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- PATIENTS AND METHODS
Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease who undergo hemodialysis and endothelial dysfunction is an early key step in the development of atherosclerosis. The aim of this study was to investigate the effect of thrice-weekly in-center nocturnal hemodialysis (INHD, 8 h per session and three sessions per week) and conventional hemodialysis (CHD, 4 h per session and three sessions per week) on endothelial dysfunction in patients with end-stage renal disease. 32 INHD and 58 matched CHD patients were enrolled, baseline and 12-month measures of blood pressure (BP), serum calcium and phosphorus, serum intact PTH (iPTH) and brachial artery flow-mediated dilation (FMD) were collected and analyzed. Baseline characteristics were similar between groups except that serum phosphorus and calcium × phosphorus were higher in the INHD group. At the 12-month follow-up, there was a significant increase in FMD (6.0 ± 1.5% to 7.1 ± 1.8%, P < 0.01) in INHD patients. Multivariate analysis showed that FMD was inversely correlated with systolic BP (SBP) (β = −0.485, P < 0.01), diastolic BP (DBP) (β = −0.428, P < 0.01), iPTH (β = −0.405, P < 0.01) and serum phosphorus level (β = −0.375, P < 0.01). There was no significant change in FMD in the CHD group. Compared with CHD, INHD improves endothelial function, and control of serum phosphorus is associated with the improvement of endothelial function.
Cardiovascular disease, mostly a consequence of accelerated atherosclerosis, has been recognized as the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD) who undergo hemodialysis (1,2). Endothelial dysfunction is an early key step in the development of atherosclerosis and has consistently been observed in patients with ESRD and may contribute to the high cardiovascular morbidity and mortality in these patients (3,4). A number of factors such as arterial hypertension, chronic fluid overload, sympathetic activation and hyperparathyroidism have been implicated in impairment of the functional arterial vessel properties in patients with renal insufficiency (5–7).
Conventional hemodialysis (CHD) (4 h per session, three sessions per week) is the most widely used modality of renal replacement therapy, but a treatment with an annual mortality rate of up to 25% (8) can hardly be considered an ideal one. There is ongoing interest in modifying standard HD regimens by focusing on increasing the time and/or frequency of HD in the hope of improving the adequacy and outcome. Previous studies of short daily HD (six sessions per week with 1.5 to 3.0 h per session) have reported improved blood pressure (BP) control, regression of left ventricular hypertrophy (LVH), higher Hb levels, and decreased risk for hospitalization (9–11). Quotidian nocturnal home HD has been reported to induce regression of LVH, decrease nocturnal hypoxemia, increase vagally mediated heart rate variability during sleep, and improve phosphorus control in selected patients (12–14). These forms of HD may have advantages over conventional HD.
However, these options present feasibility challenges (15). Indeed, short daily HD decreases available dialysis time for other patients, and patients are required to spend a large fraction of their daytime in the hospital. Quotidian home nocturnal dialysis requires the development of a home dialysis program and extensive patient training.
In-center, thrice-weekly nocturnal HD (three sessions per week with 8 h per session, INHD) may be a valuable option, providing enough dialysis doses to improve outcomes in a way that can be affordable for both dialysis centers and patients (16). Previous uncontrolled studies (17–19) of INHD have demonstrated improved BP control, higher Hb levels, and decreased serum phosphorus, compared with CHD.
Recent data have showed that dysregulation of phosphate homeostasis may contribute to the endothelial dysfunction (20–23). INHD has better serum phosphorus control than CHD, and it may have a better effect on endothelial dysfunction. Using vascular ultrasound to measure flow-mediated dilation (FMD) of the brachial artery, we performed a non-randomized control study to examine the effects of INHD compared with CHD on endothelial dysfunction in the ESRD population.
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- PATIENTS AND METHODS
The main findings of this study are: first, compared with CHD, INHD is associated with an improvement in endothelial function as determined by FMD; and second, negative correlation of serum phosphate and FMD has been observed in the study.
Acute effects of HD on endothelial dysfunction are controversial. Cross et al. (26) found a single HD treatment caused rapid clearance of endothelial toxins and transiently increased FMD. Migliacci (27) showed that HD, although largely able to remove endothelium toxic substances does not ameliorate to any significant extent endothelial function in uremic patients. Lilien (28) demonstrated that a single HD procedure contributes to a detrimental effect on endothelial function and may thereby add to the cardiovascular risk of children with ESRD.
