CME Slides Forum - J. Cannata-Andía

A joint Congress by ERA-EDTA and ISN

HOW WELL CONTROLLED IS HYPERPARATHYROIDISM IN TODAY'S PRACTICE? THE MAGNITUDE OF THE PROBLEM

Jorge B. Cannata-Andía, Oviedo, Spain

Chair: Tilman Drueke, Paris, France

Markus Ketteler, Coburg, Germany

cannata

Prof J. Cannata-Andia
Servicio de Metabolismo Oseo y Mineral
Instituto “Reina Sofía” de Investigación.
REDinREN – ISCIII.
Hospital Universitario Central de Asturias.
Universidad de Oviedo
Oviedo, Spain

Thank you Tillman. First of all I want to thank the organisers for inviting me to this symposium.

The idea is to review with you aspects related with the control of secondary hyperparathyroidism in today’s practice

and as you know, CKD leads to a parathyroid stimulation and this always goes to secondary hyperparathyroidism, high PTH and high bone turnover

but as you know, that real medical management and diabetes and age have really pushed the things to low bone turnover and in fact in the 80s 75% of patients had really high bone turnover despite the heavy aluminium intoxication and most recent series have shown that around only 40% of patients has secondary hyperparathyroidism and 60% low bone turnover.

You know that the main stimulators of the parathyroid gland are calcitriol, 25 (OH) D3, calcium and phosphorous and as I said in the 70s and 80s we had a lot of problems because other secondary regulators like aluminium were intoxicating our patients and had a great impact on PTH and we know now we’re discussing the effect of FGF23 in the regulation, I’m not going to touch upon this aspect I’m just concentrating on the main regulators of parathyroid hormone.

The role of calcium in the regulation of the parathyroid hormone in function increased a lot the knowledge when we knew about the calcium sensing receptor was cloned in 1993. As we know we need to increase serum calcium to obtain the same degree of parathyroid function in a normal state.

When there is moderate hyperparathyroidism you need a bit more calcium to suppress the same degree of PTH, with more hyperparathyroidism you need more calcium, more hyperparathyroidism you need even more calcium but we know, we have learnt that there is a limit in this regulatory mechanism of the parathyroid gland.

In fact, if I’m going to use two studies, for example one the Hispanic multicentre study done 10 years ago in 1998 and the COSMOS study with baseline completely between 2006-2007 and both studies showed the same results. As you can see here, this is PTH and this is calcium.

The respective physiological response in this group between calcium and PTH should be this line but the reality in this data are not this, are this, this is the value of calcium sampling with PTH that means that after 9.5 there is no expected relationship between PTH and calcium level in these CKD 5 populations. This means that we know that secondary hyperparathyroidism severely affects the response of the parathyroid gland to calcium increments. We know also that this increment in serum calcium may influence outcome in dialysis. Several association studies have demonstrated this. This is the most well-known study that when you increase serum calcium above 9.5, there is up to a 40% increase in mortality but again this is an association study nobody has demonstrated this in a prospective study.

Also if you look to some data from the COSMOS study and the COSMOS study is a prospective study, observational study for 3 years, this is an interim analysis in the middle of the study 18 months and you can see one of the three factors that really was related to a greater mortality in COSMOS was serum calcium higher than 9.5 with a decrease in mortality of close to 30%.

We know unfortunately, that even though when we increase calcium we cannot stop PTH, Calcimimetics can improve this poor response of the parathyroid glands to calcium

and there have been several studies published during the last years that have really demonstrated like this one published in NDT the target study in which independently if you came from the PTH level from 300-500 this in blue or from 500-880 you achieve the desirable target of PTH between 150-300 in a great proportion of patients

or the same of one study shown in this congress this year where there is again an observational study of the use of Cinacalcet for 12 months in which several countries are represented, Austria, France, the Nordic countries, Italy, Netherlands and so on and you can see here independently of the initial level of PTH at the beginning of the study after 6 months or after 12 months in all countries there was a clear decrease in PTH in the real world and we used Cinacalcet.

What about phosphorous? Well you know that during the last decade phosphorous moved from a second class to first class player in CKD-MBD.

We learnt this in the last 12 years mainly that an increase in PTH synthesis increases not only in this cell proliferation,

As a result of this important effect of high serum phosphorous on the parathyroid function we can see if this is just an academic concept or if this can be seen in the clinical practice.

If you use the same studies as I used before the epidemiological studies, the COSMOS study and the multicentre study they both had exactly the same results. This is the graph I showed you before no clear relationship between PTH and calcium when calcium is higher than 9.5 and looking at the same blood sample the relationship between PTH and phosphorous there is a clear relationship, the higher the serum phosphorous, the higher the PTH in the same kind of patient and in the same scenario.

That means that in the CKD patients serum phosphorous is a strong regulator of PTH secretion in dialysis.

We also know from several association studies that the phosphorous may influence dialysis outcome in patients and again I’m going to the Block study to show clearly that when you increase phosphorous to a higher level, you can have up to double the increase of the risk of mortality in this group of patients.

