Replacement of acetate with citrate in dialysis fluid: a randomized clinical trial of short term safety and fluid biocompatibility

Abstract

Background: The majority of bicarbonate based dialysis fluids are acidified with acetate. Citrate, a well known anticoagulant and antioxidant, has been suggested as a biocompatible alternative. The objective of this study was to evaluate short term safety and biocompatibility of a citrate containing acetate-free dialysis fluid.

Methods: Twenty four (24) patients on maintenance dialysis three times per week, 13 on on-line hemodiafiltration (HDF) and 11 on hemodialysis (HD), were randomly assigned to start with either citrate dialysis fluid (1 mM citrate, 1.5 mM calcium) or control fluid (3 mM acetate, 1.5 mM calcium) in an open-labeled cross-over trial (6 + 6 weeks with 8 treatments wash-out in between). Twenty (20) patients, 11 on HDF and 9 on HD were included in the analyses. Main objective was short term safety assessed by acid-base status, plasma ionized calcium and parathyroid hormone (PTH). In addition, biocompatibility was assessed by markers of inflammation (pentraxin 3 (PTX-3), CRP, IL-6, TNF-α and IL-1β) and thrombogenicity (activated partial thromboplastin time (APTT) and visual clotting scores).

Results: No differences dependent on randomization order or treatment mode (HD vs. HDF) were detected. Citrate in the dialysis fluid reduced the intra-dialytic shift in pH (+0.04 week 6 vs. +0.06 week 0, p = 0.046) and base excess (+3.9 mM week 6 vs. +5.6 mM week 0, p = 0.006) over the study period. Using the same calcium concentration (1.5 mM), citrate dialysis fluid resulted in lower post-dialysis plasma ionized calcium level (1.10 mM vs. 1.27 mM for control, p < 0.0001) and higher post-dialysis PTH level (28.8 pM vs. 14.7 pM for control, p < 0.0001) while pre-dialysis levels were unaffected. Citrate reduced intra-dialytic induction of PTX-3 (+1.1 ng/ml vs. +1.4 ng/ml for control, p = 0.04) but had no effect on other markers of inflammation or oxidative stress. Citrate reduced visual clotting in the arterial air chamber during HDF (1.0 vs. 1.8 for control, p = 0.03) and caused an intra-dialytic increase in APTT (+6.8 s, p = 0.003) without affecting post-dialysis values compared to control.

Conclusions: During this small short term study citrate dialysis fluid was apparently safe to use in HD and on-line HDF treatments. Indications of reduced treatment-induced inflammation and thrombogenicity suggest citrate as a biocompatible alternative to acetate in dialysis fluid. However, the results need to be confirmed in long term studies.

Trial registration isrctn: ISRCTN28536511.

Figures

Figure 1

Study design flow diagram.

Figure 2

Impact of citrate dialysis fluid on acid–base status. A) Intra-dialytic change in pH at study start (Week 0) and study end (Week 6). B) Intra-dialytic change in Base Excess at study start (Week 0) and study end (Week 6). C) Overall intra-dialytic change in carbon dioxide pressure when using citrate dialysis fluid compared to control. Black bars represent pre-dialysis values and white bars post-dialysis values. Bars show means and error bars represent SEM, n = 20. * = p < 0.05 and ** = p < 0.01.

Figure 3

Analyses of calcium balance over the study period. A) Intra-dialytic change in plasma ionized calcium levels at each sampling occasion when using citrate dialysis fluid compared to control. B) Intra-dialytic change in plasma PTH levels at each sampling occasion when using citrate dialysis fluid compared to control. Black bars represent pre-dialysis values and white bars post-dialysis values. Bars show means and error bars represent SEM, n = 20. * = p < 0.05, ** = p < 0.01 and *** = p < 0.001 and ** = p < 0.01.

Figure 4

Effect on plasma citrate levels over the citrate dialysis fluid study period. Black bars represent pre-dialysis values and white bars post-dialysis values. Bars show means and error bars represent SEM, n = 20.

Figure 5

Effect of citrate dialysis fluid on inflammation presented as overall intra-dialytic change in PTX-3 expression when using citrate dialysis fluid compared to control. Black bars represent pre-dialysis values and white bars post-dialysis values. Bars show means and error bars represent SEM, n = 20. * = p < 0.05.

Figure 6

Changes in mean arterial blood pressure during the dialysis treatment. Diamonds represent citrate dialysis fluid and squares control dialysis fluid. Symbols show means and error bars represent SEM, n = 20, * = p < 0.05.