverse relationshipbetween the duration of dialysis treatment and 5-yearsurvival rates reported from different countries: 40% inthe United States, 59% in Europe, and 61% in Japan(1,2). Compared to U.S. Renal Data System (USRDS)data, the standard mortality ratio in patients dialyzedat Tassin, France, for 8 hours three times a week hasremained at the same level over the last decade in spite ofthe worsening case mix (3). Distribution of the totalweekly hemodialysis (HD) treatment duration over 6days/week has been demonstrated to improve clinicaland biochemical status in end-stage renal disease(ESRD) patients (4). The Center de Rein Artificiel inTassin claimed, in 1994, an unparalleled 69% 10-yearsurvival rate, high hematocrit levels without erythropoi-etin, and a low incidence of hypertension without anti-hypertensives by using the “old-time method” of prolongedslow HD (5).

Based on these observations the following treatmentmodalities have evolved, giving importance to eithertime or frequency or both (6): (a) thrice-weekly treat-ment each lasting for 8 hours with a low-flux membrane(8H-TIW) (5,7); (b) ultrashort (90–120 minutes) high-fluxdialysis performed six to seven times a week (2H-QD)

(8); (c) prolonged (6–8 hours) dialysis six to seven nightsa week using low- or high-flux membrane (8H-QHS) (9);and (d) regular HD with high-flux membrane performedfour times a week with each session lasting 4 hours(4H-QIW) (10). The focus of this article is to review theevidence of frequent and longer dialysis on blood pres-sure (BP) control.

Rationale for Prolonged and Frequent Dialysis

The more efficient control of hypertension by prolongedand frequent dialysis (9,11,12) has been attributed tonormalization of extracellular volume (ECV) (13,14). Inhypertensive ESRD patients, blood volume (as estimatedby inferior vena cava diameter) is larger than in normo-tensive dialysis patients, despite attainment of “clinicaldry weight” (14,15). A small sustained increase in time-averaged ECV can have a profound effect on BP becauseof gradual changes in peripheral resistance and perpetu-ation of hypertension. However, some investigators havefailed to demonstrate a correlation between BP andvolume status (7), suggesting that accumulation of pressormolecules during the interdialytic period may also play arole in the pathogenesis of hypertension in ESRD.

Symptomatic hypotension occurs in about 25% of HDsessions. Plasma volume declines progressively duringHD with UF, but the plasma refilling rate often cannotmatch the UF rate, resulting in hypotension. EuropeanDialysis and Transplant Association (EDTA) registrydata indicate that the elderly are more likely to receive,and die, from shorter dialysis sessions (16). Thesepatients are at increased risk for silent ischemia duringhypotensive episodes, which is common during short

296 Saad et al.

HD (17). Intolerance to rapid UF may result in earlytermination of dialysis, which, when repeated, results involume expansion and resistant hypertension requiringmore antihypertensives. An increased frequency andduration of dialysis enables gradual reduction of ECVdue to more time and a smaller volume required forrefilling of the intravascular compartment. Longer andmore frequent dialysis also decreases interdialytic weightgain (5,9,10,12).

The possible reasons for hemodynamic stability with2H-QD are that the hypotension is frequent after 2 hoursof dialysis (18), when the refilling rate declines signifi-cantly (19); thirst is attenuated due to improved soluteremoval and the plasma volume is not decreased (20);and since the UF per treatment is not large, plasmavolume does not reach the critical point associated withhypotension. Although the fluid removal per treatmentis lower than in conventional dialysis, the cumulativeremoval per week is significantly higher with 2H-QDcompared to 4 hours of conventional HD performedthree times a week (4H-TIW). Daily HD also smoothesthe unphysiologic fluctuations in fluid status, whichoccurs with intermittent therapy. Thus excellent intradia-lytic tolerance with less hypotension, cramps, headache,and asthenia allows adequate UF to achieve optimal fluidstatus (8).

