Short daily hemodialysis: Blood pressure control and left ventricular mass reduction in hypertensive hemodialysis patients

Short Daily Hemodialysis: Blood Pressure Control and Left Ventricular Mass Reduction in Hypertensive Hemodialysis Patients Riccardo Maria Fagugli, MD, Gianpaolo Reboldi, MD, PhD, Giuseppe Quintaliani, MD, Paolo Pasini, MD, Giovanni Ciao, MD, Beatrice Cicconi, MD, Franca Pasticci, RD, Jean Marie Kaufman, MD, PhD, and Umberto Buoncristiani, MD ● Several retrospective and uncontrolled prospective studies reported blood pressure (BP) normalization and left ventricular mass (LVM) reduction during daily hemodialysis (DHD). Conversely, the burden of these major independent risk factors is only marginally reduced by the initiation of standard thrice-weekly dialysis (SHD), and cardiovascular events still represent the most common cause of death in hemodialysis patients. Therefore, we performed a randomized two-period crossover study to compare the effect of short DHD versus SHD on BP and LVM in hypertensive patients with end-stage renal disease. We studied 12 hypertensive patients who had been stable on SHD treatment for more than 6 months. At the end of 6 months of SHD and 6 months of DHD in a sequence of randomly assigned 24-hour ambulatory BP monitoring, echocardiography and bioimpedance were performed. Throughout the study, patients maintained the same Kt/V. A significant reduction in 24-hour BP during DHD was reported (systolic BP [SBP]: DHD, 128 ⴞ 11.6 mm Hg; SHD, 148 ⴞ 19.2 mm Hg; P < 0.01; diastolic BP: DHD, 67 ⴞ 8.3 mm Hg; SHD, 73 ⴞ 5.4 mm Hg; P ⴝ 0.01). The decrease in BP was accompanied by the withdrawal of antihypertensive therapy in 7 of 8 patients during DHD (P < 0.01). LVM index (LVMI) decreased significantly during DHD (DHD, 120.1 ⴞ 60.4 g/m2; SHD, 148.7 ⴞ 59.7 g/m2; P ⴝ 0.01). Extracellular water (ECW) content decreased from 52.7% ⴞ 11.4% to 47.6% ⴞ 7.5% (P ⴝ 0.02) and correlated with 24-hour SBP (r ⴝ 0.63; P < 0.01) and LVMI (r ⴝ 0.66; P < 0.01). In conclusion, this prospective crossover study confirms that DHD allows optimal control of BP, reduction in LVMI, and withdrawal of antihypertensive treatment. These effects seem to be related to reduction in ECW content. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Hypertension; left ventricular hypertrophy (LVH); short daily hemodialysis (DHD).

H

IGH BLOOD PRESSURE (BP) and left ventricular hypertrophy (LVH) are independent risk factors for cardiovascular morbidity and mortality in patients with chronic renal failure and end-stage renal disease (ESRD).1,2 The burden of these risk factors is only marginally reduced by the initiation of standard thrice-weekly hemodialysis (SHD), even when performed with various recent technical improvements (increase in convective component, use of sodium profile or biocompatible membranes).3 Better control of these comorbidities has been attained by increasing the number of dialysis hours with low-efficiency techniques.4 Furthermore, a number of reports based on retrospective studies and uncontrolled prospective trials suggest that short daily hemodialysis (DHD) treatment might be associated with a significant reduction in antihypertensive medications and nearnormalization of BP.5-13 Therefore, the aim of our study is to compare the efficacy of DHD with SHD on BP control and left ventricular mass (LVM) reduction in hypertensive patients with ESRD. PATIENTS AND METHODS

