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Dialysis & Kinetics

Effects of Acetate-Free Double-Chamber Hemodiafiltration and Standard Dialysis on Systemic Hemodynamics and Troponin T Levels

Selby, Nicholas M.; Fluck, Richard J.; Taal, Maarten W.; McIntyre, Christopher W.

Author Information
doi: 10.1097/01.mat.0000189725.93808.58
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Abstract

Despite sequential improvements in hemodialysis technology, intradialytic hypotension (IDH) occurs in 20–30% of hemodialysis treatments. In addition to the unpleasant symptoms experienced by patients, a fall in blood pressure (BP) during hemodialysis is an independent risk factor for mortality.1 Historically, acetate was used as the sole buffer in hemodialysis. However, it was recognized that acetate was an etiological factor in IDH, and switching from acetate to bicarbonate as the principle buffer improved cardiovascular stability and reduced intradialytic symptoms.2 Despite this, the etiology of acetate-induced IDH remains contentious. Acetate has been shown to cause vasodilatation that is mediated by nitric oxide release, but has also been shown to reduce myocardial contractility.3–6 Many of these studies were carried out in animal models, and debate remains about validity of the results from some of the studies in humans.

However, bicarbonate-based dialysis is not acetate free. Small amounts of acetate (3–4 mmol/l) are required to prevent precipitation of calcium carbonate, and although the concentration of bicarbonate in dialysate is relatively large compared with that of acetate, the difference in dialysate/plasma concentration gradients is much less because plasma acetate levels are usually very low (<100 μmol/l).7 Therefore, standard bicarbonate-based dialysis can still result in significant transfer of acetate to the patient, making up as much as 25–49% of the buffer load.7,8

Paired hemodiafiltration (PHF) is a novel online technique that uses a double-chamber dialyzer (consisting of a high-flux dialyzer and ultrafilter) that allows reinfusion to take place inside the dialyzer. PHF can be used with dialysate that is completely acetate free. In place of acetate, the dialysate concentrate contains hydrochloric acid (which is converted to water and sodium chloride during online dialysate preparation), and there is no requirement for a sterile bicarbonate infusion. One previous study has shown that PHF is a feasible technique,9 but there are no studies examining the clinical and hemodynamic response to acetate-free PHF.

Cardiac troponin T (cTnT) is a marker of myocardial ischemic damage and is commonly elevated in hemodialysis patients.10 A number of explanations for this have been proposed, including cross-reactivity of the first-generation assays with skeletal troponin, accumulation of cTnT or its fragments which may be detected by commercial assays,11 or increased release of cTnT in response to subclinical reductions in myocardial blood flow.12 However, it is recognized that chronically elevated cTnT levels are predictors of cardiovascular {missing word} and all-cause mortality in this patient group.13 cTnT levels rise acutely after standard hemodialysis, and in conjunction with data that show reductions in myocardial perfusion during dialysis,14 it seems possible that at least in part, elevated cTnT levels represent new release from myocardial cells.

In this study, we aimed to investigate whether PHF is capable of abrogating the changes in systemic hemodynamics and in biomarkers of myocardial damage seen with conventional hemodialysis.

Subjects and Methods

Patients

We recruited 12 patients on long-term Hemodialysis for a prospective randomized crossover study; two patients were female, all had been on dialysis for more than 6 months, 10 patients had native arteriovenous fistulae, and 2 were dialyzed via tunnelled internal jugular catheters. All but one patient was anuric. Remaining baseline patient information is shown in Table 1.

Table 1
Table 1:
Baseline Characteristics of Randomized Patients

A mixture of hypotension-prone and Hypotension-resistant patients were recruited. Six patients were defined as “unstable on dialysis” meaning they had episodes of intradialytic hypotension (IDH) in more than 30% of dialysis sessions in the month before recruitment to the study. IDH was defined as systolic blood pressure (SBP) of 100 mm Hg or lower even in the absence of symptoms, or a fall in SBP of more than 10% of the predialysis reading in association with any of the classical symptoms of hypotension (headaches, cramps, light-headedness). The remaining six patients were defined as “stable on dialysis.” Patients were excluded if they had a hemoglobin level of less than 10 g/dl, or if they had significant comorbidity that, in the opinion of the investigator, would make completion of the study unlikely.

