Controversy of Dialysate Calcium Concentration

  • Roundtable ID: GM24909
    Citation: Published online first.
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DR. EVENEPOEL: It’s the same one we use in HD. There’s never been an important point that we should increase the calcium dialysate bath when we switch a patient from HD to HDF. It’s certainly something not in the guidelines that we use in order to avoid the negative calcium balance during HDF. The typical points are there. It’s irrational to increase calcium in the dialysate when you switch to HDF, but again, there are no—at least to the best of my knowledge—data to support this.

DR. BUSHINSKY: We know, based on older studies—they’re 20 years old now—where Susan Hou, among three or four other investigators, actually looked at how much calcium was coming out in the dialysate.15 They collected all and measured all of the dialysate. They found that a 1.25 mmol/L bath resulted in relatively neutral calcium balance during the conventional HD treatment, 1.75 caused calcium influx into the patient, and 0.75 caused calcium efflux from the patient. That doesn’t surprise any of us, but there is absolutely a need for new studies of this important point.

DR. BLOCK: Let me make one quick comment, and then I want to introduce two things that we can end with that I think are really important. The first is, I want to summarize, Allan, what you said about Steve Brunelli’s work, because I think it’s so interesting. As we’ve all just been saying for 25 minutes, there’s so much we don’t know right now about, not only what the calcium flux actually is, but how the kinetics of the calcium movement affect cardiac function during and after the procedure, and I find it incredibly supportive that Steve’s work showed that the facilities that switched to a predominantly low calcium bath, the two things that stand out in addition to hypocalcemia are in fact nearly doubling of the risk of atrial fibrillation and heart failure. The two things that, when David introduced this conversation today said, it decreases LV function and, as you pointed out, it increased arrhythmogenicity along with all of the other things that are happening to the patient. There’s no question that, particularly as the patient moves from nondialysis to dialysis and we introduce the dialysis procedure itself, we create events. I think that’s been pretty clearly shown. The first several months of dialysis, we have this incredible increase in the events. I think we have to be concerned about the relationship between lowering dialysate calcium and making people have these events that are worse.

The two final things—I think we’re generally in agreement; there are some substantial risks to low dialysate calcium. On the other hand, there are some excellent papers that have recently come out showing there’s substantial risk to high dialysate calcium as well.16–18 I don’t think it’s prudent to ignore that aspect either. Particularly in the context of calcimimetics being a therapy that didn’t exist 15 or 20 years ago, and that are now reasonably widespread. Let’s close, David, with your thoughts on both of those concepts. What have we now learned about high dialysate calcium, either de novo, or in response to a calcimimetic-induced lower serum calcium, and its potential effects?

DR. BUSHINSKY: Yes, Geoff. As you mentioned, two important papers just came out. Merle published a paper saying that a decrease in PTH from a high to a normal value induced by a high dialysate calcium was a strong independent predictor of cardiovascular mortality 12 to 24 months later.16 The use of a high dialysate calcium, 1.75 mmol/L, induced cardiovascular mortality. Ok studied 425 patients with low PTH values who were dialyzing against a high dialysate calcium, which is greater than 1.5 mmol/L. He then randomized them to 1.25 mmol/L or 1.75 calcium baths. Those dialyzed against 1.75 had faster progression of coronary artery calcification compared to those dialyzed against the 1.25 mmol/L bath.17 We just published an editorial about that paper in Nature Reviews Nephrology.18 We talk about the risk of a high dialysate calcium and, at the end of the piece, we talk about perhaps developing an inline arterial blood ionized calcium sensor to feed back and adjust the individual’s dialysate calcium concentration with the goal of achieving an optimal calcium bath for that patient. I think this is where we have to go, not only with calcium but potassium. We have to avoid these large gradients inducing what Dr. Collins has termed "the perfect storm" for arrhythmogenesis.

DR. BLOCK: Yes, I agree. Pieter, I want to hear your thoughts on that issue, particularly as it relates to calcimimetic-induced low serum calcium. As you know, it’s really common for people on a calcimimetic to have a low normal, if not overtly low, serum calcium. The temptation, I think, under these conditions is to increase the dialysate calcium. What do you think about that approach and about what we need to learn?

