Cardiac and vascular structure and function parameters do not improve with alternate nightly home hemodialysis: An interventional cohort study

The study followed a prospective cohort design performed at a single centre. Between 2003 and 2006, consenting adults (≥ 18 years) with ESKD, established on home hemodialysis for ≥ 3 months were converted from a 3.5-6 hours/session, 3-5 sessions weekly home hemodialysis regimen to home NHD (6-10 hours overnight/session for 3-5 sessions weekly). Within the range of 3-5 sessions weekly and 6-10 hours/session, patients tailored their dialysis regimen to suit their lifestyle and sleeping habits. Interdialytic intervals of greater than 2 days were discouraged. Changes to the dialysis prescription are outlined in Tables 1 and 2

A diet low in saturated fat, salt and sugar with a daily protein intake of 1.2-1.4 g/kg dry weight/day and fluid restriction to maintain interdialytic weight gains < 3 kg was recommended. Dietary phosphate and potassium restrictions were relaxed upon commencement of NHD. Phosphate binders were ceased at the time of conversion to NHD and reintroduced only as required to maintain predialysis serum phosphate < 1.6 mmol/L. At baseline, calcitriol^® (1,25 OH₂ Vit D) was only continued in patients in whom it was required to maintain serum calcium in the normal range post previous parathyroidectomy or in those with severe hyperparathyroidism (PTH > 8 times the upper limit of normal). Vitamin D supplements were reintroduced as necessary to maintain predialysis serum calcium levels in the normal range and parathyroid hormone levels 2-6 times the upper limit of the normal range where possible. All patients were prescribed folic acid 5 mg daily, Multi B Forte ^® 1 tablet daily (Thiamine 7.27 mg, Riboflavin 6 mg, Nicotinamide 45 mg, pyridoxine 0.7 mg and ascorbic acid 45 mg) and pyridoxine 25 mg daily as oral supplements. The protocol for conversion to NHD was approved by the Princess Alexandra Hospital Human Research Ethics Committee.

Cardiovascular structure and function studies were scheduled to be performed at baseline, 6, 12, 18 and 24 months following conversion to NHD. Cardiac and vascular studies at each time point were performed at the same visit. Images were collected post-dialysis and interpreted by experienced staff, blinded to patients' clinical information.

Brachial Artery Reactivity (BAR), a measure of endothelial function, was calculated as percentage change in brachial artery diameter, measured using high resolution B mode ultrasonography, with the induction of reactive hyperemia induced by arterial occlusion for 4.5 minutes, using a sphygmomanometer cuff [27, 28]. BAR in healthy populations has been reported to range from 0.2 to 19.2% [29]. Endothelial dysfunction measured by these methods has been shown to correlate with the extent and severity of coronary artery disease determined by angiography [30].

Carotid intima-media thickness (CIMT), a measure of arterial wall thickness, was determined by averaging 3 measurements taken on each carotid artery (anteriorly, laterally and posteriorly) measuring the distance between the leading edge of the lumen-intima interface and the leading edge of the collagenous upper layer of the adventitia using high resolution B mode ultrasonography. Measures were taken in areas free of obvious atherosclerotic plaque around the level of the carotid bifurcation. CIMT is a marker for the presence and severity of arteriosclerosis and has been associated with risk factors for cardiovascular disease, all cause and cardiovascular mortality [31‐33] A systematic review has shown an increased risk of myocardial infarction with CIMT > 0.822 mm and an increased risk of stroke with CIMT > 0.75 mm [34]. Our group has shown increased cardiovascular and all-cause mortality is associated with CIMT > 0.62 mm [35].

Total arterial compliance (TAC), a measure of arterial stiffness, was calculated using the pulse-pressure method [36, 37]. Applanation tonometry (Millar SPT-301 Mikro-Tip transducer, Millar Instruments, Houston, TX), was performed on the left radial artery. BP was measured in the right arm, using a sphygmomanometer, with the patient resting supine for 10 minutes. The radial tonometric waveform was calibrated by assuming equivalence of mean [(2*Diastolic BP + Systolic BP)/3] and diastolic brachial cuff pressure. The radial tonometric waveforms were obtained simultaneously with pulsed-wave Doppler, digitized (WaveBook 512, IOTech Inc., Cleveland, OH), and transferred to a computer, where they were synchronized using the R wave of the electrocardiogram. Using specialized acquisition software, ECG gated data using tonometry and Doppler were acquired. Echocardiographic images and pulsed Doppler were acquired using a standard ultrasound system with 3.5 MHz and 11 MHz harmonic imaging probes. Stroke volume was derived from the pulsed Doppler and LV outflow tract dimensions [38]. The tonometric waveforms and aortic outflow data were analysed using a custom written program. Up to 10 cardiac cycles were averaged and central pressure was derived by applying a generalized transfer function to the radial tonometric pressure data [39] Values for TAC were then derived using the iterative method described by Stergioupulos [40]. Our group has previously documented TAC in normal subjects of 1.32 ± 0.58 mL/mmHg([41]. Our group has also shown TAC < 0.94 mL/mmHg is associated with mortality and the composite endpoint of death and hospital admissions for cardiovascular causes [42].

