A question for Dr Agar about raised PTH levels in Stage 3

Dear Dr Agar

I have Stage 3 diabetic nephropathy and while I’ve been relatively stable over the last 2 years after raised serum creatinine levels first raised it’s ugly head in 2011, I have noticed that over these past 2 years my PTH levels are set at 10.2 pmol/L (normal upper limit being 6.9). My calcium, phosphate levels have always been normal, as with everything else including potassium. The only imbalance I have is a tendency towards iron deficiency anemia (IV iron infusion given in 2012) & now maintained with a low dose Aranesp injection once monthly. I am a menstruating female with multiple small uterine fibroids I might add.

My specialist is unsure whether I may have primary or secondary hyperparathyroidism. A bone density scan was done 2 years ago that showed very healthy levels of bone density. I have the option of undergoing another one now if I wish. I am Vit D deficient but maintain normal levels of Vit D through supplementation with OTC brand of Vit D3 capsule. My specialist is about to test me for a more specialised kind of Vit D blood test that may lead to my being prescribed an alternative 'activated" type of D3. This may help my PTH levels.

I now also supplement with sodium bicarbonate capsules even though I do not suffer from metabolic acidosis. This supplement is more for preventative purposes. Apart from this, I take an ACE inhibitor & a calcium channel blocker to manage my BP.

I am worried about developing bone disease or cardiovascular problems due to this raised PTH levels. I understand that this is a difficult area that is under-researched so I would greatly appreciate any advice you can offer me about what to do to normalise my PTH levels.

Thank you.

Dear AchillesHeel …

Thank you for your question and you have very nicely set out the salient features of your problem.

The following is broken into two parts: a shorter answer to your query, and a longer explanation of the complexity of the PTH conundrum.

The key issue, in your case, is the difference between:

(A) a condition called primary hyperparathyroidism: where independently from chronic kidney disease (CKD), one of the (usually) 4 parathyroid glands spontaneously develops a benign overgrowth of normal parathyroid gland tissue … a ‘lump’ that is called an adenoma. Adenomas are benign tumours … but pesky!

The development of an adenoma - and common sites for adenomas to develop are the parathyroid and adrenal glands - is a quite common ‘out-of-the-blue’ thing to happen in humans. In the case of parathyroid adenomas, lots of people who do NOT have kidney disease have (or will develop) a small parathyroid adenoma. These are not commonly linked to CKD, and simply ‘happen by chance’ or, possibly, via genetic influences.

Less commonly, but also unrelated to CKD, two or more of the parathyroid glands can become rather more diffusely (generally) over-active (or ‘hyperplastic’). In both cases, the gland (or glands) over-produce parathyroid hormone (PTH).

This results in changes in the blood and, later, in bone.

… or …

(B) a state arising WITHIN the context of CKD, called secondary hyperparathyroidism. Here, as a result of a vastly complex interplay between FIVE seemingly separate body tissues/regions (= the gut, the blood, the bones, the kidneys, and the parathyroid glands), a chain of events results in a ‘syndrome’ that ultimately induces renal bone disease … see below …

© Finally, there are even more complex outcomes … tertiary, and even quaternary hyperparathyroidism … but I won’t go there!

While you don’t state your actual eGFR level of CKD, or whether your ‘normal’ calcium is low or high normal … and though, on balance, you probably DO have CKD-related hyperparathyroidism … a search for an adenoma seems still worthwhile as sometimes relatively common things (adenomas) do occur ‘by chance’ in very common illnesses (like CKD).

Your specialist is right on the money with tests and advice, but an ultrasound to seek any one obviously enlarged gland, or even a sestimibe scan, might be worthwhile. You are clearly tracking towards starting calcitriol as a means to suppress PTH = in my view and at your levels of PTH = the right thing to do. Assuming your calcium levels allow this and do not rise too far under the influence of calcitriol and the increased gu absorption of calcium it will induce, that is the direction I would be going too.

So … my reading of your question suggests the right answers are being sought … and actioned.

In addition, your precautionary use of sodium bicarbonate (esp. if your BP is not difficult to control, and the sodium component is not promoting volume overload) + the use of an ACEi … all reflect excellent management

BUT: understanding this complex area is a minefield for us all … whether patient, or doctor.

