Episode 18: Understanding the Complicated Factors of Bone and Mineral Management with Dr. Michael Anger
When kidneys do not work, a cycle of damaging health events is started that can ultimately lead to significant bone damage for patients. Dr. Michael Anger, Chief Medical Officer of the Renal Therapies Group, joins Field Notes to discuss the methods used to prevent bone damage, preventing the need for additional and expensive therapies for patients.

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Brad Puffer: Welcome, everyone, to this episode of Field Notes. I'm Brad Puffer, on the medical office communications team at Fresenius Medical Care North America, and your host for this discussion today. Here, we interview the experts, researchers, physicians, and caregivers who bring experience, compassion, and insight into the work we do every day.

Bone and Mineral Management is important for everyone, but especially for people with kidney failure. When a person's kidneys do not work, a cycle of damaging health events is started. Because the kidneys play such an important role in managing phosphorus levels in the body, failure to adjust to this change through diet and medication often causes a spiral of conditions, which can ultimately result in significant bone damage. It is also a spiral that can lead to additional and expensive therapies.

To help us all better understand this complicated issue, and the importance of managing phosphorus and calcium levels in patients with kidney failure, is Dr. Michael Anger, Chief Medical Officer for the Renal Therapies Group, a division of Fresenius Medical Care North America. Dr. Anger, welcome to Field Notes.

Dr. Michael Anger: Thanks, Brad. It's nice to be here today.

Brad Puffer: Well, Dr. Anger, I wanted to ask you, to start, when you were treating patients, and in your own experience, just how big an issue is phosphorus control for people with kidney failure, and why is it so important when it comes to bone health?

Dr. Michael Anger: Well, phosphorus control is a big issue. Because his kidneys start to fail, and certainly, when patients end up on dialysis, phosphorus retention and elevation of serum phosphorus levels are so prevalent. And it sets out a cascade of a lot of other issues that ultimately can cause damage to our bones, as well as other organ systems in the body.

Brad Puffer: And so what is the actual mechanism that's causing these problems? We talked about the spiral that can occur as a result.

Dr. Michael Anger: When kidneys fail, and certainly starting early in the course of the decline of their function, there's a whole variety of metabolic derangements that can take place, and ultimately lead to bone disease. As renal function declines, parathyroid hormone levels starts to rise, even at a time when calcium and phosphorus is still normal. Vitamin D3 levels fall, mostly due to an increase in something called fibroblast growth factor 23, or FGF 23.

FGF 23 is a bone derived hormone that plays an important role in the regulation of phosphorus and vitamin D metabolism. It primarily acts in the kidney to induce phosphorus excretion and suppress vitamin D synthesis in the presence of an FGF receptor and its coreceptor, called klotho. Klotho is sometimes called the anti-aging hormone, and it's a transmembrane protein that exists in renal tubules. And it's required for receptor activation.

And this inhibits proximal tubule expression of the 1-alpha-hydroxylase enzyme, leading to decreased vitamin D synthesis in the kidneys. And as GFR declines even further, phosphorus levels rise even higher, leading to more hypoglycemia, and even higher parathyroid hormone levels. And although that increase in parathyroid hormone level is intended to enhance urinary phosphorus loss, eventually, that becomes inadequate to lower phosphorus. And the elevated levels persist.

And finally, the complications can include renal bone disease, like renal osteodystrophy, osteomalacia, adynamic bone disease, and in the worst case, osteitis fibrosa cystica.

Brad Puffer: And Dr. Anger, I know we have physicians who listen and will get a lot out of that answer. Some of us may have not followed everything. So what is the key takeaway here?

Dr. Michael Anger: The key takeaway is that when kidney function declines, and certainly when it reaches end stage, the kidneys are not capable of removing all the waste products out of the bloodstream. As a result, phosphorus levels will accumulate, which will result in a decrease in calcium, and ultimately lead to elevation of parathyroid hormone levels, amongst others. But that's really the key takeaway. And that drives the future of bone disease and cardiovascular disease.