Augmentation Index (AIX), which reflects cardiac stroke volume and the effects of vascular stiffness, was calculated using the formula: AIX = augmentation pressure/pulse pressure)*100, where augmentation pressure = systolic blood pressure -pressure at the first inflection point on the central pressure wave form which was generated using a validated generalized transfer function from recordings of the radial artery pulse using applanation tonometry (SphygmoCor 7.01; AtCor Medical) and pulse pressure = systolic-diastolic blood pressure [43, 44]. Previously published studies have measured a central AIX in normal populations of 30-45% [45].

Interdialytic weight gains were calculated from pre and post dialysis total body weights measured by patients on bathroom scales. BP was recorded pre- and post-dialysis by patients using digital sphygmomanometers. Serum or plasma levels of lipids, hemoglobin, C reactive protein (CRP), albumin, parathyroid hormone (PTH), calcium, phosphate and homocysteine were measured using standard laboratory techniques on blood samples taken predialysis in the fasting state. Measures of oxidative stress including, plasma malonyldialdehyde (MDA) and red blood cell (RBC) anti-oxidant enzymes catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase (SOD) activity, and plasma GPX activity and total antioxidant status (TAS) were measured pre and post dialysis at baseline and 3 and 6 months after conversion to NHD, in the last 37 patients recruited to the study. MDA was measured using high performance liquid chromatography. Activities of CAT, GPX and SOD and TAS were measured using standard spectrophotometric methods. Prescribed medications were determined by review of the medical record and patient interview.

Eighty-seven percent of the eligible home hemodialysis population agreed to participate in the study. Demographic and dialysis prescription data are presented in Tables 1 and 3. Median kt/V urea was 1.3 (1.1-1.5) on conventional hemodialysis and 1.5 (1.3-1.9) on NHD.

Four patients died (Followed on NHD for 2, 5, 12 and 17 months)), 10 received renal transplants (Followed on NHD for 7.5 [6‐17] months) and 7 withdrew consent to participate in the study (Followed on NHD for: 9 [2‐13] months) during the 24 months follow up. The other patients without paired data for analysis failed to attend for investigations without withdrawing from the study.

Follow-up cardiac and vascular studies were performed at 18 (12-24) months. The timing of follow up investigations was determined by patient attendance at echocardiograms that were scheduled to occur 6 monthly between baseline and 24 months following conversion to NHD. The majority of patients only attended for 2 echocardiograms. The study performed at the latest time point during the 24 month follow up was utilized for analysis. Paired data was available for echocardiographic parameters in 38 patients, CIMT and BAR in 42 patients and TAC and AIX in 28 patients.

Measures of LV structure and systolic function did not change between baseline and follow up. (Table 4 and Figure 1) At baseline, 64% of patients had LVMI within the normal range. Of the 40 patients with paired data, 93% maintained LVMI within 30% of baseline measurement and only 7% had a ≥ 30% increase in LVMI. In the subset of patients with abnormal LVMI at baseline, there was no change in LVMI over time (n = 14, 57 ± 6 vs 61 ± 10 g/m^2.7).

Measures of diastolic function and filling pressure remained stable (Table 4). Diastolic dysfunction was present in 74% of patients at baseline and 70% at follow up. The most common abnormality was raised LAVol.

BAR did not change between baseline and follow-up. (Figure 2): 2.82 (1.12-6.3) vs 3.48 (1.68-7.95)%, p = 0.47. CIMT did not change between baseline and follow-up. (Figure 3): 0.66 ± 0.14 mm vs 0.65 ± 0.16 mm, p = 0.26. There was no significant change in TAC between baseline and follow-up: 1.4 (1.1-1.7) vs 1.3 (1.0-1.6)mL/mmHg, p = 0.86 (Figures 4). AIX increased from 21 (14-35)% to 27 (17-36)%, p = 0.025 (Figure 5). There was no significant change in pulse pressure between baseline and follow up: 66 (50-75) vs 60(50-73)mmHg, p = 0.46.

Changes in cardiovascular risk factors are presented in Table 5. There was significant improvement in predialysis diastolic BP. There was a trend toward improvement in predialysis systolic BP. Interdialytic weight gains increased: 2.3 ± 0.8 vs 2.7 ± 1.0 kg, p = 0.006. Antihypertensive medication doses were stable or reduced in the majority (57% dose stable, 34% reduced, 9% increased). The percentage of patients being prescribed no antihypertensive medications increased from 47% to 66%, p = 0.03. Seven patients ceased an ACE inhibitor or angiotensin receptor blocker and 5 ceased a β blocker. One patient newly commenced an ACE inhibitor. HMG CoA reductase inhibitors were prescribed to 51% of patients at baseline. The dose was stable (65%) or reduced (3%) in the majority of patients and only 8% of patients newly commenced HMG CoA reductase inhibitor medications during the study. Hemoglobin and iron stores remained stable. Weekly darbepoietin alpha dose decreased (p = 0.007). Weekly intravenous iron dose remained stable.

