The dialysis fluid (DF) is an essential element in the dialysis procedure since there is transference of different components between DF and patient. Therefore, the physical, microbiological and chemical composition of LD is essential for treatment success or failure. The recommendations on DF quality and purity are included in the Dialysis Liquid Quality Management Guidelines of the Spanish Society of Nephrology.1

From the technical point of view, to avoid the precipitation of calcium and magnesium carbonate that occurs in the DF when adding bicarbonate, it is necessary to add an acid, so the generation of DF system needs 2 concentrates, one with bicarbonate and the other with acid. The acid is usually acetic acid, at concentrations ranging between 3 and 10mmol/L. This small amount of acetate is transferred to the patient during HD, increasing its concentration in blood, since DF has concentrations 30–40 times higher than normal values in blood (0.1mmol/L). This exposure to acetate increases in techniques of online hemodiafiltration (OL-HDF)2 due to the greater amount of fluid infused. Among the side effects described with acetate are hemodynamic instability produced by vasodilation mediated by the release of nitric oxide3 and hypoxia induced activation of proinflammatory cytokines.4 Even with DF with small concentrations of acetate (3mmol/L), hemodynamic complications are present if compared with acetate-free DF.5

For years other acids have been sought as DF stabilizers. The first attempts to replace the acetate were made with hydrochloric acid. However, the relationship between sodium concentration and conductivity was modified, producing changes in the serum ions, so it was necessary to change the total and partial conductivities of bicarbonate, and its use was not clearly standardized.

The use of citrate in the DF (CDF) was developed in an attempt to improve biocompatibility by substituting acetic acid for another more physiological compound, citric acid. Citrate chelates calcium (Ca), in fact, it is used as anticoagulant by decreasing ionic calcium (Cai). It is estimated that it produces a 10% decrease in Cai, this is why most authors recommend to supplement DF with calcium when citrate is being used as an acid. As demonstrated by Steckiph et al.,6 for each mmol of citrate, the calcium concentration should increase 0.15mmol/L to maintain the calcium balance during treatment and prevent hypocalcemia. The use of CDF is increasing and presently in Spain is a therapeutic option. There are 2 CDFs, one without acetate, which is the CDF that we have use in the present study: SelectBag Citrate®, with 1mmol/L of citrate. Another CDF, Citrasate® contains small amounts of acetate, 0.3mmol/L and 0.8mmol/L of citrate. Although the CDF has been commercialized for more than 15 years, initially in the USA,7 there is limited information on the possible metabolic, coagulation or hemodynamic effects based on randomized studies. Several long-term beneficial effects have been described in relation to the use of citrate including reduced thrombogenicity,8 increased clearances,9,10 improvement of inflammation,11 nutrition,12 tolerance,13 and acid-base control with less predialysis acidosis.14 Our multicenter, randomized and controlled study aims to provide evidence to some of these issues.

Citrate is used as an anticoagulant in continuous dialysis therapies. Monchi et al.15 conclude that anticoagulation with citrate was superior to heparin to preserve the dialyzer function and reduce transfusion requirements in Intensive Care patients on continuous substitution therapies in which citrate concentration is much higher than in CDF. During dialysis with CDF, citrate binds to the circulating calcium so less calcium is available for the coagulation cascade, and the heparin requirement are reduced8; consequently, the useful surface of the dialyzer will be preserved improving clearance and dialytic efficacy. It is necessary to confirm the potential benefits of this anticoagulant effect and the impact of CDF on hemodynamic tolerance, acid base balance and metabolism of calcium and phosphate.

The objective of the present study is to compare the acute effect of HD with CDF vs. ADF on acid base balance, calcium, phosphorus and magnesium metabolism, dialytic efficacy, coagulation, inflammation and hemodynamic stability.

There were 64 hemodialysis patients initially evaluated in 2015. Fiftysix patients met the inclusion criteria and were included in the study. The flow chart illustrating the progress of the patients during the trial is depicted in Fig. 3. Their average age was 65.3 (16.4) [23–93] years, 47 men and 9 women, with an adjusted Charlson index of 6.2 (2.5). The etiology of CKD was 16 glomerulonephritis, 10 diabetes, 9 vascular disease, 4 hereditary disease, 4 interstitial nephritis, 9 other causes and 4 unknown etiology. Fifty one patients (91.1%) had native AVF and 5 (8.9%) a prosthetic AVF.

Fig. 3.

Flow chart of patients during the study.

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Thirty six patients were on OL-HDF and 20 on HF-HD.

Randomization assigned 29 patients to the ADF and to 27 to CDF. At week 16 the DF were switched from ADF to CDF and vice versa for another 16 additional weeks. Table 2 describes the baseline characteristics of the patients according to the group to which they were assigned.