Study Protocol

All patients gave informed consent before commencement, and ethical approval for the project was granted by Derbyshire Local Research Ethics Committee. Upon entry to the study, patients had their dry weight confirmed with reference to clinical examination, serial blood pressure readings, and relative blood volume monitoring. After this, dry weight and antihypertensive medications remained unchanged for the duration of the study. Patients were then randomized to group A or B. Group A patients were commenced on standard three-times-weekly hemodialysis, whereas group B patients started three-times-weekly PHF treatment. Both groups underwent 1 week of stabilization before one of the dialysis sessions during the second week was monitored. At the end of the second week, patients then crossed over to the other dialysis modality thereby acting as their own controls. After a further week of stabilization, patients underwent a second monitored session.

For each monitored dialysis treatment, noninvasive hemodynamic monitoring was undertaken using a Finometer. The finger cuff was left in place for the entire session, and the nonfistula arm was used. To obtain baseline values, monitoring was commenced 30 minutes before commencement of dialysis. Body temperature was recorded before and after each session using a digital tympanic thermometer (First Temp, Sherwood Davis & Geck, St. Louis, MO). Blood samples were collected before and after each session in lithium heparin and EDTA tubes, and biochemical analysis performed on a multichannel autoanalyzer. Cardiac troponin T analysis was performed using a third-generation electrochemiluminescence assay (Roche diagnostics, Lewes, UK). Postdialysis cTnT values were corrected individually for hemoconcentration with reference to percentage change in hematocrit and blood volume using the formula:

where cTnTpost equals postdialysis cTnT, Hctpost equals postdialysis hematocrit, Hctpre equals predialysis hematocrit, BVpost equals end-dialysis blood volume, and BVpre equals start-dialysis blood volume. Single pool Kt/Vurea values were calculated from before and after urea levels.15 Predialysis blood tests were drawn immediately after insertion of access needles, and postdialysis levels were taken from the arterial line 10 seconds after reducing blood pump speed to 50 ml/min. An investigator was present for the entirety of every dialysis session to record intradialytic symptoms.

Primary endpoints were percentage change in blood pressure (BP), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) in response to hemodialysis and PHF. Secondary endpoints were changes in cTnT in response to the two dialysis modalities.

Finometer

The Finometer (Finapres Medical Systems, Arnhem, The Netherlands) allows continuous noninvasive pulse-wave analysis at the digital artery.16 The technology uses the finger-clamp method to record digital artery pulse waveform, and from this, reconstructs a central aortic waveform that allows calculation of a full range of hemodynamic variables on a continuous basis, for each heartbeat.17 These include pulse rate (HR), BP, SV, CO, and TPR. This technology is being increasingly used to assess chronic dialysis patients.18–21 Previous work has validated the Finometer against invasive hemodynamic measurements in normals, unstable intensive care patients, and in cardiac surgery patients, a proportion of whom had vascular calcification.22–24 This has shown the Finometer to be accurate in tracking relative change. Data are therefore presented as percentage change from baseline except for BP, which is calibrated against brachial readings using a return to flow method, and for this, absolute values are shown.25

Bicarbonate Dialysis and Paired Hemodiafiltration

All dialysis treatments were performed using Formula 2000 monitors (Bellco, Mirandola, Italy). Hemodialysis was performed using either 1.8 m2 or 2.0 m2 low-flux polysulphone dialyzers as per individual patients' usual prescription (LOPS 18/20, Braun Medical Ltd, Sheffield, UK). PHF has been described in detail previously9 and was performed using Diapes polyethersulphone double chamber dialyzers consisting of a combined 1.9 m2 dialyzer and 0.7 m2 ultrafilter (Bellco, Mirandola, Italy). PHF is an on-line hemodiafiltration technique and was used in predilution mode with the ultrapure infusion rate set at 10 l/h. For both treatments, dialysate contained sodium 138 mmol/l, potassium 1–2 mmol/l, calcium 1.25 mmol/l, magnesium 0.25–5 mmol/l, bicarbonate 32 mmol/l and glucose 1g/l. For hemodialysis treatments, dialysate contained acetate 3 mmol/l, whereas for acetate-free PHF the dialysate concentrate contained hydrochloric acid at 3 g/l. For hemodialysis, sodium conductivity was set at 13.6 ms/cm. To ensure equivalent sodium removal during PHF, during the stabilizing week intradialytic sodium levels were monitored using a bedside analyser (AVL analyser, Roche diagnostics, Lewes, UK) and conductivity set to ensure identical end-dialysis plasma sodium levels. Other aspects of dialysis treatments did not differ between groups. All treatments were of 4 hours duration and anticoagulation was achieved with unfractionated heparin. Dialysate flow was 500 ml/min and dialysate temperature was set at 36°C. For each session, net fluid removal was set on an individual basis according to dry weight. Blood pump speed varied between 250 and 450 ml/min depending on patients' vascular access, but each individual patient had the same blood flow for his or her two monitored sessions.