We studied 12 hypertensive patients with ESRD (8 women, 4 men; age, 64.1 ⫾ 11.2 years; time on hemodialysis [HD] therapy, 1,218 ⫾ 951 days; body surface area, 1.62 ⫾ 0.11

m2) previously treated with SHD for at least 6 months. Diabetes mellitus was present in 3 patients. Causes of ESRD were nephroangiosclerosis (3 patients), diabetic nephropathy (2 patients), chronic pyelonephritis (2 patients), glomerulonephritis (3 patients), polycystic kidney disease (1 patient), and unknown (1 patient). During this run-in phase, all patients were on stable antihypertensive treatment. All patients gave their informed consent to the study after receiving a detailed explanation of the experimental design and procedures. The study was a randomized two-period crossover. Patients entered a run-in period of 6 months during which they underwent HD three times weekly for a total of 12 hours; ultrafiltration was strictly under control, and ideal dry body weight was assumed to be reached when intolerance because of muscle cramps or hypotensive episodes were evident. At the end of the run-in period, patients were randomly assigned to a treatment sequence defined as AB or BA, where

From the Departments of Nephrology-Dialysis and Cardiology, Silvestrini Hospital; Department of Internal Medicine, University of Perugia, Perugia, Italy; and the Endocrinology Unit, University Hospital, Gent, Belgium. Received September 12, 2000; accepted in revised form February 23, 2001. Address reprint requests to Riccardo Maria Fagugli, MD, UO Nefrologia e Dialisi, Ospedale Silvestrini, Azienda Ospedaliera di Perugia, S Andrea delle Fratte, 06100 Perugia, Italy. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3802-0018$35.00/0 doi:10.1053/ajkd.2001.26103

American Journal of Kidney Diseases, Vol 38, No 2 (August), 2001: pp 371-376

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A and B represent SHD and DHD, respectively. Both treatment programs were performed for 6 months. Throughout the study, patients maintained the same filter, blood flow, weekly treatment length (12 hours), and dialysis bath, with the intention of maintaining weekly Kt/V constant. Arteriovenous fistulas were used as blood access for all the patients. Blood chemistries, Kt/V, and clinical and pharmacological details were recorded monthly.

BP Measurements Office BP was measured using a standard mercury sphygmomanometer before each HD session. Ambulatory BP monitoring (ABPM) was performed on the midweek dialysis day at the end of each study period using an A&D TM2421 (A&D Co Ltd, Tokyo, Japan).14 BP readings were taken at 15-minute intervals from 7 AM to 10 PM and 30-minute intervals from 10 PM to 7 AM,15,16 and began at 8 AM on the midweek HD day. Awake and asleep BP were calculated by the narrow fixed-time method (awake, 10 AM to 8 PM; asleep, 12 PM to 6 AM). Systolic BP (SBP) night-day (N/D) ratio was calculated.17,18 The normal value for daytime ABPM was considered less than 135/85 mm Hg,19 and a dipping pattern was defined for N/D SBP ratio less than 0.899 for men and less than 0.901 for women.20,21

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immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA).

Bioimpedance Analysis Bioimpedance analysis was performed at the end of each study period using BIA 101 (Akern-RJL Systems, Florence, Italy), a 50-kHz phase-sensitive analyzer. Measurements were performed by the same operator 20 minutes after midweek HD; resistance and reactance values were collected and analyzed using specific formulas. We determined extracellular water (ECW) content, reported as the percentage of total body water.25,26

Statistical Analysis Descriptive values are expressed as mean ⫾ SD unless otherwise specifically stated. The method of Hills and Armitage27 for analysis of a two-period crossover trial was used to determine whether there was a treatment effect (HD schedule) on 24-hour SBP and diastolic BP, BP load, LVMI, percentage of ECW, blood chemistries, and parathormone level. Simple correlation coefficients were calculated according to Pearsons’ method. Differences between treatment means are considered significant at P less than 0.05.

