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| American
Society of Nephrology Annual Board Review Course September, 2000 Calcium and Phosphorus Regulation: Bone and Soft Tissue | ||||
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Online Slide/Audio Symposium |
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| American
Society of Nephrology Annual Board Review Course September, 2000 Calcium and Phosphorus Regulation: Bone and Soft Tissue | ||||
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Sharon M. Moe,
M.D. Associate Professor of Medicine, University of Indiana School of Medicine, Director of Nephrology, Wishard Memorial Hospital, Indianapolis, IN. |
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00:00
Anatomy and histology of bone
The third target organ is bone. Bone consists primarily of cartilage in the growth plate and trabecular or cancellous bone, which is generally in the epiphysis of the long bones. This particular type of bone is the part that is metabolically active and has a calcium turnover rate of weeks. So this is what actively remodels. The cortical bone in the shafts of long bones serves more of a protective or a mechanical function, a bioengineering function. It has a turnover rate of months.
00:00
Structure of bone
The bone structure consists of highly organized cross-linked fibers in a lamellar fashion consisting of triple helix collagen type-1; 90 percent of bone is collagen type 1. A defect in this, osteogenesis imperfect, leads to real frail bones. In addition, you have all these what we call non-collagen bone components -- proteoglycans, osteopontin, osteocalcin, osteonectin, alkaline-phosphatase. Hydroxyappetite is the main mineral component or really the major salt. It is laid down in a very active manner.
00:00
Different cells within bone
Many bone cells are present--bone cartilage, bone marrow, bone lining, bone forming cells or the osteoblasts; mature bone cells or osteocytes; and bone resorbing cells or osteoclasts.
00:00
Remodeling sequence within bone
The remodeling sequence is something that is very tightly regulated, and this is what is very deranged in renal failure. It is believed that the first step is somehow the osteoclasts know where to go on the bone. At any one point in time, only 20 percent of your bone is remodeling. So these osteoclasts, which come from mononucleated progenitor cells, fuse together, bind to a part of bone, and then basically eat away that part of the bone. Then the osteoblasts come in, fill in that pit with unmineralized bone, called osteoid, and then they actively mineralize it by a mechanism that we are pretty clueless on at this point.
00:00
Osteoblasts
Again, the osteoblasts provide the structural framework of the cell by producing both collagen and non-collagen proteins. It is unique that 20 percent of its protein product is a single protein. That is almost unheard of for any cell. But the osteoblast...despite the osteoclast being the resorbing cell, the osteoblasts have the receptors for most of these--PTH, calcitriol, prostaglandins, interleukins, TGF-beta. And so by doing this, the two cells are tightly coupled to each other. So you stimulate he osteoblasts, they turn on the osteoclast, and you get this even remodeling sequence. So changes in either one of those are going to give you abnormal remodeling.
Fifteen percent of osteoblasts become osteocytes. Ten years ago we were taught that those cells are just dead cells that got trapped in the bone. But in reality, the osteocytes, which have a canaliculi-like process that connect each other, are the regulators in mechanical loading of bone. So that is how the body senses all the changes in pressure. Remember, when an astronaut goes up in space, they lose 20 percent of their bone mass in one week. It comes right back as soon as they get some pressure near their feet.
00:00
Source of osteoblasts
The osteoblasts come from undifferentiated mesenchymal cells, probably in the marrow space. They become a flat lining cell. Then they become the cuboidal active cell, either on the endosteum or the periosteum when they are activated. They have different gene products at each of these stages, the most famous of which is alkaline- phosphatase and osteocalcin.
00:00
Osteoclasts: Where they come from
Osteoclasts, as I mentioned... it is still controversial where they originate. Some people believe they come from circulating cells; others believe that they come from the marrow space directly. Whatever it is, they then fuse together under the control of, in part, PTH, IL-1, 1,25, and then they attach to the bone, and then they polarize and become like little mini proximal tubule cells. They have a ruffled border that secretes all sorts of enzymes, and they resorb the bone. They are then inhibited by PTH and IL-1, and they are stimulated by TGF-beta, estrogen, and biphosphonates to undergo apoptosis. That is a key regulation. We now understand that this is a critical component to normal bone remodeling. When you become estrogen deficient and you lose your apoptosis, the cells go on and on and on and on.
00:00
Osteoclast function
So again, they resorb it by these proteolytic enzymes. And just to show you they are like the proximal tubule in a way, they have all of these transporters--sodium hydrogen, bicarbonate, chloride, calcium ATP-ase, sodium potassium ATP-ase. The cells move along the bone and anchor through a very active cytoskeleton that is mediated by integrins.