Troponin Analysis in the General Dialysis Population

To supplement the cTnT data, we recruited another 54 patients to obtain cTnT, creatinine kinase (CK), and creatinine kinase MB (CK-MB) profiles in a representative group of our center's hemodialysis population. All of these patients had been established on dialysis for more than 6 months, with 40 being defined as “stable” and the remaining 14 “unstable” as per the above definition. Less than 10% in each group had documented ischemic heart disease. A single predialysis blood sample was collected in each of the 54 patients. Blood collection and analysis was performed as described earlier.

Statistical Analysis

Results are expressed as the mean ± SD, or for nonparametric data as the median with the interquartile range (IQR) within parentheses. Data for cTnT underwent logarithmic transformation before analysis due to the distribution of the data points. For statistical analysis, the paired t test for parametric data and Wilcoxon analysis for nonparametric data were used. An alpha error at p < 0.05 was judged to be significant.

Results

Blood Pressure and Heart Rate

Mean BP was higher during hemodialysis as compared with PHF. During hemodialysis, mean systolic BP (SBP) for the entire session was 145.5 ± 8.0 mm Hg, mean diastolic BP (DBP) was 80.8 ± 3.5 mm Hg, and mean of the mean arterial pressure (MAP) was 104.1 ± 5.2 mm Hg. During PHF, mean SBP for the entire session was 7.7 mm Hg lower at 137.8 ± 5.3 mm Hg (p < 0.0001), mean DBP was 1.6 mm Hg lower at 79.2 ± 1.9 mm Hg (p = 0.005) and mean MAP was 3.6 mm Hg lower at 100.5 ± 2.9 mm Hg (p < 0.0001). As is apparent from the wider ranges and larger standard deviations, there was more variation in BP during hemodialysis. Blood pressure data are summarized in Figure 1.

Figure 1.
Figure 1.:
Mean blood pressure for hemodialysis and paired hemodiafiltration. During PHF, BP was lower (SBP p < 0.0001, MAP p < 0.0001, DBP p = 0.005) but there was less variation in BP. BP fell in the last 15 minutes of hemodialysis but was maintained during the same period of PHF.

The total number of IDH episodes during hemodialysis was 37, as compared with 23 episodes during PHF. There were relatively few symptomatic episodes of IHD: two during both hemodialysis and PHF. The remaining IDH episodes were asymptomatic SBP recordings less than 100 mm Hg. The difference in mean number of IDH episodes between hemodialysis and PHF did not reach statistical significance. For the asymptomatic episodes, no corrective action was taken. For two of the four symptomatic episodes, ultrafiltration was temporarily stopped and 200 ml of saline or online reinfusate was delivered (depending on modality). For the other 2 episodes, symptoms resolved with temporary cessation of ultrafiltration.

Heart rate did not differ between hemodialysis and PHF treatments, with mean values for the entire session of +2.1% ± 3.2 % and +2.9% ± 3.9 %, respectively (p = 0.199). During both treatments, there was a trend for HR to increase slightly. HR data are summarized in Figure 2.

Figure 2.
Figure 2.:
Hemodynamic changes during hemodialysis and paired hemodiafiltration. There was no difference between the responses in HR to each modality, with a trend for slight increase in HR throughout both dialysis treatments. SV and CO declined during both treatments, but to significantly greater degree during hemodialysis. TPR increased progressively throughout both treatments, but to a greater extent during hemodialysis.

Hemodynamic Data

Hemodynamic and BP measurements at baseline were compared to ensure repeatability of measurement technique and conditions. There were no significant differences in any of the parameters between hemodialysis and PHF.