Echocardiography Standard two-dimensional and two-dimensional guided M-mode echocardiography was performed with a Sonolayer ␣ SSA-270 (Toshiba, Nasu, Japan) using a 3.75-MHz transducer. All echocardiography were performed by the same operator, who was unaware of ABPM results. Echocardiograms were taken at the end of each study period on the midweek inter-HD day for patients on SHD and before the HD session on the midweek day for patients on DHD, according to the American Society of Echocardiography guidelines.22 The interval from the end of the HD session to echocardiography remained constant for each patient during the study periods. Left ventricular internal diastolic diameter (LVIDD), diastolic posterior-wall thickness (PWT), and interventricularseptum thickness (IVS) were measured. LVM was calculated using the formula of Deveraux and Reicheck23: LVM (grams) ⫽ 0.8 ⫻ 1.04[(LVIDD ⫹ IVS ⫹ PWT)3 – LVIDD3] ⫹ 0.6 LVM index (LVMI) was calculated by dividing LVM by body surface area. Specific criteria were used to determine the presence of LVH (men, LVMI ⬎ 131 g/m2; women, LVMI ⬎ 100 g/m2).24 Intraobserver variability in measurements of M-mode echocardiography was calculated as the difference between two measurements performed on the same patient divided by the mean values. Variability was as follows: LVIDD, 3.75%; PWT, 1.9%; IVS, 1.4%; and LVM, 6.3%.

Intact Parathormone Assay Intact parathormone (iPTH) levels were determined at the end of each study period by a specific and sensitive two-site

RESULTS

Clinical characteristics of patients before the randomization are listed in Table 1. All patients were administered antihypertensive medications, with only four patients on monotherapy. Antihypertensive therapy consisted of angiotensinconverting enzyme inhibitors (seven patients), angiotensin II–receptor antagonist (one patient), calcium channel blockers (seven patients), ␤-blocker (one patient), central acting ␣2-adrenergic receptor agonist (eight patients), ␣-␤blockers (two patients), and direct-acting peripheral vasodilator (one patient). For the two study periods, SHD and DHD, no differences were reported in clinical and hematologic parameters during the two different HD treatments: values for hematocrit, hemoglobin, recombinant human erythropoietin (rHuEPO) treatment, serum total protein, and albumin did not change. Throughout the study, patients maintained the same weekly Kt/V: SHD, 4.10 ⫾ 0.49 versus DHD, 4.14 ⫾ 0.66 (Table 2). Significant reductions in office SBP and diastolic BP were reported for the DHD compared with the SHD period (Table 3). For ABPM, BP during DHD was significantly lower than during SHD for both 24-hour systolic and diastolic values (SBP: DHD, 128 ⫾ 11.6 versus SHD, 148 ⫾ 19.2 mm Hg; P ⬍ 0.01; diastolic BP:

CARDIOVASCULAR COMPLICATIONS AND DAILY HEMODIALYSIS

DHD, 67 ⫾ 8.3 versus SHD, 73 ⫾ 5.4 mm Hg; P ⫽ 0.01). A significant decrease in 24-hour systolic load was also evident. However, no difference was reported in 24-hour SBP or diastolic BP SD during the two study periods or for systolic N/D ratio (Table 3). The number of hypotensive intra-HD episodes, analyzed from the HD diary, did not differ during the two different treatments (Table 2). The decrease in BP was accompanied by the interruption of antihypertensive therapy, and only 1 of 12 patients on DHD versus 8 of 12 patients on SHD were maintained on pharmacological treatment (P ⬍ 0.01). For antihypertensive treatment during the SHD period, 6 patients were on monotherapy. Patients were treated with angiotensin-converting enzyme inhibitors (2 patients), calcium channel blockers (3 patients), and centralacting ␣2-adrenergic receptor agonists (5 patients). The number of drugs for the only patient who remained on antihypertensive therapy during DHD was decreased from two to one (centralacting ␣2-adrenergic receptor agonist). All patients had LVH according to conventional cutoff values before the beginning of the study (Table 1). LVH was present in four patients during the DHD period and nine patients during the SHD period. LVMI decreased significantly during the DHD period compared with the SHD period (SHD, 148.7 ⫾ 59.7 g/m2; DHD, 120.1 ⫾ 60.4 g/m2; P ⫽ 0.01), as did LVIDD (Table 4). Taking into account weight values reported at the end of the dialysis sessions in the clinical diary, patients’ dry body weight did not change

