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10.1080/0886022X.2024.2398709
2398709
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Research Article
Hemodialysis and Peritoneal Dialysis
Switching from acetate to citrate dialysate in a central concentrate delivery system for high-volume online hemodiafiltration: a retrospective cohort study
J. Y. Lee et al.
Lee Jee Young a
Kim Ki Sung a
Cho Hyun Jin a
Joo Yoosun b
Lee Yong-Jeong c
Park Jung-Hwan a
Jo Young-Il a
a Division of Nephrology, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
b Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
c Dialysis Center, Konkuk University Medical Center, Seoul, Republic of Korea
CONTACT Young-Il Jo nephjo@kuh.ac.kr Division of Nephrology, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 05030, Republic of Korea.
9 9 2024
2024
9 9 2024
46 2 239870911 4 2024
7 8 2024
26 8 2024
KnowledgeWorks Global Ltd.9 9 2024
published online in a building issue9 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Interest in citrate-based dialysate (Cit-D) is growing due to its benefits, including anticoagulation and dialysis efficacy. However, research on safety and efficiency of Cit-D in high-volume hemodiafiltration (HDF) via central concentrate delivery system (CCDS) is scarce. This study aimed to investigate the safety and efficacy of Cit-D when switching from acetate-based dialysate (Acet-D) in high-volume HDF via CCDS. This is a retrospective analysis of 28 patients who underwent post-dilution online HDF via CCDS, who switched from Acet-D to Cit-D. The study period was divided into 3 periods for analysis: 12 weeks using Acet-D (AD period), the first 12 weeks using Cit-D (CD-1 period), and the second 12 weeks using Cit-D (CD-2 period). We collected the laboratory, dialysis, and safety parameters in each period from electrical medical records. After switching from Acet-D to Cit-D, heparin dosage decreased by 17%, whereas the incidence of complications did not increase. Kt/VBUN and urea reduction ratio increased by 4.6% and 2.1%, respectively. Pre-dialysis beta2-microglobulin concentration decreased after using Cit-D. The corrected calcium levels decreased in the CD-1 period compared to the AD period, but in CD-2, they subsequently increased to levels similar to those observed during the AD period. Symptomatic hypocalcemia did not occur, and there was no significant difference in the incidence of hyperparathyroidism. Endotoxin levels and the bacterial culture of ultrapure dialysate were unremarkable throughout all periods. These results might suggest that Cit-D could potentially offer advantages over Acet-D, such as reducing the heparin dose and increasing dialysis efficiency, in patients undergoing high-volume HDF using CCDS.

Keywords

Hemodiafiltration
citrate
central dialysis fluid delivery system
acetate
beta2-microglobulin
Konkuk University Medical Center 10.13039/100019704 Konkuk University Medical Center 10.13039/100019704 K220102 This work was supported by Konkuk University Medical Center Research Grant 2022. (Grant number: K220102)
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pmcIntroduction

With increasing evidence supporting its clinical benefits and safety, the utilization of online hemodiafiltration (OL-HDF) has increased significantly [1–4]. In a recent randomized controlled trial (RCT) comparing high-flux hemodialysis (HD) with high-volume hemodiafiltration (HDF), Blankestijn et al. reported that high-volume HDF lowers the all-cause mortality rate compared to conventional high-flux HD [5]. While the safety of OL-HDF is generally not a major concern, one issue to consider is the impact of acetate in the dialysate solution. Acet-D has several disadvantages, one of which is its pro-inflammatory effects. Even small amounts of Acet-D can be problematic, and this issue is magnified in high-volume HDF where a large amount of dialysate is used [6–9]. In addition to its proinflammatory effect, Acet-D can cause increased oxidative stress, increased production of nitric oxide, and hemodynamic instability [7–10]. Therefore, citrate is sometimes employed as an alternative to acetate for use as the buffer in patients undergoing HD and OL-HDF. A citrate-based dialysate (Cit-D) offers several advantages over Acet-D, including reduced inflammatory status of patients, enhanced anticoagulant effect allowing for reduced heparin dosage, improved dialysis efficacy, correction of acidosis, and prevention of cellular damage [11–14].

However, Cit-D not only has these advantages but also drawbacks, so caution is needed when using Cit-D in HD and HDF. One prominent drawback is hypocalcemia. Citrate can bind to calcium (Ca) in the blood to induce hypocalcemia [15]. While recent studies have reported that hypocalcemia due to Cit-D is not clinically problematic in OL-HDF [16–19], large observational studies have shown an association between hypocalcemia and mortality in incident and prevalent hemodialysis patients [20, 21]. Furthermore, research on the safety of Cit-D related to hypocalcemia in high-volume HDF, which requires large amounts of replacement fluids, remains limited [18, 22–25]. Specifically, there have been no studies conducted on the safety and efficacy of Cit-D in high-volume HDF using a central concentrate delivery system (CCDS).