As such - and beyond your question - I offer the following explanation(s) of the complexity of PTH, if only for your interest!

Hyperparathyroidism is the term used for the over-activity of one or more of the (usually) 4 little glands called parathyroid glands that hide in behind the thyroid gland in the neck.

There is often confusion between the thyroid, and the parathyroids … but, they bear NO functional relationship at all … none! The parathyroids are simply near (the Greek ‘para’ means ‘adjacent’ … like parallel lines … and nothing more) … but, their role in the body is quite different to that of the thyroid gland!

The role of the parathyroid glands is to control the blood levels of calcium and phosphate in the body. It the case of calcium, the parathyroid glands directly influence the calcium levels in bone (and, thereby, the strength of our bones) via the hormone the glands produce, parathyroid hormone (or PTH).

The 5-way inter-action between PTH/kidney/bone/gut/blood is one of the most complex areas in medicine … as it involves the interplay between FIVE seemingly unrelated bits of the body: the blood, the gut, the parathyroid glands, the bones, and the kidneys … and … the problem = where to start?

Keep in mind that we absorb calcium (from the gut), we store calcium (in the bone), we excrete calcium (via the kidneys), and we control calcium (jointly by the parathyroids and by the kidneys) … with the blood serving as the lynch-pin that links all these areas.

Two main mechanisms influence calcium control: (1) parathyroid hormone, and (2) vitamin D.

BUT: … again … how and where to start?

For want of better, let’s start with the storehouse (bone) … then see how that store is supplied and used.

Bone is much more a living, ‘happening’ place than we can ever imagine. Bone is one of the most industrious tissues in the body and is a hive of activity. Not only does the soft ‘marrow’ of bone make all our blood cells - including our red cells under the influence of erythropoietin - but the hard outer ‘shell’ of bone is in a state of constant turn-over, with new bone being built by cells called osteoblasts and old bone being broken down by an opposing set of cells called osteoclasts.

Bone is our storehouse for calcium. As any good business will know, it is important to keep the right balance between supply, storage, and removal (or use), and while bone is the storehouse, PTH is directs the traffic between ‘product supply’ and ‘product demand’ … it provides the software that balances the whole chain of supply and demand. And, off to the left of centre, the kidneys provide the equivalent of quality control!

The parathyroid glands are, primarily, all about controlling the calcium and phosphate levels of the blood … and the balance between storage and release at bone level.

U The level of calcium in the blood is controlled in two main ways:[/U]

B The parathyroid glands.[/B]

As parathyroid hormone (PTH) has a controlling influence over the osteoclast activity of bone, and if small sensors (receptors) in the parathyroid gland tissue ‘sense’ the the blood calcium level is falling, the parathyroid glands make more PTH in response to their sensor messages … and that extra PTH then stimulates the osteoclasts to chomp up a bit more hard bone and release the calcium it contains into the bloodstream. This thus restores the blood calcium level.

B The kidneys and the gut[/B]

In the first instance, calcium must be absorbed into the body from food in the gut … and this absorption is dependant on a vitamin called vitamin D. Vitamin D is where the kidneys come into the ‘calcium’ act … the kidneys provide the final step in the processing of vitamin D in the body. The kidneys convert the inactive form of vitamin D that we ingest from our food into an ‘activated’ or biologically effective form that ‘does stuff’ … and that ‘stuff’ is to assist the gut to absorb calcium. In kidney failure, this final step in vitamin D processing begins to fail. As a result, less activated vitamin D is made, and - in turn - less calcium is able to be absorbed from food.

U The level of phosphate in the blood is also controlled, in part, by PTH.[/U]

PTH also effects the function of the tubule segment of each nephron. I won’t expand on this here, except to note that PTH directly increases capacity for each nephron to excrete (remove) phosphate from the body and thus helps to maintain a normal phosphate level in the blood. As the number of functioning nephrons diminishes in the situation of progressive chronic kidney disease, eventually there will be insufficient tubules left to excrete enough phosphate - even though they are being coerced by PTH to do so, and phosphate levels then begin to inexorably rise.