Table 1. Clinical Characteristics of Patients, BP Values, and Echocardiography Data Before the Beginning of the Study Clinical Characteristics

Kt/V (weekly value) nPCR Inter-HD weight gain (kg) Dry body weight (kg) Hypotensive episodes/session/mon ECW (%) Hct (%) Hb (g/dL) Serum urea (mg/dL) Serum creatinine (mg/dL) Serum total proteins (g/dL) Serum albumin (g/dL) rHuEpo (U/Ikg/wk) BP values SPB office (mm Hg) DBP office (mm Hg) MBP office (mm Hg) 24-h SBP (mm Hg) 24-h DBP (mm Hg) 24-h MBP (mm Hg) Daytime SBP (mm Hg) Nighttime SBP (mm Hg) SBP N/D ratio Daytime SBP load (%) Nighttime SBP load (%) Echocardiography data IVS (mm) PWT (mm) LVIDD (mm) LVMI (g/m2)

3.98 ⫾ 0.37 1.2 ⫾ 0.2 2.45 ⫾ 0.79 54.0 ⫾ 7.4 0.05 ⫾ 0.08 58.7 ⫾ 13.8 30.9 ⫾ 4.3 10.5 ⫾ 1.6 156 ⫾ 25.9 8.8 ⫾ 2.0 6.7 ⫾ 0.8 3.9 ⫾ 0.7 115.5 ⫾ 81.8 146.6 ⫾ 17.3 78.2 ⫾ 7.1 101.1 ⫾ 7.9 146.3 ⫾ 12.9 71.3 ⫾ 6.3 96.5 ⫾ 6.5 153.8 ⫾ 12.7 144.4 ⫾ 19.3 0.94 ⫾ 0.1 62.5 ⫾ 25.0 48.0 ⫾ 33.4 13.4 ⫾ 3.9 9.9 ⫾ 2.8 55.9 ⫾ 7.5 172.7 ⫾ 72.6

Abbreviations: NPCR, normalized protein catabolic rate; Hct, hematocrit; Hb, hemoglobin; DBP, diastolic BP.

Table 2.

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Clinical Characteristics of Patients During the Two Study Periods

Variable

Kt/V (weekly value) nPCR inter-HD weight gain (kg) Dry body weight (kg) Hypotensive episodes/session/mon Hct (%) Hb (g/dL) Serum urea (mg/dL) Serum creatinine (mg/dL) Serum total proteins (g/dL) Serum albumin (g/dL) rHuEpo (U/Ikg/wk)

SHD

DHD

4.10 ⫾ 0.49 1.2 ⫾ 0.3 2.65 ⫾ 0.60 54.1 ⫾ 7.4 0.05 ⫾ 0.09 30.9 ⫾ 2.8 10.5 ⫾ 1.2 172 ⫾ 33.5 9.4 ⫾ 2.2 6.7 ⫾ 0.6 3.9 ⫾ 0.6 109.7 ⫾ 82.4

4.14 ⫾ 0.66 1.1 ⫾ 0.4 1.42 ⫾ 0.48 53.7 ⫾ 7.8 0.04 ⫾ 0.05 31.2 ⫾ 3.9 10.3 ⫾ 1.3 153 ⫾ 43.9 8.1 ⫾ 2.1 6.9 ⫾ 0.5 4.0 ⫾ 0.2 68.7 ⫾ 92.5

P

NS NS ⬍0.001 NS NS NS NS NS 0.05 NS NS NS (0.07)

Abbreviations: nPCR, normalized protein catabolic rate; Hct, hematocrit; Hb, hemoglobin; NS, not significant.

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FAGUGLI ET AL Table 3.

