|Year : 2015 | Volume
| Issue : 1 | Page : 39-46
|The effect of on-line hemodiafiltration on improving the cardiovascular function parameters in children on regular dialysis
Fatina I Fadel1, Samuel H Makar1, Hanan Zekri1, Dina H Ahmed2, Ahmed H Aon1
1 Nephrology Department, Cairo University Pediatric Hospital, Cairo, Egypt
2 Chemical Pathology Department, Cairo University, Cairo, Egypt
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|Date of Web Publication||8-Jan-2015|
| Abstract|| |
The cardiovascular disease is an important cause of morbidity and accounts for almost 50% of deaths in patients undergoing maintenance dialysis. Many harmful molecules of the uremic milieu, such as the middle molecules, are difficult to remove by conventional hemodialysis (HD). On-line hemodiafiltration (OL-HDF) can achieve a considerable clearance of middle molecules and, together with its sterile ultrapure infusate, may have favorable effects on inflammation and cardiovascular complications. We aimed in this study to assess the effect of OL-HDF on improving the chronic inflammatory state associated with chronic kidney disease and the possible impact of these changes on myocardial function in chronic HD children. Thirty pediatric patients [12 (40%) males and 18 (60%) females with a mean age of 11.3 ± 3.2 years] on conventional HD for at least six months were switched to OL-HDF for six months. Variables for comparison at the end of each period included the levels of serum C-reactive protein and Kt/V as well as electrocardiography and echocardiographic measurements, including left ventricular mass index (LVMI). On changing from HD to OL-HDF, there was a significant decrease in hs-CRP (from 7.9 ± 8.9 to 3.4 ± 3 μ g/mL) (P = 0.01) and frequency of diastolic dysfunction (P = 0.04), while systolic function (FS and EF) improved significantly (P = 0.007 and 0.05, respectively), while LVMI did not change. We conclude that OL-HDF was well tolerated in children with improvement of the systolic function of the myocardium and the overall frequency of diastolic dysfunction.
|How to cite this article:|
Fadel FI, Makar SH, Zekri H, Ahmed DH, Aon AH. The effect of on-line hemodiafiltration on improving the cardiovascular function parameters in children on regular dialysis. Saudi J Kidney Dis Transpl 2015;26:39-46
|How to cite this URL:|
Fadel FI, Makar SH, Zekri H, Ahmed DH, Aon AH. The effect of on-line hemodiafiltration on improving the cardiovascular function parameters in children on regular dialysis. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Aug 22];26:39-46. Available from: http://www.sjkdt.org/text.asp?2015/26/1/39/148731
| Introduction|| |
The cardiovascular disease is an important cause of morbidity and accounts for almost 50% of deaths in patients undergoing maintenance dialysis. Both systolic and/or diastolic cardiac functions may be impaired. Overall, the prevalence of heart failure is ten-to 30-fold higher among dialysis patients than in the general population.  Accordingly, dialysis patients should be evaluated for systolic and diastolic cardiac dysfunction. 
Most molecules with the potential to affect the function of a variety of cell types within the vascular system are difficult to remove by dialysis, such as the middle weight and protein-bound molecules.  Recent clinical studies suggest that enhancing the removal of these compounds, whether through improving the removal of toxins or blocking the pathophysiological pathways with pharmacological strategies, are beneficial for the survival of patients on maintenance hemodialysis (HD).  Furthermore, repetitive exposure to cytokineinducing substances (pyrogens) results in chronic inflammation, which may significantly contribute to some of the long-term cardiovascular complications in dialysis patients. 
On-line dialysis modalities, such as on-line hemodiafiltration (OL-HDF), raise particular interests because of its considerable clearance of the middle molecular weight (MMW) substances (5-50 kDa).  Moreover, the development of the on-line dialysis water purification to produce a sterile ultrapure infusate may have favorable effects on long-term morbidity and mortality in dialysis patients. 
We aimed in this study to assess the effect of OL-HDF on improving the chronic inflammatory state associated with chronic kidney disease and the possible impact of these changes on myocardial function in chronic HD children.
| Subjects and Methods|| |
This study was designed to compare pre-dilution OL-HDF with conventional low-flux HD. Pediatric patients who were treated on conventional HD for six months at the Center of Pediatric Nephrology and Transplantation (CPNT) at the Cairo University were switched to OL-HDF with a follow-up period of six months. Data collected following the period of conventional HD and OL-HDF of the same patients were compared.