The dialysate is delivered via a single-patient dialysis fluid delivery system (SPDDS), or central delivery system (CDS) Central delivery system (CDS) can be divided into CCDS and central dialysis fluid delivery system (CDDS) [26, 27]. Compared to SPDDS, CDS offers several advantages such as being cost-effective, easy to maintain, and requiring limited labor [28]. However, it has disadvantages such as the potential for contamination during concentrate preparation and the inability to adjust the composition and concentration of the dialysate to meet individual patient needs [26]. Among these disadvantages, the inability to adjust the composition and concentration of the dialysate according to individual patient needs could be a significant concern when implementing HDF using Cit-D in CDS. Because Cit-D binds to ionized calcium, it can reduce ionized calcium levels [15]. Failure to appropriately address such hypocalcemia can lead to serious side effects, making it an issue that cannot be overlooked. Nevertheless, previous studies examining the efficacy and safety of Cit-D have solely focused on its use via SPDDS. Thus, this study aimed to investigate the efficacy and safety of Cit-D during high-volume post-dilution OL-HDF using a CCDS. To date, no study has yet analyzed the efficacy and safety of Cit-D in high-volume HDF using CCDS.

Materials and methods

Study design

This retrospective study was conducted at Konkuk University Medical Center from October 2018 to July 2019, involving end-stage renal disease patients who underwent post-dilution OL-HDF. Initially, our center used Acet-D with SPDDS for HD, transitioning to CCDS in April 2008. HDF was initially performed on selected patients, and by October 2018, it was extended to all eligible patients based on our center’s growing experience with HDF. However, due to the manufacturer-related issues, we were compelled to abruptly switch from Acet-D (Dri-sate DF-220ï£̈, Dri-sate DF-240ï£̈, CJ Health) to Cit-D (CDSC powderï£̈, Pharmgenscience) for CCDS in January 2019, just three months after using Acet-D. This study retrospectively analyzes our experience of transitioning from Acet-D to Cit-D in CCDS-based high-volume HDF, aiming to investigate the safety and efficacy of citrate-based dialysate in this context.

The inclusion criteria were as follows: patients who underwent stable post-dilution OL-HDF using CCDS for at least 9 months, used Acet-D for at least 3 months, used Cit-D for at least 6 months, and were 18 years or older. The exclusion criteria were as follows: patients with insufficient data available from the electrical medical record (EMR) database during the study period, patients undergoing hybrid dialysis with HDF and PD, patients with a mean value of convection volume <23 L/session, and patients with fewer than 10 dialysis sessions per each period.

The study period was divided into three phases. The first phase was 12 weeks using Acet-D (AD period). The second phase was the first 12 weeks after switching from Acet-D to Cit-D (CD-1 period). The third phase was the second 12 weeks after switching from Acet-D to Cit-D (CD-2 period) (Figure 1).

Figure 1. Study protocol.

AD: Acet-D period, CD: Cit-D period

Data on the study parameters were collected at each period. All clinical and laboratory data were obtained from the EMR database of the research hospital. The study protocol was approved by the Konkuk University Medical Center Institutional Review Board (IRB) (No. 2019-10-002). This study was completed in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.

Dialysis prescription

After switching the dialysate from Acet-D to Cit-D, the heparin dose was set at 70% of the dose used during the AD period in all patients. Subsequently, the heparin dose was titrated for each patient based on the degree of clotting within the dialyzer, increasing or decreasing as necessary to prevent clotting. Other dialysis prescriptions were maintained throughout the study. OL-HDF was performed using 5008S Basic ONLINE plus machine (Fresenius Medical Care, Bad Homburg, Germany). Each dialysis session lasted 240 min and was performed three times each week. The FX cordiax 80 or 800 (Fresenius Medical Care, Bad Homburg, Germany) filter was used based on patient status, and the filter remained unchanged during the study. Blood flow was maintained at 270–300 mL/min based on the patient’s status, whereas the dialysate flow was maintained at 500 mL/min in all patients. Bicarbonate powder was used as the dialysate buffer (Bibag®; Fresenius Medical Care, Bad Homburg, Germany). As the acid for the dialysate, acetate was used during the AD period, while citrate was used during the CD-1 and CD-2 periods. The dialysate composition included the same Ca content (2.5 mEq/L) for Acet-D and Cit-D, acid contents of 3.0 mEq/L of acetate for Acet-D, and 2.0 mEq/L of citrate for Cit-D (Table 1). The dialysate solution was delivered via central delivery system (CDS), specifically the central concentrate delivery system (CCDS) (Figure 2).

Figure 2. Scheme of central concentrate delivery system (CCDS) for online hemodiafiltration used in the present study.

ETRF: endotoxin retentive filter, HDF: hemodiafiltration

Table 1. Dialysate composition.