Ok … back to the issues raised in your question … in chronic kidney disease (CKD), as kidney function declines, two changes begin to emerge: one affecting the blood calcium (a tendency for it to fall) and the other affecting the blood phosphate (a tendency for it to rise).

Let’s now concentrate on calcium, and leave phosphate aside … though in CKD, it really is just as important …

A fall in calcium, due (a) to less absorption and (b) to the effect that a rising phosphate has on pushing down the blood calcium level, stimulates PTH production. This turns the osteoclasts into little bone-surface Pac-men to release calcium. A bone weakening process is thus set in motion.

As the progressive decline in kidney function that IS what we call CKD continues, the stimulus to (a) and (b) continues, and the parathyroid glands continue to be stimulated to make PTH. Sooner or later, the glands permanently enlarge and grow to a point where they become big, juicy, PTH-making factories … and at this stage, secondary hyperparathyroidism become ‘self-fulfilling’ and a third (or tertiary) state is reached.

To try to prevent this, active vitamin D therapy with calcitriol is used to increase gut uptake of calcium and to raise the blood calcium level so that the parathyroid receptors (the sensors of blood calcium levels) are switched off, PTH production is reduced, and the bone-destructive effect that PTH exerts on bone through osteoclast activity is turned down.

So … step one in treatment is calcitriol.

Step two is cinacalcet = a drug that to the parathyroid calcium sensors “looks like” calcium … it ‘mimes’ calcium … and is thus called a ‘calcium-mimimg-agent’ or a ‘calcimimetic’. This drug actually ‘hoodwinks’ the parathyroid gland receptors into ‘thinking’ that they seeing calcium and that the blood calcium level is higher than it really is … and PTH production is turned down.

But, it is an expensive drug and, as there remains some disagreement over its usefulness and the circumstances in which it should be used, some countries - including Australia - have tight regulations guiding its prescription.

Step three is to move to gland removal by parathyroidectomy = usually a sub-total (or three and a half out of four gland removal).

Some might think this a radical step, but usually a sub-total parathyroidectomy is relatively easy surgery and doesn’t mean more than 3-4 days hospitalisation. In addition, it is one of the more effective ‘surgeries’ in CKD and despite a sometimes ‘avid’ sucking-up of calcium after surgery - the ‘hungry bone syndrome’ … [google it] … it can be a very useful bit of surgery. However, to this point in time, it is still regarded as a ‘last resort’.

This explanation has been provided as background information to the initial question from AchillesHeel.

But … and back to AchillesHeel … in simple terms, her problem would seem most likely to be secondary hyperparathyroidism, and her next step is thus calcitriol … with the caveat that exclusion of an adenoma - in her case - might be sensible, just to be sure there isn’t a reversible issue here.

The only reason I throw an adenoma into the ring in her case is that if she has an eGFR up towards the upper end of the CKD3 eGFR spectrum (say >45-50), then it is a little too early to suspect significant secondary hyperparathyroidism. Thus a possible adenoma in this circumstance might need consideration.

But … if her eGFR is further down … say, in the low 30’s … then secondary hyperparathyroidism will almost certainly be present and may be sufficiently ‘up and about’ to generate a biochemically abnormal PTH level, as a rising PTH from CKD-related (secondary) hyperparathyroidism becomes increasingly common as eGFR falls.

Her specialist is clearly on top of all this, and there is nothing for me to say other than to agree with the line being taken.

Her worry about cardiovascular disease and/or bone disease is a fair concern … but the early management that is being considered by her nephrologist will certainly help minimise this anxiety, and it seems like she is already on the right course to maximally achieve benefit from her therapy.

[B]OK … I know that was long … SORRY!

I know that it seemed complex … also SORRY

But - this IS one of the most complex issues in ALL of medicine …

So … give me a break …

Re-read it … mull it over … try to get your head around it … 'cos there is little else I can do to make it more simple!



Dr Agar

I don’t know how to thank you enough for your authoritative, informative & VERY helpful reply to my question! I’m doing exactly what you’ve suggested - re-reading & mulling over all the points this weekend. It has been extremely helpful in enabling me to understand the nature of the problem. My specialist did warn me that it is a complex area that is not well understood! You have confirmed this. Thank you very much.