Thirty chronic HD patients below the age of 16 years who had a permanent vascular access capable of delivering a blood flow rate of at least 5 mL/kg/min, regularly taking their medications (antihypertensive and anti-failure medications), were included in the study. Patients with associated organic cardiovascular disease, e.g. rheumatic or congenital heart disease, were excluded from the study.
OL-HDF was performed using the Fresenius 4008 dialysis system (Fresenius Medical Care, Bad Homburg, Germany). The same hemodialyzers' configurations, the same surface area of the dialyzers using polysulfone membrane-based dialyzer during OL-HDF and the same blood flow rate and dialysate flow rate (500 mL/min) and temperature (36°C) were used during both conventional HD and OLHDF. Bicarbonate powder cartridges (biBAG R system, Fresenius Medical Care) were used in both during HD and OL-HDF.
Ultra-pure water was used for the preparation of bicarbonate-containing dialysis fluid and the substitution fluid was prepared from the dialysis fluid by one additional step of controlled ultrafiltration before it was infused pre-filter into the blood. Dialysate and substitution fluid (infusate) ion concentrations were as follows: Sodium 140 mmol/L, bicarbonate 32 mmol/L, calcium 1.5 mmol/L and potassium 2 mmol/L.
We used the on-line system (ONLINE plus™, Fresenius Medical Care, Bad Homburg, Germany), which is integrated into the dialysis machine (4008 series; Fresenius Medical Care) and consists of two ultrafilters (DIASAFE® plus), an infusate pump module and disposable infusate lines. The infusate was prepared continuously by double-stage ultrafiltration. Both filters were subjected to automated membrane integrity tests before dialysis and were replaced after 100 treatments or 12 weeks of use, whichever comes first. Dialysis fluid downstream from the first filter stage entered the dialyzer; part of the stream is subjected to cross-flow the filtration in the second filter in order to produce the infusate.
The on-line HDF was performed through the pre-dilution method (replacement fluid is infused before the dialyzer) with an infusion rate of two-thirds of or equal to the blood flow rate guided by trans-membrane pressure (TMP) maintained below 200.
Baseline clinical and anthropometric measures were obtained using the growth charts for pediatrics. The mean systolic and diastolic (preand post-dialysis) blood pressure readings of five consecutive sessions were recorded. Blood pressure index was calculated by dividing the patients' mean systolic and diastolic blood pressure measurements by the 90 th percentile of systolic and diastolic blood pressure, respectively, using blood pressure charts appropriate for the patients' age and sex.  The patient were considered hypertensive if the blood pressure index was more than 1.
Standard pre-dialysis blood investigations (i.e., hemoglobin, urea, creatinine, calcium, phosphorus, alkaline phosphatase, sodium, potassium and serum albumin) were performed on samples collected before dialysis at a midweek dialysis session.
Urea kinetic using equilibrated Kt/V urea was calculated from the pre and post-treatment urea concentrations according to the Daugirdas' equation. 
Determination of the serum C-reactive protein (hs-CRP) levels was performed using Accubind ® kits (immunoenzymometric assay, Monobind Inc., Lake Forest, CA, USA). Regarding the risk of developing atherosclerotic cardiovascular disease, the patients were classified as having low risk (CRP < 1.0 μg/mL), normal risk (CRP = 1-3) μg/mL or high risk (CRP >3.0 μg/mL). 
The 12-lead electrocardiogram (ECG) for evidence of arrhythmia, ischemia or chamber enlargement was performed on a mid-week dialysis day following the session of HD or OL-HDF.
We used echocardiography to assess the left ventricular function by determination of fractional shortening and ejection fraction. The patients were considered to have systolic dysfunction if they had either fractional shortening below 28% or border-line fractional shortening with manifestations of left ventricular failure.  Furthermore, a Doppler sample volume was placed at the mitral valve leaflet tips and left ventricular diastolic function was assessed through the determination of the mitral deceleration time (DT). Doppler mitral inflow velocity determination including early diastole/atrial contraction maximal velocity ratio (E/A ratio) was also obtained. Accordingly, the patients were categorized as either having normal, impaired left ventricular relaxation (E/A < 1 or DT >275 msec) or restrictive pattern (E/A >2.5 or DT < 110 msec). 