Office BP and 24-Hour APBM During SHD and DHD

SPB office (mm Hg) DBP office (mm Hg) MBP office (mm Hg) 24-h SBP (mm Hg) 24-h SBP SD (mm Hg) Systolic load (%) 24-h DBP (mm Hg) 24-h DBP SD (mm Hg) Diastolic load (%) 24-h MBP (mm Hg) Daytime SBP (mm Hg) Nighttime SBP (mm Hg) Daytime SBP load (%) Nighttime SBP load (%) SBP N/D ratio

SHD

DHD

P

148.9 ⫾ 14.7 76.3 ⫾ 5.8 100.5 ⫾ 7.3 148.2 ⫾ 19.2 20.6 ⫾ 4.5 58.8 ⫾ 33.3 73.4 ⫾ 5.4 12.8 ⫾ 2.4 9.8 ⫾ 7.5 98.3 ⫾ 8.3 152.9 ⫾ 19.1 141.5 ⫾ 24.4 64.7 ⫾ 31.7 52.7 ⫾ 40.8 0.92 ⫾ 0.07

126.2 ⫾ 13.3 72.1 ⫾ 6.2 90.1 ⫾ 7.8 128.2 ⫾ 11.6 20.9 ⫾ 4.2 27.2 ⫾ 18.3 67.3 ⫾ 8.3 11.9 ⫾ 2 7.8 ⫾ 9.9 87.5 ⫾ 8.1 132.9 ⫾ 15.1 124.2 ⫾ 20.9 30.9 ⫾ 20.0 14.4 ⫾ 16.3 0.93 ⫾ 0.11

0.001 0.01 ⬍0.01 ⬍0.01 NS ⬍0.01 0.01 NS NS 0.001 0.01 NS (0.06) 0.01 0.01 NS

Abbreviations: DBP, diastolic BP; MBP, mean BP; SD, standard deviation; NS, not significant.

during DHD (SHD, 54.1 ⫾ 7.4 kg; DHD, 53.7 ⫾ 7.8 kg). Bioimpedance data showed a reduction in percentage of ECW (SHD, 52.7% ⫾ 11.4%; DHD, 47.6% ⫾ 7.5%; P ⫽ 0.02). Inter-HD weight gain decreased during DHD (SHD, 2.65 ⫾ 0.6 kg; DHD, 1.42 ⫾ 0.5 kg; P ⬍ 0.01). ECW content positively correlated with 24-hour SBP (r ⫽ 0.63; P ⬍ 0.01) and LVMI (r ⫽ 0.66; P ⬍ 0.01; Fig 1). Twenty-four–hour SBP correlated with LVMI (r ⫽ 0.51; P ⬍ 0.01). We measured iPTH, taking into account the possible role of this hormone in cardiac hypertrophy; no differences were reported during SHD or DHD (SHD, 150.6 ⫾ 144.5 pg/mL; DHD, 109 ⫾ 165.3 pg/ mL), and no correlation between iPTH and LVIDD, PWT, or LVMI was reported. DISCUSSION

The high mortality rate of patients with ESRD is mainly caused by the high prevalence of cardiovascular morbidity among this population, which Table 4.

Echocardiographic Parameters During SHD and DHD

IVS (mm) PWT (mm) LVIDD (mm) LVM (g) LVMI (g/m2)

SHD

DHD

P

13.7 ⫾ 3.4 8.9 ⫾ 2.5 52.3 ⫾ 7.8 239 ⫾ 91.7 148 ⫾ 59.7

11.9 ⫾ 2.3 9.9 ⫾ 3.5 46.8 ⫾ 8.3 192 ⫾ 90.4 120 ⫾ 60.4

0.001 NS ⬍0.01 0.01 0.01

Abbreviation: NS, not significant.