Brad Puffer: Well, Dr. Anger, I think you just made the case that a lot is going on in the body when we don't properly control phosphorus levels. And I understand those high phosphorus levels can really increase the risk of hospitalizations as well. And we've looked at that in our patient population.

Dr. Michael Anger: We looked at a data setof over 40,500 Fresenius kidney care dialysis patients. The risk of hospitalization increases dramatically as serum phosphorus increases. That rate increased by 9% for phosphorus levels of six to seven, 18% forlevels seven to eight, 20% forlevels eight to nine, and as high as 31% for levels greater than nine.

Brad Puffer: And when you talked about that spiral, and some of the other things that can happen when we don't control phosphorus, what are the different complicating factors that result in the end?

Dr. Michael Anger: The elevation of phosphorus promotes further increases in PTA, parathyroid hormone, by a combination of mechanisms. This includes the induction of hypoglycemia, decreases in vitamin D, and increased parathyroid hormone gene expression. In addition to bone disease, there's worsening of cardiovascular disease, due to accelerated vascular calcification, including coronary artery calcification.

In the same database that showed the increased risk of hospitalization with increasing phosphorus levels, there also was an increasing relative risk of mortality.

Brad Puffer: So if I understand this correctly, then, just by controlling phosphorus levels, we're really able to prevent an entire cycle of negative health conditions from even starting. So I guess the next question would be, how do we control phosphorus levels well? What are the medications and therapies that are best suited to achieve the results we're looking for?

Dr. Michael Anger: Phosphorus is ubiquitous in the foods we eat. So although we could consider dietary restriction as one way to control serum phosphorus levels, it's really very difficult to do so. In addition, there's a risk that by lowering the intake of high phosphorus foods, a patient might restrict protein intake, and actually become malnourished.

Therefore, really the best option is a phosphate binder, which binds phosphorus in the GI tract, and allows it to be excreted in the stool. Lastly, although phosphorus is not terribly well dialyzed, it is certainly removed somewhat. And so longer dialysis treatments, and compliance with dialysis, certainly help with its control.

Brad Puffer: Well, you mentioned phosphate binders. And I understand there's really two types. And this has developed the science over many years now, both calcium and non-calcium based. Is there one that's better than the other?

Dr. Michael Anger: Yes, it appears that one is. In November 2017, the KDIGO bone and mineral metabolism guidelines were updated from the previous guidelines in 2009, due to the publication of several randomized control trials, looking at both types of binders. These trials looked at chronic kidney disease patients, as well as the dialysis population.

In chronic kidney disease patients, those on calcium based binders had the highest change in coronary calcification and the lowest degree of cardiovascular event-free survival. In patients on dialysis, all cause mortality. All cause cardiovascular mortality, and cardiovascular mortality due to cardiac arrhythmias was significantly higher in patients on calcium based binders. Thus, it's pretty clear that non-calcium based binders are significantly better for patients.

Brad Puffer: Well, it's great to have those studies, Dr. Anger. And I'm wondering what, then, are the biggest challenges in your experience, on both making the right decisions about phosphorus control, and then actually getting compliance from our patients?

Dr. Michael Anger: I think the greatest challenge is finding medicines that the patient is willing to take, has the fewest side effects-- or perhaps none at all-- and certainly one that they can afford. Achieving these objectives, to the best of our ability, is really the way to get patients to be compliant with their phosphate binders.

Brad Puffer: And does that include pill burden as well? I imagine, it could be a lot of medications that these patients have to take.

Dr. Michael Anger: Yes, patients, especially those on dialysis, are on a tremendous number of medications. They have a lot of comorbidities. And of those, the ones that seem to be the greatest number are phosphorus binding pills. So any way that we can cut down the number of pills they take can certainly enhance compliance.

Brad Puffer: Now, if phosphorus isn't controlled, you mentioned the spiral. And I imagine that those other conditions can then cause and require a whole new cycle of medications that are needed, correct? So we're trying to avoid that, too.