There was significant improvement in predialysis serum phosphate, calcium-phosphate product and parathyroid hormone levels (PTH). Serum predialysis corrected calcium levels rose. By 12 months following conversion to NHD, seventy-three percent of patients had predialysis serum phosphate levels ≤ 1.6 mmol/L. This was achieved despite a substantial decrease in requirement for phosphate binding medications (calcium carbonate, aluminium hydroxide and magnesium trisilicate). Only 6% of patients were not taking any phosphate binders at baseline and this increased to 79% on NHD. Calcium carbonate was prescribed to 90% of patients at baseline at an average dose of 2460 mg per day. On NHD, only 15% of patients were prescribed calcium carbonate at an average dose of 1670 mg/day. Addition of phosphate to the acid component of the dialysate on NHD was required in 29% of patients at an average dose of 20 ml of Fleet/10 L (Fleet contains sodium phosphate monobasic 19 g and sodium phosphate dibasic 7 g per 118 mL and sodium content = 4.4 g/118 mL). Parathyroid hormone levels fell significantly from an average baseline of 290 (140-471) to 160 (62-290) ng/L; p = 0.03. Fifty-eight percent of patients were prescribed calcitriol at baseline in an average dose of 1.4 mcg/week. After 12 months on NHD, 53% were prescribed calcitriol at an average dose of 1.8 mcg/week.

There was no significant change in predialysis plasma MDA. The increase in MDA observed during dialysis was attenuated after conversion to NHD. Predialysis RBC-CAT activity significantly increased between baseline and 6 months and change during dialysis remained stable. Predialysis RBC-GPX activity decreased and there was no change during dialysis. Plasma GPX activity increased marginally pre dialysis and had a greater increase during dialysis at 3 months. This was not sustained at 6 months. RBC-SOD and plasma TAS levels predialysis and change in these levels with dialysis remained stable (Table 6).

There were no strong associations between change in cardiovascular outcome measures and cardiovascular risk factors measured in this study. There were no significant associations on univariable or multivariable analysis with change in LVMI. Changes in diastolic parameters were associated on multivariable analysis with changes in markers of inflammation and nutrition, iron stores and PTH: early transmitral flow velocity and CRP: 0.008 (0.00001- 0.18), p = 0.05, R² = 0.48, E/A Ratio and CRP: 0.019 (0.003-0.04), p = 0.02, R² = 0.36, E/E^I and CRP: 0.003 (0.0005-0.005), p = 0.02, R² = 0.35 and E/E^I and Albumin: 0.006 (0.001-0.011), p = 0.02, R²0.35, early transmitral flow velocity and transferrin saturation: -0.008 (-0.13 to -0.003), p = 0.005, R² = 0.48, E/A ratio and transferrin saturation: -0.012 (-0.022 to -0.003) p = 0.01, R²0.36, deceleration time and ferritin: 0.08 (0.02-0.13), p = 0.01 R² = 0.49, early transmitral flow velocity and PTH: -0.0003 (-0.0006 to-4.01e^-6), p = 0.05, R² = 0.48 and deceleration time and PTH: 0.05 (0.004-0.10), p = 0.02, R² = 0.49). LaVol Index was associated with interdialytic weight gain (9.47 (3.29-15.64), p = 0.004, R²0.45) on multivariable analysis.

Change in BAR was associated on multivariable analysis with age (-0.14 (-0.27 to -0.006), p = 0.04, R² = 0.32). Change in CIMT was associated on multivariable analysis with change in predialysis serum phosphate (0.34 (0.043-0.065), p = 0.03 and CRP (-0.002 (-0.004 to -0.003), p = 0.03, R² = 0.24). Change in AIX was associated on multivariable analysis with change in triglycerides (0.03 (0.001-0.06, p = 0.04 and CRP (0.01 (0.004-0.02), p = 0.003, R² = 0.52).

This is the largest trial examining the effects of increasing dialysis duration on multiple measures of endothelial function and arterial wall thickness and stiffness and it is the only study examining cardiac diastolic function and oxidative stress markers. Echocardiograms and vascular ultrasound studies were all performed and interpreted in one experienced laboratory. Patients were all managed in one unit with uniform policies and procedures. We performed multivariable analyses to adjust for known confounders. We were powered to detect clinically significant changes in LVMI, BAR, TAC and CIMT.

However, our conclusions are limited by the non randomized study design. The baseline dialysis regimen was not a thrice weekly regimen as is standard in most facilities and may have been responsible for the more normal baseline LVMI in our study. It could be postulated that the observation periods used in our, and other studies have been too short to allow cardiovascular remodeling. 2Dimensional echocardiography is less precise and is more reliant on derived rather than directly measured values compared to cardiac magnetic resonance imaging for assessing LVMI [75]. Furthermore, the generally poor attendance at follow up study visits may have been a source of bias in this study. Approximately 1/3 of patients did not have follow-up studies completed. Despite these draw backs, we feel it has merit to assist with hypothesis generation, power calculations for randomized controlled trials and to guide clinical practice whilst definitive studies are conducted.