00:00
Osteoprotegerins
A lot of excitement has happened in this field in the last three, four years with the identification of something called osteoprotegrin, OPG, and its ligand, which is also called RANK. Now we have a putative substance that may be the regulator of telling the osteoclasts where to land and telling it when to differentiate. And in fact, there are already drugs being developed by both Amgen and Lilly to use this as a potential anti-osteoporotic agent. So again, the osteoprotegrin appears to be key in differentiation, fusion and activation, as well as apoptosis.
00:00
How osteoprotegerin may modulate osteoclast function
To show you that, all of these things that were in that previous slide as potentially controlling osteoclasts all work probably mediated via this osteoprotegrin ligand. This may be our future little treatment. The osteoprotegrin knock-out mouse--this is a little controversial-- they always develop bone failure. And, in fact, there also may be some importance in this protein in vascular calcification.
00:00
Regulation of bone remodeling
As I mentioned, the regulation of bone remodeling probably is all tied into osteoprotegrin recently. But it also works via PTH, receptors on osteoblasts; calcitriol again also has the receptors on osteoblasts. And I think that is why osteoprotegrin is so exciting--because they finally found something on osteoclasts that makes a little more sense.
00:00
Insulin stimulates bone turnover. Glucocorticoids are important, obviously, in your transplant patients. It acutely stimulates bone resorption by decreasing calcium absorption from the gut. And long- term, it inhibits bone formation and resorption through multiple mechanisms, one of which may be this osteoprotegrin.
00:00
Summary of calcium and phosphorus homeostasis
Let's try to put all of this together to see how well you have learned what I have just been speaking about. If you have a situation here where your calcium drops, ionized calcium drops in the extracellular space, your parathyroid hormone turns on. This stimulates the conversion of 25 to 1,25 vitamin D, thereby enhancing gut absorption of calcium and phosphorus. PTH also works at the level of the bone to enhance bone turnover and release calcium and phosphorus into the circulation, and it also works at the level of the kidney to increase calcium reabsorption but to drop off phosphorus in the urine. When the phosphorus drops off in the urine, the overall effect then is just on calcium. So the phosphaturic effect of PTH negates the phosphorus absorption from the gut by vitamin D and the phosphorus reabsorption on the bone.
00:00
Deranged calcium and phosphorus homeostasis in renal failure
Let's put all this together then in renal failure. What happens? The first thing that happens in renal failure is a decrease in GFR. And that decreases your ability to excrete phosphorus and it decreases your nephron mass. So you no longer make vitamin D. So beginning with a GFR of around 50 ml/min, you start to decrease your phosphorus excretion. What that does is it creates a secondary hyperparathyroidism. At the level of the intestines, this decrease in 1,25 leads to decreased calcium and phosphorus absorption. And then your PTH gland, as mentioned, gets stimulated because you have decreased 1,25 and increased phosphorus, leading to hyperparathyroidism.
So in your patient who has a GFR of 30 or 40, their serum electrolytes will look as a slightly low calcium, 8.5/9.0 mg/dL; a phosphorus that will appear to be normal, but at the sake of increased PTH. This is important because we tend to ignore those levels in predialysis patients. In reality, what those patients should probably be doing is be on a phosphorus-restricted diet or a phosphate binder so that you can prevent all of these changes. This will probably be a K-DOQI recommendation.
00:00
Altered bone homeostasis in renal failure
Now in renal failure, your bone is also abnormal. So not only are you missing kidneys, but your bone isn't quite right. When you have increased PTH with decreased calcitriol, you have an increased resorption or an uncoupling. But when you give calcitriol, what happens is you suppress PTH and you lead to decreased bone formation and probably contribute to adynamic bone.
The problem is you have an overall positive calcium balance when you're on dialysis. Once you get on dialysis and you start dialyzing them with your various calcium baths, you are giving them a little bit of calcium. Let me show you that.
00:00
Calcium balance with various dialysates: hemodialysis
This is a very nice review article. I highly recommend that you read it. This is in hemodialysis patients. A "low calcium" dialysate, just 2.5 mEq--that is really not low, that is physiologic. That is a serum calcium of like 9.5 to 10. What happens is you are giving that patient a little calcium every time you dialyze them. The dietary intake, 500 to 800 mg--even if they don't absorb very much, you still are giving them a net positive calcium balance.
00:00
Calcium balance with various dialysates: peritoneal dialysis
The same holds true in peritoneal dialysis patients. Even with a low-calcium dialysate, you do remove a little bit of calcium. But when you take into dietary accounts, you are giving them a little calcium.