Compound	Acetate-based dialysate	Citrate-based dialysate	
Na+ (mEq/L)	138.0	140.0	
K+ (mEq/L)	2.0	2.0	
Cl- (mEq/L)	108.0	114.0	
HCO3- (mEq/L)	35.0	33.0	
Ca2+ (mEq/L)	2.5	2.5	
Mg2+ (mEq/L)	0.75	1.0	
Glucose (g/L)	2.0	1.0	
Acetate (mEq/L)	3.0	none	
Citrate (mEq/L)	none	2.0	

Variables

During the study period, dialysis parameters, laboratory parameters, and safety parameters were measured or collected. The dialysis parameters included dialysis duration, blood flow rate (BFR), Kt/VBUN, urea reduction ratio (URR), substitutional volume, ultrafiltration volume, convection volume, heparin dose, and filter clotting events. The variables were measured at every dialysis session except for Kt/VBUN and URR, which were measured once a month. The laboratory parameters included hemoglobin, albumin, total cholesterol, total calcium (Ca), corrected Ca, phosphate, sodium, potassium, chloride, intact-PTH (i-PTH), total bicarbonate (total CO2), pre-dialysis beta2-microglobulin (β2MG), β2MG reduction ratio, and high sensitivity-C-reactive protein (hs-CRP). Sampling for laboratory parameters was performed before mid-week dialysis during the first week of each month. The safety parameters included symptomatic hypocalcemia, bleeding episodes, infection/sepsis, clotting, and the endotoxin levels and bacterial culture of the dialysate.

Statistical analysis

Data are presented as the mean ± standard deviation (SD). However, phosphate binder and PTH lowering agent doses were presented as the mean ± standard error of the mean (SEM). The variables in the CD-1 and CD-2 periods after switching from Acet-D to Cit-D were compared to the AD period as a reference. To compare the means of continuous variables between two groups, we used paired t-test, whereas non-normally distributed parameters were analyzed using the Wilcoxon signed-rank test. We employed a chi-square test to analyze the differences in event rates between the two groups. For multiple comparisons among three groups, one-way ANOVA with Bonferroni’s post-hoc test was performed, whereas non-normally distributed data were analyzed using the Kruskal–Wallis test. Statistical analysis was performed using the IBM SPSS version 22 (IBM Inc., Armonk, NY, USA). Statistical significance was set at a p < 0.05.

Results

Baseline characteristics

Of the initial 33 patients who underwent OL-HDF, five were excluded, resulting in a final cohort of 28 patients. As shown in Figure 1, 4 patients were excluded because the duration of online HDF using Cit-D was <6 months, and one patient was excluded due to receiving hybrid therapy involving both HDF and PD. The baseline demographics and characteristics are presented in Table 2. The mean age was 63.5 years, 10 (36%) patients were men, and 21 (75%) were diabetic. The total duration of HDF treatment was 31.0 ± 17.2 months. The mean weekly duration of dialysis was 11.7 ± 1.2 h. The number of total dialysis sessions was 3,061.

Table 2. Baseline characteristics.

Clinical Characteristics	Value	
Patients (n)	28	
Male (n, %)	10 (35.7%)	
Age (yr)	63.5 ± 12.6	
BMI (kg/m2)	23.8 ± 4.9	
HDF vintage (months)	31.0 ± 17.2	
Cause of ESRD	 	
 DM	21 (75.0%)	
 Hypertension	5 (17.9%)	
 Others	2 (7.1%)	
hs-CRP (mg/dL)	0.212 ± 0.275	
Hemoglobulin (g/dL)	10.7 ± 1.0	
Total cholesterol (mg/dL)	142.0 ± 36.1	
Albumin (g/dL)	3.8 ± 0.2	
Calcium (mg/dL)	8.7 ± 0.7	
Phosphate (mg/dL)	5.3 ± 1.4	
Calcium x P (mg2/dL2)	47.5 ± 13.6	
Intact PTH (pg/mL)	232.8 ± 167.3	
Na (mmol/L)	136.7 ± 3.2	
K (mmol/L)	4.9 ± 0.7	
Chloride (mmol/L)	101.9 ± 3.6	
Total CO2 (mmol/L)	20.5 ± 2.8	
BMI, body mass index; DM, diabetes mellitus; ESRD, end stage renal disease; HDF, hemodiafiltration; hs-CRP, high sensitivity-C reactive protein; PTH, parathyroid hormone.

Safety parameters

No cases of bleeding, including gastrointestinal bleeding or intracranial hemorrhage, were observed throughout the study period. During the AD period, 6 cases of dialyzer clotting (0.59%) were observed out of 1,008 HDF sessions, while during the CD-1 period, 16 cases (1.54%) were observed out of 1,033 HDF sessions. However, there was no statistically significant difference (p = 0.84). During the CD-2 period, dialyzer clotting occurred in 7 cases (0.68%) out of 1,018 HDF sessions, showing no significant difference compared to the AD period (p = 1.00).