Stroke volume progressively declined during both treatments relative to baseline, but to a greater extent during hemodialysis. Mean SV for the entire hemodialysis session was –24.8% ± 8.4% and mean SV during PHF was –18.5% ± 8.6% (p = 0.003). SV at the end of hemodialysis had fallen by –47.9% of baseline, and by –30.9% of baseline at the end PHF. As a product of HR and SV, CO showed similar changes. During hemodialysis, CO declined by –37.4% from baseline, with a mean value for the entire session of –24.8% ± 6.6%. During PHF, CO declined by –24.6% from baseline and the mean value was significantly higher at –15.2% ± 6.3% (p < 0.0001).

Total peripheral resistance rose progressively during both treatments. However, in light of the changes in CO, TPR rose to a greater degree during hemodialysis. TPR rose by 71% from baseline during hemodialysis, with a mean value for the entire session of +39.3% ± 14.5%. During PHF, TPR rose by 47.9% with a mean value of +19.4% ± 10.3%. The difference in mean TPR values was statistically significant (p < 0.0001). All hemodynamic data are summarized in Figure 2.

The above data pertain to the population as a whole. Examining hemodynamic and blood pressure data for individual patients, 9 out of 12 demonstrated similar changes although 2 patients exhibited a greater increase in HR during PHF as compared with hemodialysis. One patient demonstrated no differences between hemodialysis and PHF. The remaining 2 patients exhibited opposite findings to the overall data, with greater decline in CO and a greater rise in TPR during PHF as compared with hemodialysis.

Biochemical Results

There were significant differences in cTnT between the two treatments. Pre-PHF median cTnT levels were lower at 0.03 (IQR 0.03–0.16) μg/l as compared with hemodialysis with a median of 0.05 (IQR 0.03–0.12) μg/l (p = 0.031). Posthemodialysis median cTnT levels (adjusted for hemoconcentration) rose to 0.06 (IQR 0.035–0.17) μg/l, whereas adjusted post-PHF median cTnT levels fell to 0.02 (IQR 0.01–0.07) μg/l (p < 0.0001). There was also a statistically significant difference between median prehemodialysis and adjusted posthemodialysis values (p = 0.01) and for pre- and post-PHF values (p = 0.0008). cTnT data are summarized in Figure 3.

Figure 3.
Figure 3.:
Cardiac troponin T levels before and after hemodialysis and PHF. After-treatment levels are corrected for hemoconcentration. Pre-PHF cTnT median levels were lower as compared with hemodialysis (p = 0.02). Posthemodialysis median cTnT levels rose, whereas adjusted post-PHF median cTnT levels fell (p < 0.0001). There was also a statistically significant difference between median before and after values for hemodialysis (p = 0.01) and PHF (p = 0.0008).

The cTnT data for the general dialysis population is summarized in Table 2. Predialysis median serum cTnT was significantly higher in the unstable group of patients, but there were no significant differences between the median CK or CK-MB levels. Other biochemical results from and blood samples taken before and after treatment are shown in Table 3. Most blood tests were similar between the two treatments, including plasma sodium levels. Equally, there were no differences between dialysis treatments for mean intradialytic sodium levels at 1 and 3 hours (p = 0.53 and 0.49, respectively). Median serum bicarbonate levels were 3.0 mmol/l lower before PHF as compared with prehemodialysis levels (p = 0.031), but posttreatment levels were similar between the two.

Table 2
Table 2:
General Dialysis Population Predialysis cTnT, CK, and CK-MB Levels, with Patients Classified as “Stable” or “Unstable” on Dialysis
Table 3
Table 3:
Biochemical and Hematological Results for Hemodialysis and PHF

Dialysis Details

Predialysis body weight was 76.2 ± 12.6 kg for hemodialysis and 76.3 ± 12.7 for PHF (p = 0.93). There were no differences between the two treatments in relative blood volume reduction, ultrafiltration rate, single-pool Kt/V, or change in body temperature. Fluid removal and reduction in plasma sodium were also the same for each modality. In all patients, the prescribed dry weight was achieved. These data are shown in Table 4. During the stabilizing week of PHF, dialysate sodium conductivity was tailored to deliver the same end-dialysis plasma sodium level as hemodialysis. In predilution mode, this resulted in PHF sodium conductivity being set 2 ms/cm higher than hemodialysis in all patients.