What about 25(OH) D3? You know that recently 25 (OH) D3 not so recently but in the last 8 years has become more important for us, for the nephrologists

and then I’m going to show you some data from an epidemiological study in this case I’m going to use a Spanish study that was presented 2 months ago in Oviedo and in this study done in CKD 3-5 patients the calcidiol insufficiency was observed at all CKD stages as you can see here. 80% of patients showed insufficient calcidiol levels in blood and that as I said was seen at all stages as you can see here stage 3, stage 4 and stage 5 all have a similar kind of insufficient calcitriol levels.

Going in the same line a recent study published, a multicentric study from Italy with a 6 year follow up showed that despite this good relationship between 1, 25(OH)D3 the vertical axis and 25(OH)D3 on the horizontal axis, despite this good relationship when you go to see the relationship in these CKD 2-5 patients between the vitamin D and the PTH, the best relationship was observed with 25 (OH)D3 and not with 1,25 and then 25 (OH)D3 status really directly influences the development of secondary hyperparathyroidism.

Furthermore in this study they demonstrated when you’ve got low levels of 25(OH)D3, you reach dialysis sooner and the time to death is less, that means you decrease survival or increase mortality in other words when you’ve got a very low level.

This is in agreement with several epidemiological studies also in the general population.

What about calcitriol? Well, the first study I know of that really demonstrated in non-treated patients that the calcitriol decreases early in the course of CKD was done by Martinez in Spain and they clearly showed that when the calcitriol decreases around 60-70 ml, there is an increase in PTH. Since then, since she published this study she has managed to do quite a practical interesting study demonstrating the use of low dose of calcitriol to stop the progression of secondary hyperparathyroidism.

In fact, in the ten-year treatment randomisation that we can discuss afterwards but with a non-selection of patients they studied almost 200 patients and they gave calcitriol 0.25 µgrams every 48 hours which is almost a physiological dose of calcitriol and the calcitriol levels increase and in red are the intervention calcitriol and in blue no calcitriol and as you can see here there is increasing calcitriol and a decrease in PTH in all stages that means the patients are reaching dialysis with a lower PTH level which is one of the things we wanted to achieve in this population.

Again other drugs have shown the same in this case paricalcitol in a clinical trial demonstrated that clearly they can reduce PTH in CKD 3, 4 and 5.

Well the effect of VDR and calcimimetics, first I’m going to talk about VDR on calcium sensing receptors is clear now we know that a part of the calcitriol, a part will increase the synthesis of PTH, increase the expression of VDR this is what we expected in a parathyroid gland culture but one important thing is not only the increased expression of VDR, the calcitriol increases also the expression of a calcium sensing receptor as has been demonstrated recently in a paper published in the past month in NDT from our group. That means there is a clear cooperation between VDR and CaSR to reduce PTH synthesis but this cooperation is not only when you use vitamin D calcitriol in this case, it’s also when you use calcimimetics as has been demonstrated recently by Mariano Rodriguez’s group.

When you use calcimimetics also not only do you upregulate the CaSR but also the vitamin D receptor and in this case it gives a clear explanation why it’s so useful a combination of vitamin D and calcimimetics to manage secondary hyperparathyroidism.

Now, after setting the scenario with some effects of the treatments and some outcomes I’m going to review with you briefly how much the scenario of secondary hyperparathyroidism has improved in the recent years.

I start my presentations by saying that in the last 30 years high bone turnover has decreased to 40% to 75%. We can ask ourselves is this reduction in high bone turnover related to a better management of secondary hyperparathyroidism? In my opinion and the opinion of several people is that that’s not the case because really this increment in high bone turnover and an increment in low bone turnover as I said at the beginning is due to several factors: medical management, increase of diabetic patients and the increase of age of patients and just a little may be explained by a good treatment for high bone turnover.

What was the situation 10 years ago with the prevalence of hyperparathyroidism in the first epidemiological studies we got in Europe? Well, this again is from the Spanish study which I believe was the first one of its kind with so many patients and you can see that only 22% of patients were with a PTH on target by then.

Then the two main guidelines came, the European guidelines, the KDOQI guidelines came

and the first study that also in a similar fashion demonstrated that around 20% of patients were on target was an Italian study published in June in Nephrology.

Then in the COSMOS study with this presentation as I said is a prospective study but they started their recruitment in 2006 and finished in 2008 but it can be an expression mainly of 2006-2007 in values and it ran for 3 years. The baseline PTH target achievement and COSMOS is close to 30%.

If you look at the French Observatoire data presented by Denis Fouque at the Oviedo symposium 2 months ago, in June 2005 they got almost again 30% of PTH in the range and 3 years later in the data they presented in Oviedo they increased from 29% to 33% there’s a slight increase in PTH control.

This is the Argentinean data presented also in Oviedo and they presented sorry because it’s black here in patients on target between patients 150 and 300 there was 25% of patients on KDOQI target.

