Slide 1

Actually you are very generous, I should only have ten minutes because I need at least 5 minutes for discussion. So I’ll cut my talk into half. Let’s see.

Slide 2

Treatment of uremic patients with vitamin D receptor activators. You all know this slide, the therapeutic window we have as clinicians is very narrow between secondary hyperparathyroidism on one hand and hypoparathyroidism with low-turnover bone disease with the risk of vascular calcification and increase of mortality.

Slide 3

Now, when you look at available evidence concerning active vitamin D sterols we, of course, have trials which look at surrogate markers, biochemical targets, x-ray targets but we don’t have much in terms of patient outcome.

Slide 4

We look at surrogate markers like vascular calcification but as I said for outcome, we don’t have much.

Slide 5

So let’s start with some slides on the control of secondary hyperparathyroidism mainly based on surrogate markers.

Slide 6

We have all these compounds you know quite well.

Slide 7

And I would just like to show you this study, a German multicentre study which was done many years ago which shows that when patients with CKD not yet on dialysis are treated with calcitriol as compared to placebo their PTH does not increase in contrast with the spontaneous increase in placebo for serum PTH.

Slide 8

A similar multicentre study from Europe by Hamdy and co-workers also in patients with CKD stage 3 or so shows that when giving alfacalcidol for 24 months you can avoid the progressive increase in plasma intact PTH whereas with the placebo it increases. These authors also did repeat bone biopsies in all these patients which was a great performance and showed that the progression of osteitis fibrosa could be more or less controlled with alfacalcidol, whereas it progressed seriously and significantly over the two years treatment period with alfacalcidol.

Slide 9

How about the newer analogs which have been synthesised in order to avoid or to decrease the incidence of hypercalcemia and/or hypophosphatemia? They are here, paricalcitol, doxercalciferol and in Japan maxacalcitol.

Slide 10

The problem with these is that there’s only one published controlled prospective randomised trial in CKD patients comparing novel vitamin D sterol paricalcitol with calcitriol. I’m not saying there aren’t any others with placebo comparisons but not more than one comparing the classic active vitamin D compound calcitriol with novel analogs.

Slide 11

Here is the effect on parathyroid hormone, intact parathyroid hormone although with paricalcitol the decrease in plasma PTH was a bit more rapid.

Slide 12

You will agree that there’s not much of a difference concerning the most important problem whether there are more or less episodes of hypercalcemia, well there were a bit fewer sustained episodes of hypercalcemia but the difference of the primary end point was not significant.

Slide 13

Now another study by one of our two co-chairmen was with doxercalciferol against placebo. As you can see, there’s a nice decrease in plasma PTH when you treat with doxercalciferol and when you stop it, it goes up again as compared to placebo. But in this study unfortunately, there was no control arm with calcitriol or with alfacalcidol.

Slide 14

Let’s go to the next point, avoidance of bone disease/fractures. We don’t have much here. I won’t show any slides just to mention that in the Hamdy study which I mentioned before it could be shown that you can avoid or at least slow the progression towards more severe osteitis fibrosa with the chronic administration of alfacalcidol as compared to placebo. There’s no study to the best of my knowledge comparing two different compounds in terms of bone outcome histologic or fractures.

Slide 15

The next point is avoidance of soft tissue calcifications and atherosclerosis with vitamin D treatment.

Slide 16

If you give high enough doses of in this case calcitriol to uremic rats even in the absence of increasing serum calcium you may induce severe calcification. So serum calcium is not a good marker for the danger of inducing or not vascular calcification with high doses of calcitriol or other derivatives.

Slide 17

But we also know and this slide has been shown before by the study from Gerard London’s group in Paris that vitamin D deficiency also is associated with an increase in arterial calcification as very nicely shown here. The inverse relation was there with 25 OH as an expression of vitamin D status and also with 1, 25 dehydroxy vitamin D as translation of the activated vitamin D status. By the way, in this French population the average 1, 25 concentrations were much higher as you may realise than in the study shown by Ravi just before for I don’t know which reasons. These are all non-intravenously treated patients.