Dr. Michael Anger: We certainly are. Because there are a lot of other medications that can be added, and just add to the patient's pill burden. So for example, if cardiovascular calcification and cardiac disease occurs, there may be specific medicines for their heart or peripheral vascular disease. If parathyroid hormone levels get very high, there could be a need for medications such as calcimimetics, which lower parathyroid hormones.

These are pretty expensive, and they can cause side effects-- especially GI side effects, such as nausea and vomiting. And in fact, in the 2012 Evolve trial, Cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate to severe hyperparathyroidism, who were undergoing dialysis. And then finally, as we discussed earlier, increasing levels of phosphorus can be associated with higher rates of hospitalization or death.

Brad Puffer: So I assume this also impacts cost. If we have increased hospitalizations, other health conditions, other medications that are needed, we can reduce the cost for our patients and the entire health care system, if we just manage phosphorus correctly.

Dr. Michael Anger: Without question, by preventing bone disease, cardiovascular disease, other vascular disease complications, we lower the risk for hospitalization, and of course, reducing the risk for mortality. We're doing really what's best for patients. And certainly, this reduces costs for the health care system and all of us.

Brad Puffer: Are there disagreements, Dr. Anger, about how to manage these conditions among nephrologists?

Dr. Michael Anger: Well, there can be. Because calcium based binders are inexpensive and very easy to obtain, some nephrologists still use them as first line therapy, despite the data against this approach. In addition, sometimes there's a tendency to utilize calcimimetics before the phosphorus is adequately controlled.

Increased phosphorus has been a long standing problem. And because oftentimes, the patient compliance component is such a challenging part of it, some nephrologists don't feel that phosphorous control is quite as important as other parameters in the care of end stage renal disease patients, such as dialysis adequacy and anemia control.

Brad Puffer: And hearing you talk, it really sounds like the science on how we manage phosphorus has evolved over the years.

Dr. Michael Anger: It has. We better understand the many interrelationships of numerous hormones and their impact on bone and cardiovascular disease. We've also seen the complications of older phosphate binders and have learned to try to avoid ones with long term side effects, such as those that contained aluminum.

We've also become much more patient focused. We know that there's a correlation of pill burden, just as we talked about, and patient compliance, and have created more potent binders that reduce the total number of pills that have to be taken.

Brad Puffer: So Dr. Anger, it's great to know that the science has evolved. What does the future hold? Do you think we'll get even better at preventing bone and mineral disease for people with kidney failure?

Dr. Michael Anger: I think we have a much deeper understanding of the mechanisms of phosphorus movement across the GI tract. And we may also target other mechanisms of lowering phosphorus, without necessarily having to use a binder. I think there will certainly still be continued attempts to increase potency of medications used, to further reduce pill burden.

Some binders that are chewed will likely become available in forms that can be swallowed, and vice versa. And I think we'll continue to listen to what patients want and need and adjust future treatments to align with ways to improve their quality of life, while at the same time do an even better job of preventing bone and mineral disease.

Brad Puffer: Well, I think that's a great way to end, Dr. Anger. And we certainly look to hear more future developments around this issue. It's been a really important conversation. I'm glad we had the chance to talk.

Dr. Michael Anger:  Thanks for having me, Brad.

Brad Puffer: And to our audience, thank you for joining us. Please know that your feedback is always welcome..

And to our audience, thank you for joining us. Please know that your feedback is always welcome. So if you have comments on today's episode, topics of interest to you, or speakers you want to hear from, let us know by clicking the feedback link, featured on the Field Notes website, at fmcna.com. And don't forget, you can find Field Notes also on Apple Store, or Google Play, or right here at or fmcna.com, where you'll find our annual medical report, and other featured articles. I hope you'll come back and join us, as we have many more topics to discuss in the weeks ahead. Until next time, I'm Brad Puffer, and you've been listening to Field Notes by Fresenius Medical Care. Take care, everyone.