The adjusted relative risk of death due to coronaryartery disease is 9% lower and that due to other cardio-vascular (CV) diseases is 14% lower with a 0.1 increasein

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(21). It is possible that intensive dialysis resultsin removal of potential toxins and improves the endothe-lial dysfunction in ESRD. Homocysteine is an indepen-dent risk factor for CV disease, carotid artery stenosis,and venous thrombosis. Both short daily and nocturnalHD decrease the plasma homocysteine level in ESRDpatients (22,23). Although prospective randomized trialshave not been performed to document a reduction in CVmorbidity with prolonged/frequent dialysis, these CVbenefits are biologically plausible. Thus prolonged/frequent dialysis may allow normalization of ECV (24),delivery of higher

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(5,9,21), enhanced clearance ofhomocysteine and asymmetric dimethylarginine (ADMA),alleviation of sleep apnea (25), improved nutrition (26),and correction of anemia (27), which may translate intoreduced morbidity and mortality.

Hypertension Control in Prolonged and Frequent Dialysis

While the prevalence of hypertension in ESRD patientsis reported to be 80–90% worldwide, only 2% of thepatients treated with 8H-TIW are hypertensive (5,7).Charra et al. (13) defined “dry weight” as the postdia-lysis weight in which the patient remains normotensivewithout antihypertensive medication until the nextdialysis. With 8H-TIW dialysis, gentle, yet persistentUF results in a progressive reduction in ECV, which isfollowed by a decline in BP that becomes apparentwithin 1 month, but continues for 3 months in what istermed the “lag phase.” The full expression of the anti-hypertensive effect of volume control allowed discon-

tinuation of all antihypertensives in a majority of patients(28) (Fig. 1).

To investigate the mechanism of BP control in8H-TIW, blood volume was estimated in three groups ofpatients: patients on 8H-TIW, and normotensive andhypertensive patients on 4H-TIW (14). The dose of HDas estimated by

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was higher in 8H-TIW treatmentsas compared to 4H-TIW dialysis. ECV was not differentin the 8H-TIW and normotensive 4H-TIW dialysisgroups. However, in one subset of 8H-TIW patients withnormal BP, the ECV was higher than the median ECV innormotensive 4H-TIW dialysis. The authors concludedthat more efficient removal of vasoactive compoundsalong with normalization of ECV is another factor thatallows control of hypertension with 8H-TIW (29).

In 4H-QIW dialysis, hypertension was controlled in85% of the patients who were hypertensive prior toinitiation of 4H-QIW (10,29). However, 39% of patientsrequired antihypertensive mediations. Analysis of datafrom 21,672 dialysis sessions showed that vascular insta-bility was unusual, occurring in 7% of the sessions.

A number of investigators have shown that BP controlis superior with 2H-QD dialysis (8,30,31). Analysis ofpooled data from 72 patients showed that daily HD isassociated with progressive reduction in postdialysisweight and BP; the systolic BP fell by 13 mmHg anddiastolic by 7 mmHg (32). The true reduction in BP waslikely greater because there was a significant reduction inthe number of medications required to treat hypertension(32). Results from 12 patients maintained on 2H-QDshowed that BP normalized in all the patients (8,29). Ofinterest is that 2H-QD normalized BP in previouslyhypotensive patients. The mean UF rate was 1.4 kg/hr,and intradialytic tolerance was excellent. Ambulatory BPmonitoring showed a significant reduction in 24-hoursystolic and diastolic BP during 2H-QD. However, therewas no significant change in the systolic BP night/dayratio, and therefore circadian rhythm. These investigators

Fig. 1. Effect of prolonged HD on BP control. Before induction into8H-TIW about 89% of the patients were on antihypertensives. Withprogressive UF and a low-salt diet the dry weight decreased, enablingbetter control of hypertension. Only 5% of the patients were onantihypertensives at the end of the third month of 8H-TIW. Postdialysisweight gradually increased after the third month of 8H-TIW because ofimproved nutrition.

HYPERTENSION CONTROL WITH DAILY DIALYSIS

297

attributed the hypertension control primarily to controlof volume status (29,33).