Before I really get on top of this subject more thoroughly, I might just add some more pertinent details about my case.

In early 2011, my serum creatinine level was 60 umol/L (normal for me was 65) with urea at 11.2 and PTH level was 3.8 pmol/L.

(My urea levels were the first to rise above normal before serum creatinine followed suit, for a period of approximately 8 - 12 months)

At end of 2012, my serum creatinine level was at 125 umol/L and my PTH was 10.4

At end of 2013, my serum creatinine level was 130 and my PTH was 10.2.

So it would seem that if it is a primary parahyperthyroidism condition, it arose just when my serum creatinine levels started to rise above normal. The more likely scenario is therefore secondary hyperparathyroidism. I will of course study your suggestions for the other tests in further detail.

With regards to my calcium levels, they have always been somewhere in the middle of the narrow band of normal reference values, never being borderline high or low. The phosphate levels have never breached the high or low normal values either (though I do have severe attacks of itching of my lower legs once every 2 months or so that I understand may be due to a buildup of phosphorous levels?).

As for the GFR, I find these calculations to be a bit iffy & rely more on the serum creatinine levels. I did have a nuclear GFR test in early 2012, which showed a GFR of 64. At the time of this nuclear test, my blood tests showed serum creatinine levels of 95 and an eGFR of 54-56. So there is a bit of a discrepancy between the ‘true’ GFR (if the nuclear test is more accurate, as I’ve been advised it is) and the eGFR of blood tests. This discrepancy seems to be accounted for by the creatinine raising effects of the ACE inhibitor, from what I believe (?).

My serum creatinine levels are now between 125-130 and my eGFR hovers around the low - mid 40s (the egfr formula recently being changed which has automatically lowered my eGFR a bit). I have the option of doing another nuclear test of my GFR but am a bit reluctant to expose myself to the radiation of this test if I’m going to be undergoing the bone density scan (enough radiation as it is!).

The only other detail worth mentioning is that in Aug 2013 there was a test for “25-Hydroxy Vitamin D level” done which showed a result of 51 nmol/L. Because this was done in an emergency dept, I have overlooked showing this to my specialist who is about to test me for “1.25 dihydroxy Vit D3”. I assume this is the same thing? If so, I wonder whether the result of 51 does indicate a deficiency which can perhaps be remedied by being prescribed calcitriol?

This is still a work in progress for me. I have a close female relative with severe osteoporosis, osteoarthritis who is crippled by it & I would dearly want to avoid this fate. Menopause for me is only a few years away & with kidney disease, things are not looking very optimistic where my bones are concerned. However now is the time to be trying to prevent this problem.

Dr Agar, I cannot express how grateful I am to receive your advice!

Dr Agar, I’m soon about to receive the results of my kidney function test results, including PTH levels etc but just wanted to ask you whether magnesium supplementation may be an immediately useful thing to adopt? I’ve read that magnesium plays some important role as well in regulating calcium, PTH & phosphorus levels. My magnesium levels are in the normal-high level (no doubt due to my dark chocolate vice) but I’ve heard that there may be no harm in being slightly higher than normal in CKD patients. Any advice you can offer on this?

Many thanks.

Dear Achilles Heel

If your magnesium levels are already (a) normal and (b) towards the high end of normal at that, I see no need for - nor can I advise or contemplate - any physiological benefit from any additional supplementation.

In my view, you would simply be paying for and swallowing one extra pill for which I see no need.

Your energies may be better directed towards ensuring, among other things, a good level of physical fitness, good BP management, and a healthy lean body weight = all far more important factors than worrying about a problem it seems you do not have.

Dear Dr Agar

I have finally received my latest results concerning my raised PTH levels & the situation appears to have deteriorated further. The latest results are:

PTH: 14.9 pmol/L
Calcium: 2.20
Corrected calc: 2.28
Phosphate: 1.37
Albumin: 39

25 - OH Vitamin D: 58
1,25 Dihydroxycalciferol: 85

(I take a 1,000 IU capsule of OTC Vit D each day, I should add, otherwise I would be deficient)

Though my iron levels are satisfactory for the time being (ferritin has dropped to 39 ug/L however) after needing to have an IV iron treatment in 2012 due to low iron stores - I am now quite anemic at only 94 g/L after neglecting to take Aranesp for more than a month!).