Previous studies have shown that nocturnal hemodialysis (NHD) (8 h per session, six sessions per week) has positive results on endothelial dysfunction in uremic patients. Chan et al. reported that within 1 to 2 months after ESRD, patients are converted from CHD to NHD, and endothelial vasodilation improves markedly (29). Controlled study has demonstrated that NHD improves endothelial vasodilation, the improvement in BP control by NHD may independently lead to amelioration of endothelial function, and NHD may also favorably affect a fundamental process of endothelial repair via normalizing endothelial progenitor cell number and function (30).
In our study, at 12 months follow-up, there was no significant change in FMD in the CHD group, whereas FMD increased significantly in the INHD group. At the end of follow-up, FMD in the INHD group was significant higher than that in the CHD group. The significant increase of FMD indicates the improvement of endothelial function by INHD. This is the first time the effect of INHD on endothelial dysfunction has been studied. Fathi et al. (31) examined the value of FMD in predicting cardiovascular events in a group of 444 patients with a significant risk of cardiovascular events. They demonstrated that patients with FMD of <2% had significantly more cardiovascular events than those with FMD ≥ 2.1%. However, in this study, mean FMD in both groups is ≥2.1% and change in FMD is only about 1.1% in the INHD group after 12 months follow up; although the change is statistically significant, its clinical relevance is still unknown. Our findings support the need for larger randomized trials with longer follow-up to determine whether INHD can decrease morbidity and mortality in patients who have ESRD and require maintenance HD by improving endothelial dysfunction.
The correlation of serum phosphorus and FMD seen in our study may provide a novel potential mechanism for beneficial effects of INHD on FMD. Compared with CHD (3 × 4 h), INHD (3 × 8 h) has a longer dialysis time and can provide enough dialysis doses to improve outcomes. Previous uncontrolled studies (17–19) of INHD have demonstrated decreased serum phosphorus, improved BP control and higher Hb levels. In our results, INHD had better control of serum phosphorus and BP than CHD. Recent data have demonstrated that dysregulation of phosphate homeostasis may contribute to the endothelial dysfunction. Hyperphosphatemia has been shown to induce acute endothelial dysfunction in vivo and exposure to a phosphorus load has been shown to increase reactive oxygen species production, induce apoptosis, and decrease nitric oxide (NO) production in endothelial cells in vitro (20,21). In a double-blind crossover study, FMD was measured before and 2 h after meals containing 400 mg or 1200 mg of phosphorus. The higher dietary phosphorus load increased serum phosphate at 2 h and significantly reduced FMD indicating a causal relation between endothelial dysfunction and acute postprandial hyperphosphatemia (22). Our study is the first to demonstrate that better control of phosphorus is associated with an improvement in FMD by INHD.
Some limitations deserve consideration. First, our study is a non-randomized control design, we cannot rule out the possibility of residual confounding, the baseline risk profile was more adverse among patients in INHD groups, and our findings may not be completely generalizable to all patients with ESRD or in other healthcare settings. The second is the techniques we have used to evaluate endothelial function. Changes in FMD have been described not only in the presence of classic risk factors, but also in a variety of other factors such as endogenous, exogenous, environmental, and familiar factors. This observation makes a correct serial evaluation of FMD in the same subject or a comparison of FMD between subjects very difficult because of the special attention that should be paid to all factors that can influence FMD (32). It is also operator-dependent. However, at present, this measurement is the preferred testing modality.
Antihypertensive treatment, especially ACE inhibitors and ARB, may influence FMD and influence the results in our study. Anderson et al. reported that ACEI could improve FMD in patients with coronary artery disease (33). Jawa et al. demonstrated beta-blocker treatment resulted in significant increase in FMD in African-American subjects with diabetes and hypertension (34). Cheetham et al. showed Losartan, an angiotensin type I receptor antagonist, improves conduit vessel endothelial function in Type II diabetes (35). Toma et al. showed that amlodipine may improve endothelial dysfunction in diabetes through anti-oxidant and anti-inflammatory mechanisms (36). In our study, the calcium antagonist taken by the subjects is amlodipine. At baseline, the proportion of patients who were taking antihypertensive drugs was similar and a strong influence of treatment on our results seems unlikely. At the end of follow-up, there was no significant change in antihypertensive medications in the CHD group, but the number of patients needed for antihypertensive therapy decreased significantly in the INHD group, and there were 15 patients who withdrew all antihypertensive medications. In the INHD group, with the reduced use of antihypertensive drugs, the protective effects on endothelial function of these drugs was less than that in the CHD group, but the endothelial function had still improved, which is helpful to explain that INHD is better than CHD in improving endothelial function.