In a small cross-sectional study, ambulatory BP moni-toring in patients undergoing 8H-QHS showed daytimesystolic hypertension in 13% and diastolic hypertensionin 17% of patients (34). At night, systolic hypertensionwas observed in 33% and diastolic hypertension in 29%of patients. A normal nocturnal decline in BP wasobserved in 25% of patients. Twenty-four-hour BP didnot correlate with interdialytic weight gain,

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, orhydration status. In another study examining the mech-anism of BP control with 8H-QHS, the ECV and neuro-hormone levels did not differ between 4H-TIW dialysisand 8H-QHS treatments (35). Muscle sympathetic activitywas increased in both 8H-QHS and 4H-QIW treatments,but cardiac sympathetic activity tended to be higher dur-ing 4H-TIW dialysis. A significant reduction in systolic(145

±

20 mmHg to 122

±

30 mmHg), diastolic (84

±

15 mmHg to 74

±

12 mmHg), and pulse pressure (145

±

20 mmHg to 122

±

13 mmHg) has been reported withchangeover from 4H-TIW to 8H-QHS dialysis, despite areduction in the number of BP medications (24). Inaccordance with previous reports, the decrease in BP wasnot accompanied by a change in postdialysis ECV, indi-cating that improvement in BP is related to multipleother factors such as normalization of sympathetic activ-ity, improvement in vascular reactivity, resolution ofsleep apnea, and removal of larger molecular weightsolutes mediating hypertension (36).

Regression of Left Ventricular Hypertrophy in Prolonged Frequent Dialysis

Uncontrolled hypertension and increased vascularstiffness are important mediators of left ventricularhypertrophy (LVH) and de novo cardiac failure in ESRD.The prevalence of LVH is approximately 75% in patientsstarting renal replacement therapy (37). There is progres-sive cardiac enlargement, particularly left ventricular (LV)dilatation with compensatory hypertrophy in patients ondialysis. Only a minority of the patients on dialysis experi-ence a reversal of cardiac hypertrophy. Deterioration ofLV function following ultrashort HD has been reportedby a number of investigators (38).

In contrast, regression of LV mass and LV end diastolicdiameter has been reported with 2H-QD dialysis and 8H-QHS dialysis (24,33). Switching from 4H-TIW to 2H-QDdialysis provided a significant reduction in LV mass index(LVMI) (164 g/m

2

to 132 g/m

2

) at 6 months (30). Therewas a progressive and significant reduction in LV posteriorwall thickness, interventricular septum, LV end-diastolicdiameter, and ejection fraction (EF) with the duration of2H-QD even beyond 6 months of treatment (12). Thechange in cardiac dimensions correlated with a reductionin ECV and total body water (33).

In an observational cohort study, 28 patients switchedfrom 4H-TIW to 8H-QHS dialysis underwent echocardio-graphy at baseline and after 3.4

±

1.2 years of 8H-QHStreatment (7). The LVMI decreased from 147

±

42 g/m

2

to 114

±

40 g/m

2

and correlated with systolic BP, butnot with ECV.

To examine the effect of 8H-QHS on LV function andgeometry, six patients were studied before (on 4H-TIW)and 3.2

±

2.1 years after conversion to 8H-QHS dialysis.There were significant increases in EF (28

±

12% to41

±

18%) and a trend toward greater LV fractionalshortening (20

±

10% to 38

±

17%) (39). The improve-ment in cardiac function was associated with a reductionin systolic, diastolic, and mean arterial BP.

On the other hand, despite good BP control, echocar-diographic evidence of LVH was documented in 76% ofthe patients on 8H-TIW dialysis for a more than 10 years(40). This raises a question whether LVH is inevitablewithout more frequent dialysis.

Economic Advantage

The collaborative experience from more than 200patients worldwide claim a constellation of clinicalbenefits with prolonged and frequent dialysis, which isspeculated to reduce mortality and morbidity in ESRDpatients. An economic evaluation comparing daily (2H-QD and 8H-QHS) with 4H-TIW dialysis showed that thedialysis facility will incur an additional 10–20% increasein cost per patient per year to provide daily dialysis (41).However, a decrease in hospitalizations (30–100%) andthe use of erythropoietin (41%), BP medications (36–62%),and other interventions with daily dialysis translated intosignificant cost savings (41). While preliminary evi-dence indicates daily dialysis decreases hospital stays by30–100%, an 8% reduction in hospitalizations will renderthe therapy to be cost saving over 4H-TIW dialysis (41).

DePalma (42) defined adequate dialysis as that whichpermits the patient to be rehabilitated, eat a reasonablediet, make blood, maintain a near-normal BP, and pre-vent the progression of neuropathy. Frequent and pro-longed dialysis allows better control of hypertension anddecreases CV morbidity, suggesting that such therapymay be needed to meet this definition of adequacy.

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