No cases of sepsis were observed during the AD or CD-1 periods, and only one case was observed during the CD-2 period. During the entire study period, symptomatic hypocalcemia did not occur. However, one case of asymptomatic but severe hypocalcemia during the CD-1 period. For this patient, HDF was carried out using SPDDS with Acet-D (Ca 3.5 mEq/L) instead of CCDS with Cit-D (Ca 2.5 mEq/L). Once the calcium levels normalized, CCDS with Cit-D was resumed for HDF.

The levels of endotoxins were analyzed in the pre-filter and ultrapure dialysate, and was found to be <0.03 EU/mL in all three periods. Bacterial cultures performed using pre-filter and ultrapure dialysate samples showed bacterial counts <0.1 CFU/mL in all three periods.

Dialysis parameters

The convection volume was 24.1 ± 2.0 L/session during the AD period, 24.0 ± 2.2 L/session (p = 0.150) during the CD-1 period, and 24.8 ± 2.3 L/session (p = 0.161) during the CD-2 period, with no significant differences across periods. All mean values met the criteria for high-volume OL-HDF, with 82.1%, 82.1%, and 89.2% of patients exceeding an average convection volume of 23 L/session during the AD, CD-1, and CD-2 periods, respectively. No significant differences were observed in terms of the BFR and dialysis session time among the three periods. The heparin dose was significantly reduced by 17% during the CD period compared with during the AD period (AD vs. CD-1: 4330.4 ± 1208.1 unit/session vs. 3610.6 ± 866.4 unit/session. p < 0.001; AD vs. CD-2: 4330.4 ± 1208.1 unit/session vs. 3724.3 ± 948.4 unit/session, p < 0.001). The difference among the three groups was also significant when compared using one-way ANOVA with Bonferroni’s post-hoc test (p = 0.021) (Table 3).

Table 3. Dialysis parameters for postdilution online hemodiafiltration.

 	AD period	CD-1 period	p*	CD-2 period	p**	
Blood flow rate (ml/min)	292.0 ± 15.8	291.5 ± 16.7	0.786	293.3 ± 13.8	0.328	
Session time (hour/weak)	11.9 ± 1.3	11.9 ± 1.3	0.326	11.8 ± 1.3	0.247	
Ultrafiltration volume (L/session)	2.61 ± 1.1	2.71 ± 1.1	0.115	2.58 ± 1.1	0.738	
Substitution volume (L/session)	21.6 ± 1.7	21.2 ± 1.8	0.019	22.5 ± 2.0	0.088	
Convection volume (L/session)	24.1 ± 2.0	24.0 ± 2.2	0.150	24.8 ± 2.3	0.161	
Heparin dose (unit/session)	4333.0 ± 1208.0	3610.0 ± 866.0	<0.001	3724.0 ± 948.0	<0.001	
* p: AD vs. CD-1.

** p: AD vs. CD-2.

Dialysis efficiency

URR was 78.7 ± 5.4% during the AD period, increasing to 79.8 ± 5.9% in the CD-1 period (p < 0.05) and 80.4 ± 5.6% (p < 0.05) in the CD-2 period (Figure 3-A). Kt/VBUN showed a significant elevation, with 1.920 ± 0.357, 1.993 ± 0.393 (p < 0.05), and 2.010 ± 0.391 (p < 0.05) in the AD, CD-1, and CD-2 periods, respectively (Figure 3-B). The β2MG concentration predialysis decreased significantly from 26.8 ± 5.4 mg/L in the AD period to 23.7 ± 4.9 mg/L (p < 0.05) in the CD-1 period and 25.2 ± 5.0 mg/L (p < 0.05) in the CD-2 period (Figure 3-C). The β2MG reduction ratio did not differ significantly among the three periods (AD vs. CD-1 vs. CD-2 period: 79.2% vs. 79.7% vs. 78.2%) (Figure 3-D).

Figure 3. Comparison of URR, Kt/V, pre-β2MG, β2MG reduction ratio between periods. After switching from acetate-based dialysate (Acet-D) to citrate-based dialysate (Cit-D), the CD-1 and CD-2 periods were individually compared to the AD period, with the AD period serving as the reference.

*P < 0.05

AD: Acet-D period, CD: Cit-D period, β2MG: beta-2 microglobulin, URR: urea reduction ratio

Changes in clinical and laboratory parameters

Total carbon dioxide (tCO2)

tCO2 decreased significantly during the CD-1 period compared with the AD period (AD vs. CD-1: 21.0 ± 1.8 vs. 20.1 ± 1.9 mmol/L, p = 0.005), followed by an increase in the CD-2 period with no significant difference from that obtained during the AD period (AD vs. CD-2 period: 21.0 ± 1.8 vs. 20.5 ± 1.6 mmol/L, p = 0.130). The amount of oral sodium bicarbonate administered for treatment of acidosis was not significantly different among the three periods (1 tab = 500 mg, AD vs. CD-1 period: 1.35 ± 0.32 vs. 1.46 ± 1.67, p = 0.498; AD vs. CD-2: 1.35 ± 0.32 vs. 1.71 ± 1.64, p = 0.080)