arises above all from the persistence of hypertension and cardiac hypertrophy. The latter are poorly controlled by the current SHD schedule (4 hours three times weekly), essentially because of the unsatisfactory control of fluid and salt homeostasis arising from the shortness of sessions and lengthy gaps between them, which condition insufficient removal and considerable accumulation of fluids, respectively. Therefore, the rationale underpinning DHD was the reduction in interdialytic overload of fluids and salts by shortening the inter-HD period and consequently, controlling hypertension more efficiently.28 This was observed during the first clinical experiences with DHD, even when total weekly dialysis length was significantly reduced.29 The favorable effect of DHD on BP has been repeatedly confirmed by our group in large retrospective and uncontrolled prospective studies,5-7,10 and the reduction in BP was accompanied by a regression in cardiac hypertrophy.8,9 Furthermore, our results have recently been confirmed by other groups.11-13 Taking into account the design of the studies previously reported and that weekly Kt/V increased in some studies during DHD, but not in others, interpretation of such results appears to be difficult in view of possible causes linked to such variables as time and delivered HD dose. Our study was performed with the intention of bypassing these two variables. As far as BP is concerned, the data reported

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Fig 1. Bivariate correlation of ECW to LVMI and average 24-hour SBP. (F) Daily HD; (‚) standard HD. (Bivariate density ellipses contain the mass of points determined by the 95% probability. The density ellipsoid is computed from the bivariate distribution fit to the X and Y variables.)

show that DHD is more efficient than SHD in the control of hypertension: during DHD, reduction of both systolic and diastolic values was evident. Moreover, 90% of patients on DHD therapy did not require antihypertensive therapy, and the number of drugs for the one patient who was maintained on pharmacological treatment was decreased from two different types to only one. The reduction in BP was not accompanied by changes in N/D ratio and therefore circadian rhythm. Causes of hypertension during HD are multiple,30,31 although there is increasing evidence of a link with fluid retention.32-34 Inferior vena cava measurements do not appear to be correlated with the decrease in BP observed during long HD (8 hours three times weekly), reported by Luik et al.4 Conversely, Katzarski et al35 observed a reduction in ECW content in body composition studied with bioimpedance in normotensive patients compared with hypertensive HD patients. In our study, we found that during DHD, ECW content and inter-HD body weight increase were less, and a correlation between ECW and SBP also was seen, thus confirming the close relationship between ECW and BP in HD patients. The ability of DHD to induce a normalization of BP appears to be correlated to fluid overload control. The reversal of LVH was an important end point of our study because of the well-known prognostic significance in terms of cardiovascular events and mortality. DHD also appears to be more efficient than SHD in the control of LVH: both LVIDD and LVMI decreased significantly during the daily treatment. Again, the correlation with ECW content was highly significant. The reductions in BP and LVM were not caused by an increase in HD

delivered dose because weekly Kt/V was constant during both periods. Several factors are involved in LVH, such as hypertension, anemia, hyperparathyroidism, and hypercynetic flux. In our patients, we did not observe a significant change in values for hemoglobin, rHuEpo treatment, or iPTH, probably because of the short period of study. Therefore, we could suppose that DHD allows a reduction in LVMI mainly because of the reduction in volume overload and decrease in SBP. In conclusion, short DHD appears to be superior to SHD in terms of BP control and LVH reversal. This HD schedule allows the withdrawal of antihypertensive therapy in the majority of patients after only a few months of treatment. The cause of such results appears to be linked to the reduction in ECW content and interdialytic weight gain. Nevertheless, other mechanisms of BP control during DHD remain to be investigated. REFERENCES 1. Parfrey PS, Foley RN: The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 10:1606-1615, 1999 2. Coresh J, Longenecker JC, Miller ER III, Young HJ, Klag MJ: Epidemiology of cardiovascular risk factors in chronic renal disease. J Am Soc Nephrol 9:S24-S30, 1998 (suppl 12) 3. Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE: Long term evolution of cardiomyopathy in dialysis patients. Kidney Int 54:1720-1725, 1998 4. Luik AJ, Charra B, Katzarski K, Habets J, Cheriex EC, Menheere PPCA, Laurent G, Bergstro¨m J, Leunissen KML: Blood pressure control and hemodynamic changes in patients on long time dialysis treatment. Blood Purif 16:197210, 1998 5. Buoncristiani U, Quintaliani G, Cozzari M, Giombini L, Ragaiolo M: Daily dialysis: Long term clinical metabolic results. Kidney Int 33:S137-S140, 1988 (suppl 24)

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