DR. EVENEPOEL: It is certainly an important point. We increasingly use calcimimetics to control the PTH levels. Of course, one of the side effects is the lowering of the calcium. Of course, heating the discussion, calcium and especially the calcium gradient over the membrane is really determining the calcium flux during dialysis, so you can envision that a patient with hypocalcemia following calcimimetic treatment will face an increased calcium influx during dialysis. This increased calcium influx can be hypothesized to offset any advantage of calcimimetic treatment. I certainly would advocate that, at this time, we shouldn’t be that afraid of low calcium levels in people treated with cinacalcet. I think it’s not the same. The cardiovascular implications of calcimimetic-induced hypocalcemia may differ from hypocalcemia in calcimimetic-naïve patients, e.g. caused by low calcium intake. Indeed, calcimimetics render the calcium-sensing receptor more sensitive to calcium, as it is reflected by the leftward shift of the calcium set point. We shouldn’t be that afraid of hypocalcemia in the setting of calcimimetic treatment, and therefore warrant against correcting this hypocalcemia aggressively, for example, by increasing the calcium dialysate to 1.75 mmol/L.

DR. BLOCK: Thank you, Pieter. Allan, in closing, tell us your thoughts on that particular topic, the facts that both low dialysate calcium can be arrhythmogenic and potentially high dialysate calcium can exacerbate the issues David talked about with too much extracellular fluid calcium and deposition into non-skeletal tissue.

DR. COLLINS: I think the other two have already articulated this. I’m in complete agreement with them. The other issue is with trying to infuse calcium with the dialysate when you’ve got hypocalcemia induced by, let’s say cinacalcet treatment. The challenges, as you load the patient during the dialysis run with ionized calcium, it’s going to be a pretty potent PTH calcium sensor stimulator to suppress the PTH even further. We’re all trying to sort of balance out how to get them through these low calcium periods without disrupting and causing too many other collateral issues that are going on. Geoff and I have talked many times about trying to treat through hypocalcemia induced by cinacalcet and all the challenges you have to go through. It actually is almost impossible to correct the calcium until the gland and the adaptation of what’s happening in the bones has sort of passed. Then, everything sort of stabilizes out. I don’t know what everybody else’s experience is, but when I tried to do this, it was impossible.

DR. EVENEPOEL: I think we should be more patient. I mean, if you lower the calcium with cinacalcet, like you said, you should wait until the bone recovers and is able to normalize calcium levels physiologically again. This takes some time.

DR. BUSHINSKY: We also have to recognize that cinacalcet is altering the set point for calcium PTH release, and we’ve now changed the thermostat in the room. We’ve changed it from 70 degrees to 65 degrees, for example. That’s what the alteration of the set point is doing, and to try to overcome that change in set point by loading the patient with calcium can’t work because what determines the blood level of ionized calcium isn’t the calcium content in the body, it’s the level of the hormones regulating the calcium concentration. For example, a woman or a patient with primary hyperparathyroidism has a high serum calcium but a total reduction in bone calcium, and is more fracture-prone because the regulatory hormone, which is PTH, is not being properly regulated by calcium.

DR. BLOCK: Yes. I think it’s a fantastic point, and one that’s great to end with, David, because I think that point really is the critical issue with regard to trying to understand how dialysate calcium manipulation will result in these collateral effects that are unrelated, actually, to calcium balance and the potential harmful effects of trying to achieve this balance concept by manipulating the concentration of dialysate, and thereby neglecting the essential important piece, which is regulation of ionized calcium in the blood, and the consequences of that.

I think it’s been a fantastic discussion, honestly. I can’t imagine three better people to discuss this topic than the three of you, and I can’t thank you enough. It’s a fascinating thing, and I hope I’m not misstating when I say that all of us agree that we should have some serious reservations about using low dialysate calcium concentration as a method to achieve neutral calcium balance. Similarly, we have reservations about the use of high dialysate calcium concentration, and I think, at the end of the day, the KDIGO recommendations,19 an update of which will be available for public comment hopefully within this calendar year, suggest that a 1.25 calcium dialysate is, in fact, a very reasonable approach to balance this issue of kinetics and calcium balance. Thank you all very much.