Now the average age of a dialysis patient these days is what? Sixty, I think. So the normal balance situation in a 60-year old is that it is neutral. Most 60-year olds do not absorb any calcium; they remain in neutral balance. What we are doing is we are making an unphysiologic state.
00:00
Phosphorus balance in dialysis patients
Phosphorus, of course, we don't clear well at all, and so we ...we do pull a little bit, but it doesn't keep up with daily intake.
00:00
Effect of phosphate binders
Then we feed them phosphate binders. If you feed a patient--and these are healthy volunteers in a well-done study where they lavaged them clean from above and below. Then they gave them a set meal that had a set amount of phosphorus, a set amount of calcium, and they gave them various binders: placebo, aluminum, Phoslo, and calcium carbonate or TUMS. Aluminum was the best and the most potent phosphate binder. Calcium carbonate was a little bit less effective than Phoslo (calcium acetate). So gram per gram, Phoslo is a more efficient phosphate binder. That is kind of what the Phoslo reps tell you, however the number of pills you have to take to get this is almost two-fold; so the net result is that pill for pill, they are about the same.
00:00
Calcium and phosphorus disposition in dialysis patients
What is not known is ...you sit there and you tell your patients, "You take this calcium pill when you eat, and it binds up all your phosphorus and you poop it out and you don't absorb anything." But in reality, you absorb a lot of this calcium. And, in fact, your patients where you have them on five TUMS with each meal-- you are giving them almost an extra gram a day of calcium in somebody who probably should be neutral balance, and somebody in positive phosphorus balance.
So where does all this calcium and phosphorus go? Well, in a normal situation what would happen is you would excrete it. The excess phosphorus would go out in the urine. The excess calcium would go out in the urine or it would be pushed into the bone with appropriate bone remodeling. But you don't have a kidney and you don't have normal bone remodeling.
00:00
Vascular calcification: One example
So where it really goes probably is here, which is what we see... this is not an uncommon x-ray in our dialysis patients. It is often said that this is from metastatic calcification. I want to take just a few minutes to comment on that because it is going to set the stage for the renal osteodystrophy talk tomorrow.
00:00
Metastatic calcification and calcium x phosphorus product
What you get in package inserts and various other things is that you want to keep this calcium/phosphorus product less than 70 mg2/dL2. Where did this number, 70, come from?
On one of my compulsive days, I sat in our IU library for five hours and tracked it back to the original source to see what data really supports that number. In fact, the Zemplar insert suddenly changed to 75. What support is there of that? It came from an editorial by Michael Parfitt, who is a brilliant bone biologist. But it was an editorial. He basically said the product corresponding to calcium/phosphate precipitation, basically in vitro, is about 60; but in uremia it is probably around 70. So they are saying in normal patients, maybe around 60 you start to see this. When you put calcium and phosphorus together in a test tube, it lands out.
The problem is that we manage our dialysis patients with this feeling that we have a safety net, that as long as our calcium/phosphorus product is under 70, our patients are okay. But maybe what we have really been doing is hurting our patients with that concept that is not based on any factual information. Now there are lots of... there are probably at least 300 studies in the literature trying to associate calcium/phosphorus product with metastatic calcification, whether it is vascular or soft tissue, etc.
The problem is there really didn't exist any very specific and sensitive techniques by which to quantify this. So how can you really look at it? Something new is called an electron beam CT. This is a new ultrafast CT mechanism that gates to the heartbeat and can quantify the calcification in blood vessels.
00:00
Cardiac calcification in dialysis patients: initial results
This particular study, which was done in Germany a few years ago quantified the calcification in the coronary arteries of dialysis patients and compared them to controls with CT and a cardiac cath. Of note, more than 50 percent of the patients had calcified valves.
00:00
This just shows you, in the white bars, which are basically non- existent, that your non-hemodialysis patients with no cath, a negative cath, normal coronaries. In the green are your non-hemodialysis patients with coronary artery disease. In the red are the dialysis patients: Two- to five-fold more coronary artery calcification than in age-matched counterparts with proven cath disease.
00:00
They did a step-wise regression analysis and they didn't find any correlation with calcium/phosphorus product, but they only used a single time point. And they did all these patients again a year later, and they found an increase in calcification in all of the patients.