What about surgical management when we failed with secondary hyperparathyroidism in Europe? The COSMOS study as many other studies have demonstrated when you increase the time on dialysis, you increase the possibilities of receiving a parathyroidectomy and patients with more than 5 years,

other studies have demonstrated patients with more than 10 years between 17% and 20% of parathyroidectomy in those types of patients.

But I will look at the differences between Europe and then the whole of Europe is different and the attitude or the behaviour when they decided to do a parathyroidectomy and as you see 52% of Europe decided to do parathyroidectomy with levels higher than 1000, another 35% with levels between 750 and 1000 and of course a minority with lower levels.

Well we asked whether there were differences between regions in Europe, we tried to play with the data. I’m going to show you one data as this is a comparison between the northern countries and we call the southern countries, in this case the Mediterranean countries that are in yellow in this and as you can see and if this data is correct the northern countries tried to perform parathyroidectomy before the southern countries, there is 42% compared with almost 26% with values higher than 750. Meanwhile in the Mediterranean countries we wait a little bit more apparently to perform parathyroidectomy.

I tried to review this scenario just to make the introduction for the other talks for secondary hyperparathyroidism showing some epidemiological data

but I think I want to finish with one slide showing that really I think we’ve got more pathophysiological and more clinical data to support the idea that we need to control phosphorous in CKD 2-5 because phosphorous we say has a great impact on parathyroid function.

We tried to see what happened with phosphorous in the last years and again if we go to the COSMOS study, the mean value of the baseline is 50% with phosphorous out of control and if you look at some particular studies in some countries in 2005-2008, some countries have made an improvement and some countries for example when you compare data from 2004-2005 with data from 2008 some of them have been able like Spain to reduce the phosphorous out of range from 55% to almost 30% which is some kind of an achievement in the last 5 years.

Then the other thing is that really we’ve got enough I think basic and clinical experience now to support the idea that the combination of vitamin D --- and calcimimetics can help us a lot with controlling the phosphorous to manage the secondary hyperparathyroidism and I hope and we hope that in the near future we will have better results with it.

Chairman: Thank you very much Jorge, you have perfectly stayed in time so we have time for 5 minutes discussion, comments questions from the floor. Maybe I can start with the first question? When we look at the different achievements in Europe from the north to the south, I have the impression that in the south of Europe the control of PTH is better in general than in the north. Can you confirm this with the COSMOS data? If so why?

Prof. Cannata: I think this is not quite different, it’s quite similar and what is different is in the management I think. The use of vitamin D and parathyroidectomy. I had the impression before looking at the data that for example, we used more vitamin D in the south part of Spain.

Prof. Cannata: Any analogue than in the Northern part of Spain. According to the COSMOS data which I said is 2006-2007 that mainly was calcitriol and 1 alpha in northern countries you see 5% more than in the southern countries and 45% of use in the southern countries and 52% of use in the northern countries. If you put this together with parathyroidectomy data I showed you I think I have the impression that the northern countries start earlier the treatment of secondary hyperparathyroidism than the southern countries. -- in northern southern countries -- because really for example France is in the middle, we don’t see France in this case as being in the northern countries but there really was a kind of division. We also made divisions between eastern and western countries and again when we measured eastern and western the main changes were age driven and diabetes driven because the prevalence of diabetes was almost 8% lower in the so-called former eastern countries.

Question: One question, you mentioned the importance of the frequency of vitamin D deficiency in these individuals everywhere around the world. So what do you think is the role of 25 vitamin D in the replacement in the prevention or management of secondary hyperparathyroidism?

Prof. Cannata: I think that this is very important because I think all studies studying CKD 2, 3, 4 and 5 have clearly demonstrated that there is a great deficiency. This is the Spanish data it was 81% but all the others are between 70% and 80% deficiency. These are pre-dialysis patients I think we can have a separate discussion for the dialysis patients but what is surprising is that really in pre-dialysis patients and after passing this kind of message for almost 8 years now or maybe 6 years that really the high prevalence of 25 hydroxy the reduced number of people using 25 hydroxy in the daily work and I mean in the daily life even the COSMOS study you can get a false figure saying that 20% is receiving but you know that there are two countries that drove the results Germany from which I’m really using the results, partially France and other countries but really if I have to pass a message is that really we are under using the replacement of vitamin D as a nutrient in all our patients and it’s something we have to start soon.

Chairman: I would still say a word of caution, nobody has shown so far that the repletion of deficient vitamin D sores in these patients is of benefit in terms of heart outcomes. It’s easy to increase serum 25 levels and PTH goes down and down, when you supplement with native vitamin D or with calcidiol but in terms of heart outcomes we don’t know.

Prof. Cannata: Yes, but we are for example, we don’t have perfect data but there are two data that I think are quite encouraging. For example we have been using in our out patient clinic in osteoporosis with ladies that currently even though they don’t have proteinuria, they have a reduction of renal function replacement and then we start having in our population 15% of secondary hyperparathyroidism and we reduce half of this just putting the level at 13 mg and I think this is something that really is important and apart from that the window for intoxication is so big. You can reach 40-50 without any problem until 200 we never had any problem using 500.000 units per day.