Ca

The pre-dialysis Ca concentration decreased significantly during the CD-1 period and CD-2 period compared with the AD period (AD vs. CD-1 period: 9.0 ± 0.6 vs. 8.5 ± 0.7 mg/dL, p < 0.001; AD vs. CD-2 period: 9.0 ± 0.6 vs. 8.6 ± 0.7 mg/dL, p < 0.001). The corrected Ca concentration significantly differed among the AD, CD-1, and CD-2 periods at 9.2 ± 0.6, 8.7 ± 0.7, and 8.9 ± 0.7 mg/dL, respectively (AD vs. CD-1 period, p < 0.001; AD vs. CD-2 period, p = 0.011). Furthermore, the incidence of hypocalcemia (defined by corrected Ca <8.4 mg/dL) increased significantly from 7.1% during the AD period to 32.1% during the CD-1 period and 23.8% during the CD-2 period.

Phosphate

The serum phosphate concentration increased significantly during the CD-1 period compared with that obtained during the AD period (AD vs. CD-1 period: 5.0 ± 0.9 vs. 5.6 ± 1.0 mg/dL, p < 0.001) but decreased again during the CD-2 period, showing no significant difference from that obtained during the AD period (AD vs. CD-2 period: 5.0 ± 0.9 vs. 5.2 ± 1.1 mg/dL, p = 0.272).

i-PTH

The i-PTH concentration increased significantly during the CD-1 and CD-2 periods compared with the AD period (AD vs. CD-1 period: 226.6 ± 167.8 vs. 290.6 ± 96.6 pg/mL, p = 0.004; AD vs. CD-2 period: 226.6 ± 167.8 vs. 299.1 ± 118.0 pg/mL, p = 0.003). The percentages of patients with hyperparathyroidism with a PTH concentration ≥ 300 pg/mL did not differ significantly among the AD, CD-1, and CD-2 periods at 36.9%, 38.0%, and 35.7%, respectively.

hs-CRP

No significant changes were observed in the hs-CRP levels after changing to Cit-D from Acet-D (AD vs. CD-2 period: 0.212 ± 0.276 vs. 0.145 ± 0.173 g/dL, p = 0.620, no date at CD-1 period).

Albumin

Albumin did not significantly differ between the AD and CD-1 periods (AD vs. CD-1 period: 3.8 ± 0.2 vs. 3.8 ± 0.2 g/dL, p = 0.603), but was significantly lower in the CD-2 period (AD vs. CD-2 period: 3.8 ± 0.2 vs. 3.7 ± 0.2 g/dL, p = 0.002).

Phosphate binder doses

We analyzed the alterations in the phosphate binder daily dosages per patient following the transition from Acet-D to Cit-D. The relative phosphate-binding coefficient per gram of compound (RPBC) of each phosphate binder was calculated with reference to that of Ca carbonate (1.0). The RPBC for Sevelamer hydrochloride was 0.75, while that for lanthanum carbonate was 2.0 [29]. The doses of the phosphate binders increased significantly during the CD-1 period compared with the AD period, but decreased again in the CD period-2, showing no significant differences from those obtained during the AD period (AD vs. CD-1 period: 3.49 ± 0.51 vs. 4.15 ± 0.58 tab/day, p = 0.003; AD vs. CD-2 period: 3.49 ± 0.51 vs. 4.02 ± 0.61 tab/day, p = 0.076) (Figure 4-A).

Figure 4. Changes in the dosage of phosphate binder (A) and PTH-lowering agent (B) after switching from acetate-based dialysate to citrate-based dialysate. There were no significant changes in the dosage of either phosphate binder or PTH-lowering agent (p > 0.05).

Doses of PTH lowering agent

Calcitriol 1 mcg, cinacalcet 25 mg, and paricalcitol 5 mg were set as 1 unit, and the monthly doses were compared among the three periods. Compared with the AD period, the intravenous calcitriol dose slightly increased during the CD-1 and CD-2 periods, albeit not to a significant extent (AD vs. CD-1 vs. CD-2 period: 4.78 ± 0.97 vs. 5.50 ± 1.18 vs. 5.33 ± 1.22 unit/month, p = 0.969). The cinacalcet dose tended to decrease during the CD-2 period compared with the AD period, although also not significantly (AD vs. CD-1 vs. CD-2 period: 12.12 ± 4.28 vs. 12.49 ± 4.61 vs. 9.27 ± 4.3 unit/month, p = 0.716). During the CD-2 period, there was a tendency for the paricalcitol dose to increase compared to the AD period, although this was not statistically significant (AD vs. CD-1 vs. CD-2 period: 1.07 ± 0.74 vs. 0.70 ± 0.49 vs. 1.42 ± 0.81 unit/month, p = 0.845) (Figure 4-B).