00:00
American Heart Association guidelines re coronary calcification
Well, what does this mean? The American Heart Association has a consensus statement, which was first published in 1996 and a recent statement just came out this month. Unfortunately that journal was gone from our library, so I don't know what it says, but I assume it is about the same thing. That is it confirms the presence of coronary atherosclerotic plaques. This is in non-dialysis patients. The greater the amount of calcium, the greater the likelihood of obstructive disease, but there is no one-to-one relationship. A high- calcium score may be consistent with a moderate to high risk of a cardiovascular event within the next two to five years, independent of diabetes, hypertension, homocysteine, etc., etc., etc.
00:00
Cardiac calcification in young ESRD patients
Well, recently Bill Goodman out of UCLA and Salusky and their colleagues published this article in The New England Journal just a few months ago. This was in their kids. What they did is the measured the calcification score in the heart. What they found was that as soon as the kids' bones quit growing, all of that calcium went into their hearts. And the kids, at age 25 and 30, had coronary calcium scores that were equivalent to 50-year old men with heart disease.
00:00
Coronary calcification and duration of dialysis
The other big factor was the duration of dialysis. This is the proportion of patients with calcification. I preached to you earlier that what we have in renal failure is no kidneys to get rid of these loads. We have abnormal bone that cannot incorporate these loads, and yet we feed our patients calcium way above an RDA for a postmenopausal woman.
00:00
Coronary calcification increases with time in children with ESRD
This just shows you even in these kids, these are adolescents, only one patient went down, one stayed the same, but everyone else over the period of a year had an increase, similar to the work in Braun in adults.
00:00
Risk factors for coronary calcification in children
Now of note is the correlation that they found here. Age had an effect and duration of dialysis was the most suggestive stimulators. The other thing was the dose of oral calcium. So those kids who got over 6 grams/day -- this was prescribed dose; we don't really know what they took. Six grams of calcium had increased calcification compared to those who got three grams of calcium. In addition, the serum phosphorus was marginally or really not quite... almost significant. The calcium/phosphorus product was significant, but look at the level at which they found a difference. Calcification didn't occur when the product was 56, but it did occur when the product was 65--well below our "standard" of 70 and 75.
00:00
Why calcification is important
Now calcification in a plaque is important because it confers that stiffness factor to the plaque and is probably what causes the rupture, and that is when you get the clinical event.
00:00
Bone formation capability by smooth muscle cells
Just a side note, the calcification process...those smooth muscle cells behave like little osteoblasts. You can take them out and culture them and make them form pieces of bone.
00:00
But all of the regulators that stimulate those in bone have an opposite effect in the heart so that your oxidized LDL increases it in the heart but decreases it in the bone compared to regular LDL. In at least one in vitro study there was increased vascular calcification with increasing concentrations of calcium and phosphorus in vitro. There is also an epidemiologic study using coronary caths that show that an elevated phosphorus level, all within the normal range, in non-dialysis patients correlated with angiographic disease.
00:00
Summary and overview
So in our patients, they are set up for increased atherosclerosis, and then we throw them into an environment of an elevated calcium and an elevated phosphorus. What we get is calcification. And so we have to think about... for years you talk about sodium and salt and water in the closed-box model of your dialysis patients. What goes in must come out. You fill them to capacity of your box, and then you have to stop. Somehow we have negated that whole process when we are talking about calcium and phosphorus in our patients. We have been filling them up and filling them up and filling them up thinking it was all good for them. In reality, there is no place for it to go unless the bone is normal, and it is not normal in renal failure.
00:00
So again, accelerated calcification. This number "70" is theoretical. And in fact, what we probably need in our patients is a normal calcium/phosphorus product. We want to avoid this in our patients. Thank you.
References
1. Eriksen EF, Axelrod DW, Melsen F. Bone Histomorphometry. Lippincott Williams and Wilkins, 1993.
2. Favus M. Primer on Metabolic Bone Disease. Lippincott Williams and Wilkins, 1996.
3. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res. 2000 Jan;15(1):2-12. Review.
4. Brown AJ, Finch J, Grieff M, Ritter C, Kubodera N, Nishii Y, Slatopolsky E. The mechanism for the disparate actions of calcitriol and 22-oxacalcitriol in the intestine. Endocrinology. 1993 Sep;133(3):1158-64.
5. Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis. 1997 Apr;29(4):641-9.
6. Sheikh MS, Maguire JA, Emmett M, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS. Reduction of dietary phosphorus absorption by phosphorus binders. A theoretical, in vitro, and in vivo study. J Clin Invest. 1989 Jan;83(1):66-73.
7. Parfitt AM. Soft-tissue calcification in uremia. Arch Intern Med. 1969 Nov;124(5):544-56. Review. No abstract available.
8. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis. 1996 Mar;27(3):394-401.
9. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000 May 18;342(20):1478-83.