Table 4
Table 4:
Comparison of Dialysis Parameters between Hemodialysis and PHF

Discussion

Intradialytic hypotension remains a major clinical problem within the hemodialysis population. Acetate transfer is significant during bicarbonate-based hemodialysis and may be a factor in the etiology of IDH. This study demonstrates that acetate-free PHF is associated with improved hemodynamics and a lower BP, but with a trend toward less IDH and lower cTnT levels compared with hemodialysis.

The hemodynamic response to PHF was characterized by attenuation of the characteristic decline in SV and CO seen with hemodialysis, and as a result, a smaller increase in TPR was observed. These differences were present despite identical fluid removal, relative blood volume change, and plasma sodium levels before, during, and after dialysis. It remains contentious as to whether acetate transfer during dialysis causes myocardial depression. Although several studies do show that acetate causes a reduction in myocardial contractility,3–6 there are other studies that do not confirm this. It has been postulated that acetate directly affects myocardial contractility, although it is also possible that increased endothelial NO production stimulated by acetate affects the baroreflex arc.4,26 In terms of the findings of our study, it is possible that the lack of acetate transfer during PHF treatments resulted in less suppression of myocardial contractility. However, one potential weakness of our study is that we were unable to measure plasma acetate levels, although previous work has confirmed significant acetate transfer occurring during bicarbonate dialysis.7,8

An alternative explanation for our results would be that the improved hemodynamics seen with PHF are due to the comparison of a predominantly convective with a diffusive technique. However, there is accumulating evidence that the acute benefit of convective therapies on improved stability during dialysis is due to increased patient cooling, which is mediated by a greater rise in TPR. When the therapies are matched for extracorporeal energy balance, low flux dialysis is equivalent in terms of IDH frequency and changes in systemic hemodynamics to both pre- and postdilution hemodiafiltration.27,28 These results also show that differences in solute clearance cannot explain the improved hemodynamics of hemodiafiltration. In our study, we seem to have avoided significantly greater cooling during PHF by reducing the dialysate temperature during hemodialysis. Change in patients' body temperature did not differ between the two modalities, and TPR was lower during PHF. However, one potential weakness of our study is that we did not have access to thermal energy measurement equipment to formally document energy transfer during dialysis treatments. Other suggested mechanisms to explain improved stability with convective therapies include differences in sodium removal and improved biocompatibility. In our study, treatments were matched for changes in plasma sodium, and the membranes and lines were of sufficient similarity to make a difference to biocompatibility unlikely. Therefore, it seems more likely that the lack of acetate as opposed to the difference in convection explains our results, although the design of this study cannot exclude other, as yet undiscovered, advantages of convective therapies.

Vasodilatation, another well-recognized effect of acetate, did not seem to be predominant because TPR was higher during hemodialysis. The higher TPR seen with hemodialysis may have occurred in response to the greater fall in SV and CO, suggesting that a greater degree of vasoconstriction was required during hemodialysis to prevent hypotension. These observations were unexpected, because many studies have shown that acetate can cause vasodilatation, although most of this work is in respect to acetate dialysis where acetate transfer would be higher as compared with standard bicarbonate hemodialysis. If acetate is responsible for the observed differences in our study, then this might suggest that the myocardial depressant effects of acetate are the predominant influence at the levels experienced during bicarbonate dialysis.

Overall BP was lower during PHF, but was preserved with fewer fluctuations compared with hemodialysis. This was especially evident in the last 15 minutes of the treatments when BP during hemodialysis dropped but during the same period of PHF was maintained. In addition, there was a trend toward fewer episodes of IDH during PHF treatments. This study was not powered to detect a significant difference in IDH episodes, and it may be that this trend towards less IDH would have been statistically significant if participant numbers were larger or more sessions were studied. In support of this, acetate-free biofiltration, a technique that uses base-free dialysate and a postdilution infusion of ultrasterile bicarbonate, has been shown to reduce IDH as compared with standard dialysis.4 Furthermore, one longer-term study showed acetate-free biofiltration to provide improved control of predialysis BP that is consistent with our findings of lower blood pressure during PHF, but without increased instability.29 The results from our study show that the higher BP with hemodialysis was due to an excessive rise in TPR (greater than that required to compensate for the larger fall in CO), but the mechanisms behind this remain obscure.