Discussion

The results of this study suggest that the use of Cit-D for high-volume OL-HDF via CCDS may offer potential advantages over Acet-D, such as reducing heparin dosage and improving dialysis efficiency. However, it is important to consider the limitations of this study, which is a small-scale retrospective analysis conducted over a short duration.

Using Acet-D with CCDS offers several advantages beyond cost-effectiveness compared to SPDDS, making it suitable for use not only in HD but also in OL-HDF [30]. In contrast to SPDDS, CCDS poses difficulties in tailoring the composition of dialysate to individual patient needs. Since high-volume HDF requires a substantial amount of replacement fluid, it is crucial to determine the safety and efficacy of using Cit-D for high-volume HDF through CCDS. However, previous studies on the use of Cit-D in online HDF have all been conducted with SPDDS [18, 19, 22]. To our knowledge, this study is the first to investigate and demonstrate the efficacy and safety of Cit-D in high-volume post-dilution HDF conducted using CCDS.

The use of Cit-D allows for a significant reduction in heparin dose during high-volume HDF, which can potentially lead to meaningful clinical benefits. Whether using SPDDS or CDS, one of the most important limiting factors influencing the efficiency of HDF is clotting in the extracorporeal circuit [18]. This clotting is particularly problematic in post-dilution mode HDF compared to the pre-dilution mode. In the post-dilution mode, hemoconcentration occurs between the dialyzer and the venous chamber, exacerbating clotting. Therefore, anticoagulants, such as unfractionated heparin or low-molecular-weight heparin, are essential for preventing clotting during OL-HDF. However, the use of anticoagulants poses the risk of bleeding. Therefore, research has focused on ways to prevent clotting while minimizing the risk of bleeding, and citrate dialysate has shown promise in this regard. Generally, the concentration of citrate in Cit-D is approximately 2 mEq/L, as in this study. Thus, when using Cit-D for HDF, the citrate concentration in the blood leaving the dialyzer will be lower than the level needed to achieve regional citrate anticoagulation. Some studies have suggested that even light doses may be sufficient to evoke an anticoagulant effect within the extracorporeal circuit [19, 31–33]. Nakornchai et al. reported that the use of citrate dialysate allows for the reduction or complete exclusion of the heparin dose in both pre-dilution HDF and post-dilution HDF [18]. Richtrova et al. conducted a study using citrate in pre-dilution HDF and successfully eliminated heparin [19]. Aniort et al. reported the safe use of Cit-D in post-dilution HDF and the ability to remove heparin in most patients [24]. Consistent with previous literature, our study significantly reduced the heparin dose but did not completely discontinue heparin. However, this could be attributed to the retrospective nature of our study.

Lowering the heparin dose in dialysis patients not only reduces the risk of bleeding but also positively affects bone metabolism. Long-term use of heparin in dialysis patients may adversely affect bone metabolism, as evidenced by a potential association with loss of lumbar spine bone mineral density (BMD) [34]. Furthermore, online HDF generally requires approximately 10% more heparin for anticoagulation compared to conventional HD, potentially exacerbating issues related to chronic heparin use and bone metabolism [35]. Therefore, the significant reduction in heparin dose with Cit-D could be considered a meaningful benefit in terms of bone metabolism. However, as this study did not investigate its effects on bone metabolism, conducting an RCT is necessary to conclusively determine if using Cit-D in high-volume HDF via CCDS positively impacts bone metabolism.

This study showed that using citrate dialysate (Cit-D) in high-volume HDF patients significantly increased Kt/VBUN and URR, potentially leading to significant clinical benefits. Despite no changes in convection volume (CV), session time, or dialyzer, merely replacing Acet-D with Cit-D led to an improved dialysis efficiency. These results are consistent with those of previous studies. Molina et al. reported that the use of Cit-D in OL-HDF improved Kt/VBUN [16]. The anticoagulatory effect of citrate preserves membrane permeability and the patency of capillary fibers, facilitating the removal of solutes, such as urea [36]. Additionally, a significant decrease in predialytic β2MG levels and an increase β2MG reduction rates were observed during the CD period. This finding is consistent with previous reports; Kossmann et al. demonstrated that Cit-D lowered the pre-dialysis β2MG levels during HD [13], while Panichi et al. reported a reduction in predialytic β2MG with the use of Cit-D in OL-HDF [23]. The decrease in β2MG due to Cit-D can be attributed to two mechanisms. Firstly, the anticoagulant effect of citrate may play a role. Citrate prevents clotting in dialyzer pores, leading to an improved dialysis efficiency and a decrease in β2MG [16, 37, 38]. Secondly, the anti-inflammatory effect of citrate may also play a role. Citrate inhibits the activation of complements and pro-inflammatory cytokines through Ca chelation, leading to reduced systemic inflammation and lower β2MG production [16, 23]. However, it remains unclear from this retrospective study whether the improvements in URR, KT/VBUN, and β2MG, which indicate enhanced dialysis efficiency, will translate into significant clinical benefits such as improved patient survival. Recent RCTs have shown that survival benefits associated with online HDF are linked to convection volume [5, 39–41]. Since all patients in our study were already undergoing high-volume HDF, it is uncertain whether the significant improvements observed after switching from Acet-D to Cit-D will lead to enhanced patient survival. To clarify the clinical benefits of improved dialysis efficiency with Cit-D, long-term and large-scale RCT is necessary.