Unfortunately my eGFR has come down to only 35 (serum creatinine 150 umol/L & urea 13.9). I am hoping being dehydrated on the day of testing is what is behind these deteriorating numbers … (hoping so anyway).

With regards to the raised PTH levels - I’m wondering whether this is at a sufficiently high level to cause bone weakening damage or is there some “tolerance” that the skeletal system may have at this level?

My next visit to see my Neph is in a few weeks and he is unfortunately too busy to return calls. I do find it very hard to just wait around until my next visit when I know things are wrong. This is why I am propelled to seek advice and support from as many other avenues as I can in the meantime. I would appreciate any advice you could provide on these results. I am very grateful for your advice so far as it has enabled me to be far better informed about the issues in preparation for my next meeting with my specialist.

Thank you very much Dr Agar.

Dear Achilles Heel

I have made this point to you in an answer to another of your posts … you are following a course I believe unwise. You need to become less active on the Internet and more engaged with a real doctor - a face-to-face doctor - your doctor! This is not the way to resolve your issues.

This site - and my involvement here - is to explain issues around dialysis … and, more specifically, home haemodialysis. While clearly I have some understanding of CKD, at an eGFR of 35, you are a long way from dialysis and are in the CKD 3-4 range.

You seem to have some probably unwarranted fixations around your PTH level … which, at present, is not likely to be significant, nor a cause for clinical symptoms or major concern.

I say ‘probably’ and ‘unlikely’ as I do not know you, and do not have the required information to judge the unlikely circumstances where - in your situation - a PTH of 14 might be relevant … however, my best guess is that it is not.

Even were it to be relevant, then it unlikely that at an eGFR of 35 (and you say it has fallen further to 35 which suggests that it has been even better in the recent past) that your mildly elevated PTH is related to CKD, but perhaps more to a small CKD-unrelated adenoma. An elevated PTH due to CKD alone at an eGFR of 35 (or greater) is a bit unusual, and another cause like a small adenoma needs consideration.

As Internet distance, such subtle distinctions are not possible. Nevertheless, my guess is you a barking loudly up the wrong tree.

The temptation - to which I fear you may be succumbing - is, when faced with diminishing renal function - to place all blame, all symptoms, all laboratory abnormalities at the feet of CKD to the exclusion of other possibilities. That is rarely wise. CKD is common, and common other problems can commonly co-exist with it, or occur in parallel. I would urge you to consider this as you wrestle with your problems.

However … the surprise in your most recent question(s) and/or posts has been your Hb of 94! … something you just tossed in almost as an after-thought.

CKD at an eGFR does not normally induce an erythropoietin-related anaemia of 95!

Indeed, I think it is vanishingly unlikely that an anaemia of this severity is CKD-driven. it would be rare thing indeed to find a CKD patient with an eGFR of 35 needing an ESA (erythropoietin-stimulating agent) like Aranesp on the basis of an anaemia driven by CKD alone … and especially an anaemia with an Hb <110.

Again, you need to have this sorted out by a proper doctor, not an Internet advice line, even if that Internet source is reputable (which I hope this site is).

I would be fast turning my thinking away from minor (and most likely clinically irrelevant) perturbations in PTH etc., and getting the anaemia (and it’s cause) sorted.

Again, it is likely that there is much more to your anaemia than CKD.

It might be sensible to have a face-to-face doctor consider blood loss (you mentioned that you needed an iron infusion some time back and that your ferritin is falling again … both of which are unlikely to be CKD-driven at your relatively reasonable eGFR).

Blood loss - or perhaps a detailed serum protein analysis - might be a better line to follow up on … and set aside all your concerns about PTH while you follow up on this far more pressing problem.

That all said, Achilles Heel … I doubt I can help you more.

I suggest you see you medical advisors for further help. This website, and the intent of the advise it offers, is not for you.