To our knowledge, this is the first report of the use of RCA in HDx. We specifically focused on the performance of our standard citrate protocol (developed and tested for high-flux HD membrane ) with MCO membrane.
In order to avoid high citrate infusion rate to the patient our standard citrate protocol includes the use of calcium-free dialysate and blood flow of 250 mL/min with a consequentially moderate citrate infusion rate. If necessary, higher blood flow rates with increased citrate infusion rate can be safely used, because of high citrate clearance through dialysis membrane.  If citrate load is a concern, it may be avoided by stopping citrate 15–30 min before ending HD (in an “anticoagulant-free” dialysis mode), to allow remaining citrate to be dialyzed completely. It is also possible to use calcium-containing dialysate. The use of calcium-containing dialysate, although usually less complex and safer in comparison to the use of calcium-free dialysate (no risk of profound hypocalcemia),  has a problem of insufficient anticoagulation in dialysis circuit (especially venous part) despite higher citrate dose, as shown in our previous study.  Insufficient anticoagulation in turn reduces HD efficiency and may further complicate the procedure. Additionally, the citrate load on the patient may be higher. Potential beneficial effect of citrate anticoagulation to biocompatibility [2,3,4] may be decreased. In light of all this, we strongly believe that the use of calcium-free dialysate is superior to the use of calcium-containing dialysate during high-flux HD and HDx with RCA.
Previous studies have shown that small solute clearance is as effective with the MCO membrane as with high-flux membrane. [21, 22] Since calcium, magnesium and citrate are all small molecules, we did not expect any significant differences in behaviour of these molecules during HDx in comparison to high-flux HD. Therefore, we expected that our standard citrate protocol for high-flux membrane could also be used with MCO membrane without modifications. Our results show that the adoption of a standard citrate protocol developed for high-flux membranes could indeed be done without modifications and RCA could be a safe anticoagulation option in HDx. All in all, electrolyte and acid-base balances were relatively well-controlled and anticoagulation was excellent. However, the behavior of calcium and magnesium during HDx with RCA needs further attention.
Although mild hypocalcemia was allowed during the procedure (the lower limit for iCa was set at 0.95 mmol/l) in order to achieve a more neutral calcium balance, we had no cases of severe or symptomatic hypocalcemia and only one case of hypocalcemia, in which the patient was asymptomatic. There were no cases of hypercalcemia. We opted for the approach of allowing mild hypocalcemia because of previous data, which showed that maintaining values of iCa in the strictly nominative normal range during high-flux HD with RCA resulted in a significantly more positive calcium mass balance as compared to mild hypocalcemia during the procedure.  Aiming to achieve a more neutral calcium balance is especially important when RCA is used for prolonged periods in selected chronic HD patients. As we have not yet found any studies investigating this issue specifically on MCO membranes so far, our approach allowing mild hypocalcemia in patients undergoing HDx with RCA needs to be further validated.
In comparison with calcium balance, magnesium balance during intermittent HD has been studied in less detail: there is some data on the effect of RCA on serum magnesium levels in intermittent HD [12, 21], but the topic has received scant attention.  It is important to emphasize that hypomagnesemia is not to be ignored, since some cohort studies have reported that lower serum magnesium levels are associated with an increased risk of all-cause and cardiovascular mortality among HD patients.  Magnesium’s behavior during RCA is complex. As a divalent cation, magnesium is bound by citrate and its clearance is therefore increased in the form of citrate-magnesium complexes. However, the decrease in iMg could increase magnesium flux from the dialysate.  The results of patients on high-flux HD show that RCA may decrease serum magnesium levels, possibly due to a negative magnesium balance. [10, 17] Our findings show that a decrease in serum magnesium levels might occur in HDx as well: we observed three cases of mild, post-dialysis asymptomatic hypomagnesemia, which did not require magnesium substitution. It is expected, as citrate is metabolized to bicarbonate, that magnesium (as well as calcium) would be released after HD. To underline, the effect of RCA on serum magnesium levels needs to be further validated. Specifically, more attention needs to be given to the magnesium concentration in dialysate, or even additional magnesium supplementation. Calcium-free dialysate, which was used in our study and is also used for RCA in the majority of protocols, has a magnesium content of 0.5 mmol/l. Since citrate binds to both calcium and magnesium, an increase in dialysate magnesium concentration may require a higher citrate dose, so this is a complex issue.
Previous study, which was done in our center has shown that hypocalcemia (< 0.9 mmol/L) during high-flux HD with RCA is rare.  Although the risk of hypocalcemia according to the results presented here appears to be higher during HDx, it is impossible to justly compare these results as our number of patients was quite low. Judging from our personal observations with MCO membranes, it seems that the risk of hypocalcemia and hypomagnesemia with RCA is similar in high-flux HD and HDx, which is in accordance with comparable clearance of small solutes during both types of dialysis. [21, 22]
According to the visual assessment of anticoagulation in the circuit and the measurements of post-filter iCa, anticoagulation was excellent. Since the blood clotting times measured by slide method varied strongly among patients, the measurement of iCa in the circuit proved to be a more reliable indicator of anticoagulation. All in all, it seems that our protocol is optimal in regard to anticoagulation efficiency.