Left ventricular internal diameter in diastole (LVIDD), posterior wall thickness in diastole (PWTD) and interventricular septum thickness in diastole (IVSTD) were measured and left ventricular mass index (LVMI) was calculated using the equation proposed by the American Society of Echocardiography (ASE):
LVMI = 0.8 (1.04 [(LVIDD + PWTD + IVSTD) 3 - (LVIDD) 3 + 0.6 g
Then, LVMI was indexed to the patient's body surface area. Left ventricular hypertrophy (LVH) was considered present in children when the LVMI was >103 g/m 2 in males and >84.2 g/m 2 in females, or if the IVSTD was above the normal value for patient's body surface area (BSA) and weight using the normal echocardiographic values chart. 
Echocardiography was performed by the same operator, on a mid-week dialysis day following the session of OL-HDF and conventional HD. The echocardiographic assessment was performed by means of a Hewlett Packard Sonos 5500 ® echocardiography system (Hewlett Packard, Palo Alto, CA, USA) immediately following the end of the dialysis session using S4 and S8 ultraband cardiac transducers with a frequency range of 2-4 MHz and 3-8 MHz, respectively. The echocardiographic assessment was performed through the apical four-chamber and the long axis left parasternal views.
A written informed consent was obtained from the patients' custodians prior to the study. The current study agreed with the Declaration of Helsinki and its revisions, and it was approved by the committee on human experimentation in the Center of Pediatric Nephrology and Transplantation (CPNT), Cairo University Children Hospital, and received as well the approval of the research and scientific committee of the general pediatric department, Cairo University.
| Statistical Analysis|| |
Numerical data were expressed as mean, standard deviation and range. All statistical testing was performed using the SPSS statistical package (version 16.0 for Windows, SPSS Inc., Chicago, IL, USA). Data were analyzed by using the paired t-test for normally distributed continuous variables and the chi-squared test for categorical variables. The Pearson correlation test was used for evaluating the correlation between the variables. A P-value of < 0.05 was considered statistically significant.
| Results|| |
The study included 30 patients on regular HD; 12 (40%) males and 18 (60%) females with a mean age of 11.3 ± 3.2 years (range from 4 to 16 years). The mean duration of HD was 53 ± 32 months (range from 6 to 147 months). [Table 1] and [Table 2] show the clinical and laboratory parameters in the study patients. The distribution of causes of kidney disease in the study group is summarized in [Figure 1].
The mean of the hs-CRP level during the OLHDF was 3.4 ± 3 μg/mL (range from 0.2 to 13 μg/mL) compared with 7.9 ± 8.9 (range from 0.3 to 35.7 μ g/mL) during conventional HD (P = 0.01). The frequency of the patients with a high risk of developing atherosclerotic cardiovascular disease (using increased hs-CRP as a marker for this risk) during the conventional HD and the OL-HDF was 18 (60%) versus nine (30%) patients, respectively, P = 0.01.
The results of the echocardiographic assessment and the ECG abnormalities are summarized in [Table 3]. There was a significant improvement in systolic function (FS) when changing to the OL-HDF, while diastolic dysfunction appeared unchanged. However, the frequency of diastolic dysfunction in the form of decreased relaxation or restrictive pattern during HD was greater than that during the OL-HDF, P = 0.04. There was a significant improvement in the overall frequency of patients without diastolic dysfunction during the OL-HDF compared with the frequency during the conventional HD (n = 25 vs. n = 19, respectively), P = 0.003, [Figure 2].
|Figure 2: Frequency of myocardial diastolic dysfunction among the study group.|
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|Table 3: Electrocardiogram (ECG) and echocardiographic findings in the study group (n = 30).|
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LVMI, as an indicator for LVH, did not significantly decrease during the OL-HDF when compared with the conventional HD (P = 0.73), and there was no significant change in the frequency of patients with LVH during HD and OL-HDF (n = 18 vs. n = 19, respectively), P = 0.39.
Finally, there was a positive correlation between pre and post-dialysis MBPI and LVMI, both during the conventional HD and the OL-HDF [Figure 3].
|Figure 3: Correlation between mean blood pressure index (MBPI) and left ventricular mass index (LVMI) both during conventional hemodialysis (left) and on-line hemodiafiltration (right).|
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| Discussion|| |
The results of our study showed that the systolic function of the myocardium improved in this study, as shown by significant improvement in FS and EF. As for the myocardial diastolic function, we found that both indices of diastolic function used (DT and E/A ratio) lie within the normal range and without significant difference between the conventional HD and the OL-HDF, but there was a significant reduction in the overall frequency of patients with diastolic dysfunction during the OL-HDF compared with the conventional HD.