Slide 18

The explanation may come form this very recent study by Shroff and co-workers from the UK that is in patients who have very low levels of 1, 25(OH)2D or patients who get pharmacological doses of 1, 25(OH)2D. You may have an increase in vascular calcification or in this case cardiac calcification as compared to the patients who are in the middle range.

Slide 19

Now interestingly Shroff and co-workers from the UK also found a direct association between the dose of alfacalcidol administered to their paediatric haemodialysis patients and the carotid intima media thickness as an early expression of atherosclerosis. So maybe pharmacologic doses of vitamin D, active vitamin D compounds in this case alfacalcidol could favour atherosclerosis.

Slide 20

Shroff and co-workers again looked ate multivariate analysis here,  there was a relation a U curve type relation between serum 1, 25(OH)2D levels and intima media thickness in the carotid artery. So very low levels and very high levels of 1, 25 (OH)2D are associated with more atherosclerosis again pointing to the narrow therapeutic window which we have in these patients.

Slide 21

Now, another study which is of interest shows that for apparently equivalent doses in terms of PTH decrease not all vitamin D analogs maybe equal at least in the animal study by Mizobuchi and co-workers already shown before by Doctor – group.

Slide 22

In this case you see for instance that 1, 25D3 or 1 alpha D2 doxercalciferol were able to increase aortic calcium content but not 19-nor. But there are other studies which cannot confirm this. This shows just histological slides.

Slide 23

Let’s come to the last point improvement of cardiovascular and all-cause outcome. Well I could stop here and say there are no prospective randomised trials, so we don’t know if we give more or less high doses of this or that active vitamin D compound do we have more or less cardiovascular disease and more or less outcomes?

Slide 24

Of course we have a large number of observational studies as so often in CKD patients. I would like to show this study rapidly by Inaguma and co-workers in CKD stage 3-4 patients where there was a clear difference in patient outcome, in patient survival between patients who had relatively normal 1, 25D levels and patients who had low 1, 25D levels. Of course, the low levels were associated with higher mortality.

Slide 25

This study has been shown two times, survival advantage in patients with CKD stage 3-4 who received calcitriol as compared to no vitamin D treatment but again, don’t forget these are all observational studies so there maybe selection bias from the beginning.

Slide 26

We have seen this study several times in nicer slides by Doctor Ravi’s group in Boston in patients on haemodialysis who received active vitamin D in this case either calcitriol or paricalcitol as compared to patients who are not receiving activated vitamin D derivatives have a much higher survival rate. Again observational studies. It’s difficult to conclude. The same is true for the paricalcitol versus calcitriol study. Observational retrospective study in very large numbers of patients. There are very good arguments in favour of paricalcitol but again these are observational studies.

Slide 27

The explanation of the difference in survival with a paricalcitol versus calcitriol observational study probably does not rely on a better control of serum phosphorous and serum calcium.

Slide 28

As you can see here in the paricalcitol group there was an increase of 6.7% for serum calcium and of 12% for serum phosphorous. In the calcitriol group during 1 year of observation an increase of 8.2 and 13.9% differences are very small. So probably if there is a survival benefit it must be by something else, let’s say immunologic, infectious whatever but not in terms of calcium, phosphorous and PTH.

Slide 29

Let me conclude saying that it is very important to choose the best possible treatment for the patients as pointed out by several of the speakers probably the best possible solution for a patient does not come from one compound but from the association of different compounds let’s say phosphate binders optimal plus vitamin D derivatives, plus calcimimetics plus a good dialysis in those who are on dialysis and let us not forget that the administration of excessive doses may well lead to the opposite, to more harm than benefit, the opposite of what we are looking for and finally of course, we don’t think that the CKD --- problem is the only one which determines the outcome of our patients.

Slide 30

Thank you.

Slide 31

Chairman: Thank you very much Tillman for this comprehensive overview of where we stand today. We even have a couple of minutes, I don’t know if I could ask you to come up here. Please. Maybe then I can in the meantime apologise to the audience for the Chairman not being able to keep the time but I think we had really wonderful talks and I’m sure there will be some questions. Yes please?

Question: Thank you very much for these very nice talks. I enjoyed it. I have got a big problem now I think together with the KDIGO this morning. As clinicians we want to use randomised controlled trials as guidance. We don’t have any trials more or less, we don’t know what to do. We are sitting in the practice room we don’t know what to do. Surely I think we need to have a little bit of mercy with ourselves and say strong or robust observational trials should guide us at this time point. What is your opinion?

