1. PODCAST TRANSCRIPT:
SECONDARY HYPERPARATHYROIDISM, AN OVERVIEW
Mohamed G. Atta, MD, MPH
When we talk about secondary hyperparathyroidism we are talking about the development
of this disorder in kidney patients as they lose their kidney function. One aspect that I would
like to start with is the implications of hyperparathyroidism in kidney patients. In 2003, the
American Heart Association came up with a statement indicating that kidney disease is a risk
factor for the development of cardiovascular disease. They went on and indicated that
kidney patients have the additional risk factors for cardiovascular disease including the age,
male sex, hypertension, dyslipidemia and diabetes and so on. But also those patients have
unique characteristics that can actually increase the risk for cardiovascular risk factors such
as albuminuria, anemia and also abnormal calcium phosphate metabolism. If we look at the
focus of today’s topic on secondary hyperparathyroidism in kidney patients, we find that
according to observational data the prevalence of hyperparathyroidism in those patients
would be around 40% in stage III chronic kidney disease and stage III indicated that the GFR
or estimated GFR is between 30 and 60 mL per minute. If we move from stage III and go to
stage IV about 70% of the patients will have secondary hyperparathyroidism. So it is a
common disease in this population and as a result it is an important factor that may be
implicated not just in bone disease, but also cardiovascular disease. That is the initial
overview that I would like to introduce in the topic of secondary hyperparathyroidism in
kidney patients.
Now the main function physiologically of parathyroid hormone is to regulate serum calcium
levels. As I generally say to the medical students and residents, the parathyroid gland
probably exists just to regulate serum calcium, and therefore the parathyroid hormone or
the PTH is driven in large parts by the changes in serum calcium level. If serum calcium
decreases for any reason, there is an increase in the secretion of PTH; (which occurs at the
stimulation of the calcium sensing receptor, which in fact gets inhibited as long as serum
calcium is low,) PTH will be released as a result of the inhibition of the calcium sensing
receptor, which is expressed on the chief cells of the thyroid gland. On the other hand if
serum calcium goes up, that will stimulate the calcium sensing receptor, which will inhibit
the release of the PTH from the thyroid gland and therefore serum calcium will start to
decline again as a result of the reduction in PTH secretion.
So, the main action of the PTH is really regulation of serum calcium, bringing the level within
a very tight range and to do that the PTH acts on several organs to maintain serum calcium
within normal range. It acts on the gastrointestinal tract, it acts on the bone and it acts on
the kidney. On the bone the most important action of PTH is really stimulation of the
osteoclasts and also the osteoblasts, so it induces bone turnover as it stimulate the
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2. osteoclasts more than the osteoblasts and this is very important in the normal pattern of
bone turnover. PTH also will stimulate the 1-alpha-hydroxylase enzyme activity in the
kidney, which will result in the activation of 1,25-hydroxy vitamin D and indirectly vitamin D
will act on the small intestine to increase calcium absorption in the setting of hypocalcemia.
High PTH now works on the bone to stimulate the osteoclasts, which will increase bone
resorption and also increase calcium in the serum through this pathway and also indirectly
on the small intestine by activating vitamin D through the 1-alpha-hydroxylase enzyme in the
proximal tubular cells of the kidney. Activation of vitamin D will lead directly to calcium
absorption from the intestine in the setting of hypocalcemia as well.
The other function of the parathyroid hormone that is important, is the excretion of the
phosphorus, so high PTH is associated with increased urinary phosphorus and the
mechanism by which PTH induces phosphaturia is through the inhibition of the sodium
phosphate co-transporter located on the brush border of the proximal tubular cells. As a
result phosphate leaking in the urine takes place. So, inhibition of that co-transporter is an
important action or important mechanism by which PTH increases phosphate loss in the
urine and that is why in early kidney disease, because of the increase in the PTH, serum
phosphate remains within normal limits as a result of the high PTH in those patients.
Now, an essential component of the homeostasis of mineral metabolism in normal
individuals is vitamin D, and as you know vitamin D gets activated first in the liver at the 25-
hydroxy vitamin D level and becomes 25-hydroxy vitamin D and then gets activated in the
kidney by the 1-alpha-hydroxylase enzyme secreted by the proximal tubular cell and
becomes 125-hydroxy vitamin D. As I mentioned before, 125-hydroxy vitamin D is involved
in increasing calcium and phosphorus absorption from the intestine, but also has a critical
role in suppressing intact PTH via its direct action on the vitamin D receptor, which is
expressed on the parathyroid gland. The disruption in the interaction between intact PTH,
calcium, phosphorus and vitamin D are critical components in the development of what we
call mineral disorder disease in CKD patients. Although the pathophysiology of this disorder
is not fully understood, there is lot of advances in the last 10 years that have shed light on
some of the new pathways in the development of mineral disorders in CKD patients. It is felt
right now that the initial component disorder starts with the changes in serum phosphorus
or smaller decline in kidney function, which triggers the release of a specific hormone from
the bone by the osteocytes called fibroblast growth factor 23. That hormone is a
phosphaturic hormone, so it leads to the PTH inhibiting the sodium phosphate co-
transporter on the brush border of the proximal tubular cells and leads to phosphaturia as a
result of the inhibition of this co-transporter. In addition, the rise in FGF23 leads to
inhibition of the 1-alpha-hydroxylase enzyme in the proximal tubular cells and as a result
there is inhibition of the activation of vitamin D, so that would be the second step in this
process.
So high FGF23 decline in vitamin D activation and vitamin D deficiency, and as a result there
is inhibitory effect of vitamin D on parathyroid hormone release and those ones will develop
Developed in collaboration with the Johns Hopkins University School of Medicine, through a strategic
educational facilitation by Medikly, LLC
Supported by and unrestricted educational grant from Abbott Laboratories

3. hyperparathyroidism. In conjunction, the lack of vitamin D leads to decreased serum calcium
absorption by the intestine and hypocalcemia as indicated before is critical mechanism by
which PTH starts to increase as well.
So, the interplay between serum calcium and vitamin D deficiency and FGF23, all of that as a
result of the changes in serum phosphorus initially and also the declining kidney function,
lead to the syndrome of the disordered mineral metabolism in kidney patients. It is
important, however, to realize that those patients with this disorder will not have early
symptoms and it is important that those patients are screened for that disorder by looking at
both hyperparathyroidism by checking the intact PTH level early on and also by checking the
vitamin D level early on to determine whether those patients need early intervention to
prevent the complications of the disorder as we will discuss later.
Developed in collaboration with the Johns Hopkins University School of Medicine, through a strategic
educational facilitation by Medikly, LLC
Supported by and unrestricted educational grant from Abbott Laboratories