The impact of Cit-D on patient survival varies across existing studies. Poitier et al. conducted a population-based retrospective multicenter observational study with propensity score matching (PSM) analysis, finding no significant effect of citric acid–based bicarbonate hemodialysis on all-cause mortality [9]. Similarly, Bellocchino et al. in a multicenter historical cohort study with PSM analysis, did not observe a significant increase in mortality among patients exposed to citric acid dialysate [10]. In contrast, Couchoud et al. reported that long-term exposure to citric acid–based dialysates is associated with lower mortality compared to acetic acid [11]. However, since these studies are observational studies rather than RCTs, a causal relationship cannot be confirmed. Our study cannot definitively conclude whether the clinical benefits of Cit-D observed here improve patient survival. Conducting RCTs is essential to accurately assess the impact of Acet-D or Cit-D on mortality in clinical practice.

Cit-D provides offers several advantages but is also associated with certain drawbacks. Reported adverse effects of Cit-D include muscle cramps, worsened calcium balance, and exacerbation of secondary hyperparathyroidism [42]. Moreover, citrate theoretically has the potential to cause hypocalcemia due to the Ca-chelating effect of citrate [20]. In the present study, following the switch from Acet-D to Cit-D, there was a significant increase in the frequency of hypocalcemia defined as a corrected calcium concentration in the blood of <8.4 mg/dL during the CD-1 period. No significant change was observed during the CD-2 period compared to the AD period. Except for one case, all instances were asymptomatic hypocalcemia. However, even when asymptomatic, rapid-onset hypocalcemia can lead to serious, potentially life-threatening events such as seizures, refractory heart failure, laryngospasm, if left untreated [43]. Therefore, asymptomatic hypocalcemia should not be overlooked in HDF patients.

However, serum calcium binds to proteins, which means that in cases of hypoalbuminemia often seen in dialysis patients, the total calcium concentration may not accurately reflect the physiologically significant ionized calcium level. Therefore, it is crucial to measure ionized calcium. When regular monitoring of ionized calcium is challenging, it is recommended to correct the total calcium level based on serum albumin concentration using a calcium correction formula [44]. However, in patients with hypoalbuminemia, relying on corrected calcium values to estimate ionized calcium often leads to misclassification of calcium status. According to Yamaguchi et al. in a retrospective cohort study, ‘hidden hypocalcemia’ is prevalent among dialysis patients, where ionized calcium levels are low despite normal corrected calcium levels [20]. This phenomenon raises concerns about its potential association with increased mortality rates. Yamaguchi et al. also noted that while true hypocalcemia was a significant risk factor for all-cause mortality and cardiovascular events, hypocalcemia defined by corrected calcium levels did not exhibit such associations [20]. Therefore, recognizing hidden hypocalcemia as a critical predictor of death and cardiovascular events in hemodialysis patients is essential.

In this study, only corrected calcium levels were assessed, not ionized calcium, making it impossible to determine the prevalence of hidden hypocalcemia. The increased incidence of hypocalcemia, defined by corrected calcium levels, following the switch from Acet-D to Cit-D is likely due to the relatively low calcium concentration of 2.5 mEq/L in Cit-D. As mentioned earlier, relying solely on corrected calcium measurements may fail to detect hidden hypocalcemia and could lead to asymptomatic hypocalcemia triggering serious events. Therefore, it is recommended to measure ionized calcium when performing high-volume HDF with Cit-D in CCDS. Hypocalcemia by citrate dialysate can be particularly exacerbated in high-volume HDF due to the large amounts of replacement fluid used. If the composition of citrate-based dialysate used in CCDS results in a low calcium concentration, hypocalcemia can become a clinically significant issue in high-volume HDF. In order to mitigate this issue, it is crucial to maintain a higher calcium concentration in the dialysate during high-volume HDF with Cit-D. According to research by Tadashi et al. regarding the composition of dialysis fluid used in CDS, a recommended Ca concentration range of 2.5 to 3.5 mEq/L is suggested [45]. Schmitz et al. have reported that to obtain similar calcium and PTH values after switching to Cit-D, a higher Ca concentration dialysate than acetate dialysate is required [42]. Nakornchai et al. compared the Ca, ionized Ca, and PTH in heparin and citrate anticoagulation in predilution and post-dilution HDF, respectively, and found that the Ca, ionized Ca, and PTH were comparable between groups [18].