In their review of the literature, Locatelli et al concluded that evidence supports that the HDF is associated with improved myocardial function. This was based on what Teo et al found in their randomized crossover study, where they showed that higher convective transport achieved with the HDF was associated with improved myocardial function in both the short-and the long-term follow-up, with significantly higher ejection fraction and fractional shortening on the HDF than on the conventional HD. , The Cochrane study reviewing 20 randomized controlled studies performed on 657 patients until 2006 was unable to demonstrate whether convective modalities including the OL-HDF have significant advantages over the conventional HD regarding clinically important outcomes, including mortality, dialysis-related hypotension and hospitalization.  Nevertheless, the authors mentioned that the studies were generally small, with suboptimal quality. In a more recent large study on 906 patients equally subdivided into equal groups to conventional HD and OL-HDF. Maduell et al showed that the OL-HDF was associated with a 33% lower risk of cardiovascular mortality and 30% lower risk of all-cause mortality. 
Another recent meta-analysis of 65 trials (29 crossover and 36 parallel-arm) performed on 12,182 patients showed that convective therapy showed a significant decrease in cardiovascular mortality but a non-significant decrease in all-cause mortality and no change in cardiac morpohological parameters. 
In our study, the improvement in the systolic and diastolic myocardial function could not be attributed to changes in hemoglobin or hematocrit levels, which were proved to be significantly unchanged, and it could not be attributed to changes in blood pressure because all values and calculated indices proved to be also statistically unchanged. Many authors also support the evidence that there is no change in blood pressure values between the convective (i.e., OL-HDF) and the diffusive (i.e., low-flux dialysis) therapies. ,,, This improvement also could not be attributed to change in anti-failure medications (that actually were less used, but not statistically significantly, during the OLHDF).
In our study, there was no statistical improvement in Kt/V during the HDF compared with the conventional HD, but there were significant improvements in the pre-dialysis blood urea nitrogen levels. This could be due to the improvement of the chronic inflammatory state thus reducing the rate of catabolism and urea formation. Similar results were found in the RISCAVID  and other studies. ,
In the current study, there was a significant reduction in the hs-CRP serum levels during the OL-HDF compared with the conventional HD. The frequency of patients with elevated hs-CRP during the OL-HDF was also significantly lower compared with those on the conventional HD. This may be attributed to the observation that the OL-HDF combines the use of high-flux synthetic membrane with ultrapure dialysis fluid.  Multivariate analysis adjusted for comorbidity and demographic characteristics showed CRP as the most powerful mortality predictor (P < 0.001), followed by IL-6. 
The on-line-HDF was well tolerated, with no significant difference in blood pressure change during the dialysis session between the conventional HD and the OL-HDF, indicating that the OL-HDF does not cause hemodynamic changes more than the conventional HD. Some studies found that the OL-HDF can be performed safely and for an extended period up to six years. 
There were some limitations in our study. First, the small number of patients limited the power of the study and its conclusions. Second, this was a short-term study, and prolonging its period may result in more improvement in some variables that need a long time to change, such as LVMI. Finally, we could not elucidate the exact mechanism by which the OL-HDF could be associated with better myocardial function than the conventional HD. However, several explanations may be proposed: The removal of a wider spectrum of uremic solutes, improved intra-dialytic hemodynamic stability and the combination of the high-flux synthetic biocompatible membranes with the ultrapure dialysis fluid. 
We conclude that our study suggests that the use of the OL-HDF in pediatric HD patients can result in improvement of the systolic function of the myocardium. Also, there was a significant improvement in the overall frequency of diastolic dysfunction. LVMI remained unchanged all through the study period; however, a longer follow-up duration may be needed before evaluating the impact of the OL-HDF on LVH. At last, the value of the OL-HDF in improving the chronic inflammatory state commonly seen in dialysis patients could add to its beneficial effects in decreasing the risk of the different cardiovascular morbidities.
Conflict of interest
No conflict of interest is present in this work and no grants were provided for this study.
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Dr. Samuel H Makar
Nephrology Department, Cairo University Pediatric Hospital, Cairo
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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