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- PATIENTS AND METHODS
Atherosclerotic complications have a significant effect on mortality in patients undergoing hemodialysis (HD) therapy. However, anti-atherosclerotic and cardioprotective effects of on-line hemodiafiltration (HDF) remain to be elucidated. We prospectively compared the anti-atherosclerotic and cardioprotective effects in two randomly divided groups, i.e. on-line HDF group (n = 13) and conventional HD group (n = 9) for 1 year. Surrogate markers were brachial-ankle pulse wave velocity (baPWV), intima-media thickness (IMT) of carotid artery as an atherosclerosis marker, and cardiac functional surrogate markers included left ventricular mass index (LVMI), ejection fraction (EF), and LV diastolic capacity represented as E/A and deceleration time (DT). LVMI in on-line HDF patients showed significant regression after 1 year of treatment (131.9 ± 25.8 to 116.5 ± 24.7 g/m2, P = 0.03), while LVMI in HD patients did not show any significant change (148.0 ± 47.1 to 142.3 ± 35.5 g/m2). Levels of baPWV in HD patients showed a significant increase (11.4%) from basal levels, while on-line HDF groups showed no significant increase. Furthermore, HD patients showed significant worsening of LV diastolic capacity (E/A: from 0.87 ± 0.12 to 0.79 ± 0.08, P = 0.03), while it was not shown in on-line HDF patients. Ejection fraction and IMT did not show any significant change in both groups. Serum albumin, C-reactive protein, β2 microglobulin, blood pressure, and anti-hypertensive drug use did not change in both groups. On-line HDF showed a significant improvement in LVMI and prevented a significant worsening of baPWV or LV diastolic capacity compared with patients on conventional HD therapy.
Atherosclerotic complications including ischemic cardiac disease (IHD), stroke, and peripheral arterial disease (PAD) are serious problems and have a significant effect on mortality in patients on dialysis therapy (1–7). Since Lindner et al. (8) described that atherosclerosis is accelerated in dialysis patients, atherosclerotic problems in hemodialysis (HD) patients has been attracting much concern in nephrologists.
Hemodiafiltration (HDF), which was first reported in the literature in 1985 (9), has now been used as a dialysis modality. HDF can remove middle-sized uremic solutes more efficiently than diffusion-dependent conventional HD by combining convective clearance with diffusion. HDF therapy has some variations according to the differences of dilution methods such as pre-dilution, post-dilution, mixed-dilution (pre- and post-), and push-pull methods. Differences of substitution fluid also cause variations of HDF such as bottle-type HDF (off-line HDF), on-line HDF, and push-pull HDF. Direct infusion of dialysate into the blood line also as a substitution fluid is the most important methodological characteristic of on-line HDF. Therefore, purification of dialysate should be strictly controlled to perform on-line HDF.
Using ultra-pure dialysate not only as dialysate but also as substitution fluid, on-line HDF stabilizes the patients' circulation status during dialysis sessions better than the standard HD (10,11). On-line HDF has also been reported to improve anemia (12,13), skin lesions (13), amyloidosis (14), and bone complications (15). However, the anti-atherosclerotic effect of on-line HDF has never been reported in the literature.
Atherosclerosis surrogate markers such as left ventricular mass index (LVMI) (16), pulse wave velocity (PWV) (17), ankle-brachial pressure index (ABI) (18), and intima-media thickness of carotid artery (IMT) (19) are reported to be independent predictors of cardiac events and/or prognosis in HD patients. Therefore, the purpose of this study was to verify whether on-line HDF has anti-atherosclerotic and cardioprotective effects in patients with end-stage renal failure using several atherosclerosis surrogate markers including LVMI, PWV, ABI, and IMT along with left ventricular systolic and diastolic functional markers.
- Top of page
- PATIENTS AND METHODS
Our present study clearly demonstrated that on-line HDF has anti-atherosclerotic and cardioprotective effects. A significant LVMI regression, prevention of worsening of LV diastolic functional abnormality and arterial stiffness were shown in on-line HDF group compared with the HD group. These effects were obtained by on-line HDF with 40 L pre dilution method. Furthermore, these effects were independent from bloodpressure control and/or drug use such as ARB and ACE-I.
Arterial stiffness and LVMI are the important predicting factors for prognosis in HD patients (16,17). Arterial stiffness is multifactorial, and many independent associating factors are reported, i.e. age (22), long HD duration (22), vascular calcification (22), blood pressure (23,24), leukocyte aggregates (25), glucose metabolism (26), high molecular adiponectin (27), and inflammation (24). LVMI is also multifactorial (23,28) and closely associates with arterial stiffness (29). Increased afterload by increased aortic/arterial stiffness promotes LV hypertrophy (LVH) by loss of Windkessel pressure compensation mechanism in the aorta. Therefore, it is theoretically acceptable that improvement in arterial stiffness might improve LVH. Although the exact mechanisms are unknown, 1 year on-line HDF treatment improved LVMI without changing arterial stiffness represented as baPWV.
The HD group showed progressive worsening of LV diastolic function, while the on-line HD group did not show significant worsening of LV diastolic function. This may be due to the difference of the change of LVMI between the two groups. Increase of LVMI promotes cardiac dysfunction in both a systolic and diastolic capacity. However, it is reported that LV diastolic function may be disturbed earlier than LV systolic function in HD patients (30). In general, one third of patients with heart failure have normal LV systolic function, and heart failure might be caused by single LV diastolic failure. Therefore, diastolic dysfunction (or diastolic failure) may be very important in consideration of the effect of heart failure on the prognosis of HD patients. Although LV systolic function (EF) did not change in both groups after the 1-year follow up period, LV diastolic function showed a significant decrease in the HD treated group in our present study, while it was not shown in patients with on-line HDF. Whether this difference in the change of LV diastolic function may lead to subsequent differences in LV systolic function between the HDgroup and the on-line HDF group may need a further follow up study.
In contrast to no change in the conventional HD group, serum BUN and creatinine levels significantly increased in the on-line HDF group 1 year later from their basal levels. On this point, Masakane reported an excellent manuscript about how much convective volume would be appropriate to achieve a good clearance of small and middle molecules in pre-dilution and post dilution on-line HDF (31). In pre-dilution HDF, it is certainly not evident that “more is better”. Plasma water may be diluted in pre-dilution HDF, thereby clearance may be attenuated. On the contrary, in post-dilution HDF, more will be probably better. However, convective volumes are limited by high trans-membrane pressure, membrane clotting and machine alarms. There may exist many conditions in performing HDF, especially on-line HDF. Selection of membrane, dilution method (pre-dilution or post-dilution), and convective volume may have to be carefully selected.
Clearance of middle molecules including β2MG is usually expected to increase with HDF therapy. However, contrary to our expectation, serum β2MG did not decrease in the on-line HDF group in our study. Although we do not have a clear explanation, the influence of residual renal function might be one of the reasons why serum β2MG did not decrease in the HDF group (32,33). We did not examine urinary volume and urinary β2MG excretion in the on-line HDF group. Therefore, we could not clarify this possibility.
The present study has some limitations. The numbers of patients were small and the follow up period was short (only 1 year) although we conducted a prospective randomized study. There was no cardiovascular event in patients in both groups during the follow up period. Therefore, we could not clarify whether cardioprotective and anti-atherosclerotic effects of on-line HDF confirmed preliminarily in this study consequently would lead to an improved patients' outcome.