Chariman: Tillman?

Prof. Drueke: I didn’t get the last part of your question.

Question: Surely until we have got more randomised controlled trials, if they ever happen possible mortality we should be guided by strong observational studies because otherwise I don’t really know what to do as a clinician.

Prof. Drueke: Yes we have integrated in the KDIGO guidelines which will come out soon but which are open to review as you know at present. We have integrated large observational studies, so studies like the TENTORI study and others are integrated. Since these large observational studies also do not give a clear cut answer as to whether there’s an advantage in terms of one compound to the other of active vitamin D administration versus no administration we cannot come up with something more than saying it is up to you in terms of patient counselling, patient data to make the best possible proposition and not to give very clear cut recommendations.

Chairman: Yes please.

Question: Just as an additional thing. I think observational studies when they’re well done and you’re really clear how the cohort was derived and they’ve controlled for things I think those things are helpful. I think what we need to do is have a very low tolerance for poorly done but very large observational studies similarly as very large any studies that may not have the methods as clearly described. So there was a session earlier in this meeting on STROBE and the way one needs to properly define observational cohorts and be clear who you’re applying what to. I think that this is a way to get over this hurdle but another thing is why are we as nephrologists so not able to, we all say we don’t know and yet we all can’t enrol our patients in our CTs so there’s a bit of a disconnect in terms of our commitment in actually getting the data but that would be an editorial comment.

Chairman: Ok thank you. I don’t see anybody else at the microphones. Maybe I could just….Ok.

Question: If I might I just want to make a comment and maybe for Doctor Drueke to comment on this. You were saying and unfortunately I don’t fully agree with you that there are absolutely no bone data, no histomorphometric bone data on the new vitamin D compounds even if that’s not completely true because there’s one study by Doctor Saluski and that’s the only study I have seen showing bone histomorphometric data in an adolescent treated with doxercalciferol obviously with an interesting improvement in the bone turnover.

Prof. Drueke: I agree this is true but this was a rather small study and before looking at any of these studies we defined criteria which maybe subjective for a certain minimum requirement of numbers in 2 patient arms for instance, for studies with biochemical outcomes only we requested I think at least 100  and 100 in each arm. For studies with bone biopsies we said at least 10 and 10 or so or 20 and 20 I don’t remember now. This study was just below the level but it is true that this study shows an advantage with either doxercalciferol or calcitriol as compared to no treatment. So I agree.

Chairman: Ok last question.

Question: CKD 5 patients with no increase in PTH should we use or not use vitamin D?

Prof. Drueke: Which PTH which level?

Question: CKD5 patients with intact PTH.

Prof. Drueke: Which level?

Question: Which level?

Prof. Drueke: With which assay?

Question: Third generation less than 200.

Prof. Drueke: With third generation this means this would be roughly 400 with the ALLEGRO assay. Well, here we are exactly at the level where with the KDIGO guidelines as we said we are at the level where we can think of giving active vitamin D treatment but especially in those patients in whom you see a progressive rise in PTH. If you see a PTH of 400, you said 200 with whole PTH or biointact PTH 400. You measure it again and once again you have 300 then I would say no treatment but if you see 500 the next time maybe 600 then you should clearly start treatment. That’s what our guidelines will say. I’m sorry I can’t say more.

Question: --- but as you know, the reason for using vitamin D is not for bone or intact PTH control but cardiovascular protection, so should I use or not in patients with normal intact PTH?

Prof. Drueke: Show me the prospective randomised trial which show that the patient outcome is better with any vitamin D analog in CKD patients and I will agree with you.

Question: If I might add something, I mean there are two things one is with a classic dose treating secondary hyperparathyroidism and the another one is replacement. Certainly you shouldn’t treat secondary, I mean you shouldn’t give pharmacological big doses because you’re inducing another bone disease you know a dynamic bone but I understand the answer it’s a complicated issue anyway.

Chairman: Ok thank you very much, that concludes the session I apologise for the lack of time for questions and would like to thank the speakers very much for the wonderful time.