DR. BLOCK: My name is Dr. Geoffrey Block. I’m the Director of Clinical Research at Denver Nephrology. Joining me today are Dr. David Bushinsky, Professor of Medicine at the University of Rochester Medical Center; Dr. Pieter Evenepoel, Professor of Medicine at the Department of Immunology in Belgium; and Dr. Allan Collins, Professor of Medicine at the University of Minnesota, Director of the Chronic Disease Research Group, and the Executive Director of the Peer Kidney Care Initiative. I’m really grateful to all three of you for being here and having this discussion today.
I think that this will be an interesting discussion. It’s an interesting topic, and all three of you are experts in this area. I’m looking forward to seeing what you think. Pieter and I have had discussions along this line, in the not too distant past, through our participation in the Kidney Disease Improving Global Outcomes (KDIGO) workgroup.
The topic that we’re discussing is the controversy of dialysate calcium concentration. Let me frame the discussion from my perspective, which is what I think is leading to this so-called controversy, if there is one, is the fact that it’s been recommended recently—or at least acknowledged—that most dialysis patients are likely to be in positive calcium balance when they’re given active vitamin D therapy and particularly when they’re given calcium-containing phosphate binders. In an effort to try to theoretically address this positive calcium balance issue, a number of people have suggested over the last few years that we reduce the dialysate calcium concentration, and by doing so, would potentially allow for a neutral calcium balance because we’re administering so much calcium orally, that we might be able to achieve a neutral balance by lowering calcium or increasing calcium lost during the dialysis procedure.
I think all four of us know that this is not as straightforward as it sounds. I’d like to start with that particular concept, which is using dialysate calcium to allow us to achieve a so-called neutral calcium balance. David, tell me, what are we missing when it seems like a reasonable—on-the-surface—proposal to adjust calcium dialysate to allow for this balance issue, but not sure that it actually is quite so simple? What do you think?
DR. BUSHINSKY: Dr. Block, that’s an interesting concept. Let’s go back to 2010. We began to think about this and actually wrote in the Clinical Journal of the American Society of Nephrology1 and then Nephrology, Dialysis, Transplantation2 about extracellular fluid calcium content in dialysis patients. We were concentrating on what you mentioned, the calcium intake. We determined through review of a lot of studies and mathematical modeling that without vitamin D, people could safely take in about a gram and a half of elemental calcium per day, and with vitamin D, about a gram of elemental calcium per day. Any more calcium than that, they would be in positive calcium balance. This was based on the thought that if you absorb calcium and you have essentially no renal function, there’s no way to excrete that calcium. Once the bone calcium needs were met, that calcium would accumulate in the extracellular fluid, and since the level of serum calcium couldn’t continue to rise, that calcium would be deposited in soft tissues including the vasculature.
Along with the thought of diet calcium, you bring up the great point of dialysate calcium, and it’s the same concept. If you establish a gradient of calcium from the dialysate into the patient, you will achieve a positive calcium balance, and the calcium will deposit in the soft tissues. The thought of using a low calcium dialysate to cause an efflux of calcium from the patient to the dialysate, which would allow the use of oral calcium, especially with activated vitamin D is, on the surface—as you say—reasonable. However, calcium is not urea. Calcium is not a waste product. It’s an active signaling molecule. If you dialyze people on a low calcium bath, their arterial blood ionized calcium will fall. Their parathyroid hormone (PTH) will rise, and the low calcium will induce cardiac instability. That has been amply shown in several studies. We, years ago, demonstrated that dialyzing against a low calcium bath reduced left ventricular (LV) function.3,4
Patients’ cardiac output went down. Patients’ blood pressures went down. Dialyzing against a low calcium bath is not without the hazards of hypotension, reduced LV ejection fraction and, as Jack Coburn showed years ago,5 increased PTH. I could expand upon this, but perhaps it’s time to pass this on to someone else.
DR. BLOCK: That’s fantastic, David. Thank you. It is pretty remarkable, isn’t it, that the whole concept of reducing dialysate calcium—honestly, from what I can tell—is meant to provide this theoretical room to give more and more calcium orally? The irony being, as you just said, that by using a low dialysate calcium, you will end up increasing PTH, and potentially increasing phosphate—and we can talk about one of the clinical studies that actually showed that—but if you increase phosphate and you increase PTH, you end up having to provide even more drug therapy. You’re actually making a cycle of events worse, or at least theoretically worse.
Allan, what are your thoughts on this whole concept? You’ve been doing dialysis and running a dialysis center for a very long time. What are your thoughts on trying to manipulate the dialysate calcium for the purpose of achieving a neutral calcium balance?
DR. COLLINS: Let me bring in this perspective that you’ve heard me talk about. What does any of this stuff have to do with sudden death that’s going on with the dialysis population, the largest cause of cardiac death? A number of years ago, David and Geoff and Pieter, a number of you heard me when I was running the United States Renal Data System (USRDS) articulate this issue that arrhythmic complications, as you approach the end of a dialysis procedure, increased. Anybody who sat in a dialysis unit could actually see this, either by asking the nurses how many extra systoles they had at the end of the run, but if you look at the electrocardiograms at the end of the run—those of us who did a lot of research—you’d find that the QT intervals tend to lengthen out during the run.
I come at it from the fact that, when David articulates this issue of what the low calcium bath is doing toward the heart, that by the end of the run, you sort of have a perfect storm that’s going on relative to electrolyte abnormalities. The ionized calcium is falling. The bicarbonate is rising, so that’s also driving the ionized calcium down. The magnesium is falling because we dialyze on a very low magnesium bath. The QT interval increases. The beta-blockers are dialyzed off. The angiotensin-converting enzymes are dialyzed off. Everything that protects the patient from arrhythmic complications actually gets worse by the time you get to the end of the run. Dialyzing on calcium baths, even if the ionized calcium was equal to the blood calcium, the fact that we push the bicarbonate up means that we drive the ionized calcium down, so that sudden death may actually be exacerbated by low calcium bath. That’s my concern about that.
DR. BUSHINSKY: Didn’t Pun show in a review of the DaVita database6 that, yes, a low potassium bath was associated with increased cardiovascular mortality, but so was a low calcium bath?
DR. COLLINS: Yes. They both potentiate each other. So, the low potassium, the low calcium, the low magnesium, and the high bicarbonate all are impacting the QT interval and are all arrhythmogenic by their nature.
DR. BLOCK: Let me ask a question to both of you before we hear Pieter’s thoughts. We know that with potassium, as both of you brought up, that the gradient between the patient and the dialysate is of really utmost importance. It’s not just what is the potassium bath, it’s what’s the gradient in either direction, and I guess what I’m hearing is that—it’s not exactly the same, but similar to the concept here—the gradient between the patient and the bath is going to be ultimately quite important here as well.
DR. COLLINS: Yes.
DR. BUSHINSKY: Yes.
DR. COLLINS: David, if you really look at the sweet spot of where the potassium is supposed to be, whether it’s from Kam Kalantar’s papers or a few of the other papers, either in dialysis populations or nondialysis populations, really, you’d like the potassiums to be between 4 mg/dL and 5 mg/dL.7–9
DR. BUSHINSKY: Absolutely, Allan. We, as nephrologists, are always worried about the high potassium, but our cardiology colleagues impress upon us that a low potassium is also arrhythmogenic and associated with increased mortality, so this perfect storm that you speak of, of a low calcium, a low potassium, a low magnesium in the presence of a high bicarbonate is potentially, incredibly arrhythmogenic and may well explain much of the mortality at the end of those dialysis treatments.