The results being presented correspond to the acute effect of DF, which we consider to occur during the dialysis session, such as hypotension or coagulation and changes in blood parameters from pre to post dialysis. For this we have taken the results of the baseline visit corresponding to the pre/postdialysis values after the washout period with acetate, once the randomization was done that corresponded to 56 patients. Later some of the results these pre/post values throughout the study will be commented.

Table 3 shows the pre-hemodialysis acid-base values, biochemistry, PTH, and hematological parameters in ADF and CDF groups. Likewise, the post-hemodialysis acid base values, some biochemical and PTH parameters are also shown.

In relation to acid base parameters, post-dialysis bicarbonate levels were significantly lower in the CDF group, with no differences in the delta of bicarbonate.

Regarding the effect on mineral metabolism, the increase in Cai and post-hemodialysis Mg was lower in CDF than ADF and the post dialysis iPTH value was greater in CDF than ADF (Table 3).

No differences were observed with LDA or LDC in the dialysis efficacy assessed by pre and post hemodialysis urea (Table 4). Neither when analyzed by treatment group (HD vs. HDF); the respective KT with ADF and CDF were: in HD 52.7 (9)L vs 48.7 (10.6)L, and in HDF 53.1 (7.2)L vs 57 (5.9)L.

The doses of heparin remained stable during the study. None of the 56 basal HD sessions had significant coagulation problems of the dialyzer or the venous chamber. The thromboplastin time was analyzed as a coagulation parameter only pre HD and no differences were found between the two groups (p=0.388).

There were no significant differences in the coagulation score of the cameras between the HD performed with ADF and CDF; it was 0 (absent) or 1 (minimum) in 80% of the sessions; likewise no differences were observed between the dialysis techniques. The hemostasia time was 1.4 (2.7)min longer in CDF than in ADF, p<0.05.

No significant difference was observed in the C-reactive protein values (2.8 (3.8) vs 4.7 (7.3), (p = 0.253) in ADF and CDF respectively.

Regarding the tolerance of HD sessions, there were fewer episodes of hypotension during the sessions at the baseline visit with the CDF (1 vs 3) (p=0.04), and the MRBV as measured by hemoscan® biosensor was also lower with the CDF [−3.4 (7.7) vs −5.1 (8.2)] although without statistical significance. The results are the same throughout the total of the study sessions. The 46 patients who completed the study performed 4416 HD sessions, 2208 with ADF and 2208 with CDF citrate. Hypotension occurred in 311 sessions (14.1%) with ADF, and in 238 (10.8%) with CDF (p<0.01).

In the 29 patients in whom pre hemodialysis bio-impedance was performed, no significant differences were found in the total extracellular water or in relative overhydration (overall overhydration adjusted to the extracellular water, measured in % (OH/AEW)), being the values of 2.06 (1.25) vs 1.7 (1.19)L and 12.4% and 11.15% with the ADF and CDF respectively.

As in some previous work,17 our study found that CDF improves the control of acid base balance, avoiding or decreasing postdialysis alkalosis. Other authors such as Kuragano et al.18 found greater alkalization during dialysis with citrate versus acetate (from 7.38 to 7.50 and 21 to 29.2mmol/L vs 7.39 to 7.45 and 22.4 to 24.3 for the pH and bicarbonate values with DF with citrate and acetate respectively). Schmitz et al.19 also found less overcorrection of acidosis (bicarbonate>32mmol/L) with CDF than with ADF. The acute alkalemia induced by the gain of bicarbonate during dialysis is a problem of considerable clinical importance, since it has been related to important adverse effects such as hemodynamic instability,20–22 cardiac arrhythmias, paresthesia-cramps,23 decreased cerebral blood flow, respiratory depression,24,25 headache and a procalcifying effect.26 Finally, also a higher concentration of bicarbonate in the dialysis fluid has been associated with increased mortality,27 which led the FDA 28to alert physicians about such a risk and to consider the impact of acetate and other sources of alkali when the DF is prescribed. However, despite a lower postdialysis alkaline with CDF, the delta bicarbonate was not statistically different: −5.4 (2.7) vs −4.1 (2.4) in ADF vs CDF respectively. And the post-HD bicarbonate levels, although with statistically significant differences, in none of the groups was very high (28.5 vs 26.9 in ADF vs CDF). This is probably related to a fine adjustment of the DF bicarbonate concentration that was done in a protocolized manner prior to randomization.