We observed significant differences between hemodialysis and PHF in serum cTnT levels both before and after dialysis. Levels were lower before PHF than before hemodialysis, and after PHF the levels fell further. After hemodialysis, cTnT levels rose. Elevated troponin levels in the absence of an acute coronary syndrome have been shown to be a strong predictor of death in dialysis patients,13 and an acute rise in cTnT after hemodialysis is well described.10 Dialysis patients are at risk of myocardial hypoperfusion without acute atherosclerotic plaque rupture,12 and dialysis has been shown to induce myocardial perfusion defects.14 Therefore, one explanation for the acute rise in cTnT after dialysis is that the BP fluctuations and change in volume status seen during hemodialysis may be sufficient to induce subclinical myocardial ischemia. This is supported by our finding of higher cTnT levels in IDH-prone patients in our general dialysis population, who are more at risk of myocardial hypoperfusion. If dialysis does cause subclinical myocardial ischemia, then this may have the potential to impair cardiac performance. The lower pre dialysis cTnT levels (possibly signifying reduced overall release) and the improved myocardial performance may indicate that this effect is less with PHF.

Alternatively, it is possible that the fall in cTnT levels with PHF was due to increased clearance across the high flux membrane. High flux membranes clear molecules up to 15 kd by diffusion and can clear larger molecules up to 25 kd by convection. However, cTnT is a charged molecule that is 38 kd, and some individual patients demonstrated as much as a 50% reduction in cTnT levels. It has been shown that smaller cTnT fragments (8–25 kd) are also present in the serum of dialysis patients,11 and these might be cleared significantly by PHF. However, it has not been possible to quantify the amount (if any) that these fragments contribute to the current third generation commercial assay results.11 Therefore, to determine the mechanism of the reduced cTnT levels seen with PHF, it would be necessary to compare pre- and postdialysis cTnT levels with PHF versus a standard hemodiafiltration technique that provides similar clearance.

Pre-PHF bicarbonate levels were noted to be slightly lower than prehemodialysis levels, although there was no difference in postdialysis levels. This may reflect the fact that acetate will continue to be converted to bicarbonate in the immediate postdialysis period, and as a result, serum bicarbonate levels can initially continue to rise. In contrast, the postdialysis serum bicarbonate with acetate-free dialysis represents the maximum level achieved. Our results suggest that bicarbonate conductivity should be set 3–4 ms/cm higher for PHF than hemodialysis to achieve equivalent overall acid-base control. Sodium balance during predilution hemodiafiltration remains a matter of debate, with different authors reaching different conclusions. We took a pragmatic approach to ensure the dialysis modalities were matched in terms of change in plasma sodium concentrations but did not perform detailed sodium balance studies. However, our findings of slightly higher conductivity settings during PHF have been previously reported during predilution hemodiafiltration.30 We can only speculate as to possible causes, but this may be due to large infusion volumes added before the dialyzer leading to a reduction in the Donnan effect. Therefore, despite the relative hypotonicity of the reinfusate, the ultrafiltrable sodium fraction may have been increased.

Small patient numbers may potentially limit our study findings. However, by providing data for each pulse wave, the Finometer offers extremely high resolution of data differences. This allows accurate detection of even small degrees of change in any of the hemodynamic variables measured and at least partially compensates for the effect of smaller sample size.

Conclusion

This study demonstrates that acetate-free PHF is associated with a lower BP without increased instability and significantly less deterioration in systemic hemodynamics as compared with cool temperature low-flux bicarbonate-based dialysis. One possible explanation for this is the absence of acetate that may be important in maintaining myocardial contractility, although this remains speculative at present. Standard dialysis may result in subclinical myocardial damage that may in part explain elevated cTnT levels, whereas PHF may be associated with a reduction in myocardial cell injury, increased clearance of cTnT across a high-flux membrane, or a combination of both. This study provides initial evidence that PHF may be a superior treatment in select patient groups (IDH prone, severe coronary artery disease). However, further studies are required to further delineate the underlying mechanisms of the hemodynamic response to PHF and examine the potential beneficial effects of PHF on long-term patient outcome.

Acknowledgments:

The authors gratefully acknowledge Bellco, who provided the consumables and dialysis monitors for this study.

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