The serum phosphorus concentration increased during the CD-1 period but decreased during the CD-2 period, showing no significant difference compared to the AD period. The decrease in the serum phosphorus concentration during the CD-2 period appears to be attributed to the increased use of phosphate binders, as the actual usage of phosphate binders increased significantly during the CD-1 period. These findings suggest that although the serum phosphorus concentration may increase with Cit-D use, it can be regulated by phosphate binders. Additionally, i-PTH level increased significantly after switching to Cit-D from Acet-D, possibly because of increased i-PTH secretion in response to hypocalcemia [46]. However, despite the increase in i-PTH concentrations, the average value remained within the target range (150–300 pg/mL) throughout the study period. Furthermore, the percentage of patients with high PTH levels (≥300 pg/mL) did not differ among the three periods (AD: 36.9%, CD-1: 38.0%, CD-2: 35.7%). These findings suggest that although i-PTH may increase due to hypocalcemia with Cit-D use, it is possible to regulate i-PTH within the target range through the administration of PTH-lowering agents.

Low predialysis bicarbonate levels are associated with increased mortality risk in dialysis patients [47]. Therefore, the ability of Cit-D to correct acidosis compared to Acet-D is regarded as a significant advantage [36]. In contrast to previous reports, our study found an increase in tCO2 concentration during the CD-1 period following the switch from Acet-D to Cit-D. The decrease in the tCO2 concentration during the CD-1 period may be attributed to the lower bicarbonate content in the Cit-D used in this study compared to Acet-D (HCO3 in Acet-D: 35 mEq/L, Cit-D: 33 mEq/L). During the CD-2 period, tCO2 levels returned to baseline and showed no significant difference compared to AD. This recovery of tCO2 levels observed during the CD-2 period suggests that citrate is metabolized in the body to bicarbonate, thereby improving acidosis [48]. Therefore, when switching from Acet-D to Cit-D, it may be necessary to adjust the oral bicarbonate dose based on tCO2 levels and the bicarbonate concentration of the dialysate.

Albumin levels exhibited a slight decrease during the CD-2 period. Previous studies have indicated that acidosis affects the nutritional status, including the albumin levels [49, 50]. In this study as well, acidosis may have influenced the albumin levels to some extent.

On the other hand, high-volume OL-HDF using CDS may be structurally vulnerable to infections. To monitor this, in our study, the endotoxin levels were evaluated and microbiological monitoring was conducted in pre-filter and ultrapure dialysate, respectively. Throughout the study period, the endotoxin levels were <0.03 EU/mL and bacterial cultures were <0.1 CFU/mL, indicating no issues. The CRP levels also showed no differences between the AD and CD periods. These results suggest that the safety of conducting hemodialysis with Cit-D in high-volume OL-HDF using CDS with regards to the risk of infection. However, long-term studies analyzed with multiple inflammatory markers should be conducted for conclusive evidence.

This study suggests potential benefits of using Cit-D in CCDS-based high-volume OL-HDF, potentially including a reduced heparin dosage and improved dialysis efficiency, with no significant observed adverse effects. However, it is important to consider the various limitations of this study, as they restrict the generalizability of the findings. First, this study is a small-scale retrospective analysis conducted over a short duration, rather than a RCT. Second, this study did not incorporate a washout period between each period, which is an inherent limitation of its retrospective design rather than a prospective study. Third, ionized calcium was not routinely measured, and corrected calcium based on albumin concentration was used instead. While corrected calcium is commonly employed when ionized calcium measurement is unavailable, this approach may not accurately reflect the true calcium status in the body. Considering reports indicating that hidden hypocalcemia could affect all-cause mortality, future studies should prioritize measuring ionized calcium. Forth, this is a short-term study and not intended to assess the long-term effects of Cit-D in high-volume HDF via CCDS. Therefore, future research should evaluate the long-term effects of Cit-D, particularly with regard to bone metabolism or patient survival. Finally, hs-CRP was the sole inflammatory marker utilized in this study. Other inflammatory markers, such as interleukins, should be employed to assess the impact of Cit-D in high-volume HDF via CCDS on inflammation. Due to these limitations, a large-scale RCT is essential to definitively evaluate the efficacy and safety of Cit-D in CCDS-based high-volume HDF patients.

Conclusion

Our study findings suggest that Cit-D might potentially offer advantages over Acet-D in high-volume HDF patients using CCDS, such as potentially reducing the heparin dosage and potentially improving dialysis efficiency. While no adverse events such as clotting or symptomatic hypocalcemia were observed, it is important to consider that even asymptomatic hypocalcemia can lead to severe, life-threatening events. Therefore, careful monitoring of dialysate calcium levels and efforts to detect hidden hypocalcemia should be emphasized when employing Cit-D in CCDS-based high-volume HDF treatments.

Acknowledgments

The authors appreciate colleagues from hemodialysis center of Konkuk University Hospital for their dedication in treating hemodialysis patients and support in this study.

Disclosure statement

The authors have read and understood Renal Failure’s policy on disclosing conflicts of interest and declare that authors have none.
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