Chemical characteristics of citrate may explain a reduced alkalemic effect whose metabolism is fundamentally hepatic and also muscular, being metabolized to generate bicarbonate and energy. Unlike what happens with acetate, the metabolism of citrate is not completed during the dialysis, since the hepatic and muscular metabolism occurs partly after the end of the technique. In addition, there are fast and slow metabolizing patients depending on liver function and muscle mass, factors that must be taken into account. In patients who are given citrate as a regional anticoagulation, plasma citrate levels are 1mmol/L, and HD patients have levels similar to those with normal renal function,29 but patients with liver insufficiency in the clearance of citrate is reduced by 50%.30

In relation to calcium and phosphate metabolism, with CDF the values of Cai and Mg postHD were significantly lower than preHD, and PTH values were increased after dialysis with CDF. This did not happen with ADF. As previously mentioned, citrate binds calcium and as such it causes alterations in the concentrations of this ion. It is known that low calcium in dialysis favors hypocalcemia in plasma, which stimulates PTH, bone turnover and the appearance of cramps, arrhythmias and the increased risk of hypotensive episodes, and therefore, when patients treated with CDF we increased the concentration of Ca in the DF. Despite this correction, the use of CDF resulted in a decrease in post dialysis Cai. However, other authors have not found the same results, Gabutti et al.,9 after calcium supplementation to the dialysate bath did not appreciate significant differences between the Cai values pre-dialysis and post-dialysis in patients treated CDF, while those treated with ADF with Ca supplementation there is a significant increase in post-dialysis calcium, which may have inhibitory effect on PTH secretion. Although hypomagnesemia has been shown in the regional anticoagulation with citrate,31 this is the first time that a reduction in Mg is described in relation with the use of CDF. Although not previously described, this result is not a surprise, since citrate may chelate ions such as Mg. A CDF formulation with a Mg concentration higher than the usual (0.5mEq/L) should solve the problem.

No differences were observed in the dialytic efficacy measured by Kt, Ktsc or eKt/V in ADF vs CDF. However, other authors such as Ahmad et al. found an improvement in dialysis adequacy measured by Kt/V in the citrate group (1.23±0.19 vs 1.34±0.20, p=0.01) in a study that included 25 patients,7 as well as Kossman et al.10 in a study of 146 patients (1.51±0.01 vs 1.57±0.01, p<0.0001). Although the mechanism underlying this beneficial effect are not known, some authors propose the anticoagulant effect of citrate that would prevent the coagulation of dialyzer fibers as a cause of the improvement in dialysis efficacy.

Regarding coagulation, we did not find differences in the coagulation scores, however the time of hemostasia 1.4 (2.7)min higher with the CDF than ADF. A possible explanation for the absence of differences in the coagulation scores could be that the dose of heparin used is high and small differences in coagulation may not have an impact on the scores analyzed, which showed absence or minimal alterations in 80% of the sessions. Although the hemostasis time is a gross measure of coagulation, this result is in line with that described by most authors and is due to the anticoagulant effect of citrate.

Finally, the result that appears to be most important to the study investigators is the effect of CDF on hemodynamic stability, with fewer episodes of arterial hypotension. And without significant differences in total extracellular water or relative overhydration. The MRBV measured by Hemoscan® biosensor was also lower in CDF than ADF, although without statistical significance. Daimon et al.13 describe a reduction in the frequency of hypotensive episodes in a sample of 44 patients during hemodialysis with CDF, especially in the most symptomatic and severe episodes of hypotension. Gabutti et al.9 describe greater hemodynamic stability with CDF, with a significant reduction in peripheral resistances and systolic blood pressure. However, other studies32 have found significant variations in tolerance. This greater hemodynamic stability seems to be related to the absence of acetate, which produces vasodilation mediated by the release of nitric oxide3 and the activation of proinflammatory cytokines by hypoxia.4 Smith et al.33 found a moderate and constant increase in acetate values of around 1mmol in the blood obtained in patients after dialysis with Acetate dialysis fluid concentrations of 4 and 8mEq/L.

In summary, from our results by from previously published reports there some situations in which patients could benefit from using CDF. These have been detailed in Table 5. Patients who could be harmed by the use of CDF could be summarized as follows: in patients with hypocalcemia, hypomagnesemia and uncontrolled secondary hyperparathyroidism.

In conclusion, the results of the present work show that dialysis with citrate achieves a better control of post-dialysis acid base balance by decreasing/avoiding postdialysis alkalemia. Post-dialysis levels of Cai and magnesium decrease with CDF and the PTH increases. These results together with lower alkalemia support a less calcifying profile of LD with citrate. Compared with the ADF, the CDF offers greater hemodynamic stability producing fewer episodes of hypotension.

P. de S., R.P.G., M.M. they have received honoraria for participation as a speaker at meetings of Fresenius and Baxter-Gambro and sponsorships of scientific congresses by Nipro, Fresenius and Baxter-Gambro.