Slide 1

Dear Chairmen, thank you very much. The task I have is to talk about the role of vitamin D and calcimimetics on the bone after renal transplantation.

Slide 2

Now, we know that the metabolic alterations after transplantations are quite present. These are all the elements here. We do have in a fair number of patients persistent hyperparathyroidism. Elevated PTH and subsequently hypercalcemia and hypophosphatemia are very frequent. There is also persistent hyperphosphatonism. FGF-23 levels are quite high and contribute to the hypophosphatemia which we see in these patients. Also in a fair number of patients we have altered vitamin D status with low 25-OH-vitamin D3 levels. Furthermore, the patients are being treated with immunosuppressants which have various effects on the bone such as the steroid-induced osteoporosis.

Slide 3

Now, the scenario is that we have bone disease before transplantation. Obviously there is the situation where we have persistent or even worsening bone disease after transplantation, and there are factors which are dependent on the renal disease and  factors that are associated with the transplantation. I’m not going to cite them all but they’re listed up here.

Slide 4

Just the principal one that transplantation per se can worsen renal disease and contribute to the bone disease after transplantation.
The main lesions we have heard are the osteopenia or osteoporosis where the main contributor seems to be steroid treatment but there is in many patients persistent osteitis fibrosa cystica and it’s perpetuated by the persistent hyperparathyroidism in these patients. Osteomalacia can be present due to vitamin D deficiency and as we have heard, quite a few patients present features of adynamic bone disease in the bone biopsies that have been performed in some studies.

Slide 5

Now, what are the clinical consequences finally of altered bone disease after transplantation?
Patients can suffer bone pain and athralgias and quality of life can be altered by the disease.
Regarding fractures we have heard that the number is relatively low, but they can incapacitate patients and there may be a link to cardiovascular disease. These vascular calcifications which the patient has acquired from dialysis – and the reduced bone mineralization can contribute or can have a link to cardiovascular disease.

Slide 6

So how to attack this problem? There is the level of prevention, there is the level of treating diseases and the complications and we would like to inhibit further progression.

Slide 7

The approach to the patient with bone disease after transplantation of course, we do not neglect physical activity, dietary advice or certain lifestyle things but mainly we have resorted to all these pharmaceutical treatment components such as calcium supplementations, use of bisphosphonates, which we have heard about and now I’m going to focus on vitamin D and calcimimetics.

Slide 8

Now, there is a fair number of studies which have documented that vitamin D deficiency is frequent in renal transplantation. I’m going to show here this one study that has just come out which is representative of quite a few and shown here are women and men with vitamin D insufficiency in the range of 40-75 nmol/L and only about 10-20% of all patients are by this definition here vitamin D sufficient. So it is frequent among the renal transplant population.

Slide 9

The risk factors for vitamin D deficiency in these patients can be low sun exposure; it’s more frequent apparently in Nordic countries and in winter season. We see here in this one study the annual fluctuations that vitamin D levels go up during the summer time. Transplant patients do have to avoid the sun, it’s for protection of sun for skin cancer and obviously this can contribute that the patients have more vitamin D deficiency. Smoking and black race are additional risk factors for that.

Slide 10

So, vitamin D could be substituted but what’s more often done is it’s repleted in pharmacological doses and there is also a fair number of studies that have shown that vitamin D in combination and only in combination with calcium supplementation has a beneficial effect on the BMD loss after transplantation.
So we see here the lumbar spine in this study of about 110 patients. It’s more severe in patients that have no treatment versus the calcium and vitamin D treatment and it’s still a negative balance here but it seems to be less severe in vitamin D treated patients.

Slide 11

So we can prevent some of the loss but it is still a loss of BMD despite treatment with calcium and vitamin D and in guidelines this is the recommendation that we should substitute vitamin D plus calcium. This may have a role to prevent some of the loss.
Now, obviously the correction of the vitamin D deficiency can be difficult in hypercalcemic patients. If there is hypercalcemia we may not use vitamin D and so it’s some kind of tricky situation.

Slide 12

That hyperparathyroidism is persistent is shown in this study by Evenepoel who has looked at the PTH levels after transplantation and we see that many patients here are in a range that’s quite high.

Slide 13

The resolution of this hyperparathyroidism is incomplete in about 50% of the patients at 1 year post transplantation. Only about 25% of the patients with intact graft function have normal PTH levels after two and a half years after transplantation. There is a significant decrease of the PTH levels. It is most pronounced during the 3 first months after transplantation but it persists in many patients. The hypercalcemia that ensues and the hypophosphatemia is quite pronounced in many patients, so that about 50% of the patients remain hypercalcemic after 3 months.

Slide 14

We have done a cross-sectional analysis in our centre at the University of Zurich. This is a slide given by a co-worker of mine Doctor Patrice Ambühl. This is a cross-sectional analysis showing the calcium levels in these patients and quite a few patients here remain hypercalcemic in this cohort of 797 patients.

Slide 15

At the same time their phosphate levels tend to be on the low side. When we look at this whole cohort here we had 647 different patients where we had the phosphate values, and a number of patients here are hypophosphatemic.

Slide 16

There seems to be a correlation between the severity of the hyperparathyroidism before transplantation and the hyperparathyroidism after transplantation. So, the higher the values are before transplantation, the higher they tend to be and the more severe this persistence seems to be after transplantation.

Slide 17

So what are the consequences of this persistent hyperparathyroidism?
It is a risk factor for bone disease and this persistence of the high parathyroid values with hypercalcemia may predispose to vascular calcification and this could be linked to enhanced cardiovascular morbidity and mortality.
Also it’s known that these high PTH values correlate with some decrease in graft function when this is examined later than 1 year after transplantation. So treatment of this persistent hyperparathyroidism could be useful at many different levels.

Slide 18

The study by Gwinner et al from Hannover has examined protocol biopsies for graft calcifications, and what they found is that the patients with the calcifications, that’s the open circles here after 6 weeks, 3 months and 6 months after transplantation tended to have significantly higher intact PTH levels. So the more PTH you have in the circulation, the more you tend to have these graft calcifications and there seems to be a link with the occurrence of chronic allograft nephropathy due to these calcifications with a trend also to decreased graft function.

Slide 19

So, obviously we would like to do something for hyperparathyroidism, and there is the option of parathyroidectomy or to use calcimimetics.

Slide 20

The parathyroidectomy has its risks and problems. There are the surgical risks, the unwillingness of the patients, and there is also a risk of deteriorating graft function or even graft loss.

Slide 21

This is again a study by the Hannover group. They have looked at the deterioration of graft function in their cohort of patients that had a parathyroidectomy and they subdivided them in a group that deteriorated and a group that did not deteriorate, and you can see here the GFR after the parathyroidectomy in the non-deteriorating group and in the deteriorating group and there was here in the deteriorating group a trend to a higher PTH level before and in the non-deteriorating they had lower levels and also after surgery the PTH levels were not suppressed completely. So the higher the PTH and the lower it goes after parathyroidectomy, the higher the risk of graft function deterioration or even graft loss.

Slide 22

Cinacalcet is very effective in correcting the hypercalcemia after transplantation. We did a study in Zurich where we included 11 hypercalcemic patients and treated for 6 months with cinacalcet at the dose between 30 and 60 mg and as long as you give the drug you have a nice suppression of the hypercalcemia. As soon as you stop the calcium the values go back up again.

Slide 23

The effect is dose-dependent when we treat with 30 mg or 60 mg. Here this is a 2 week study; the calcium over 24 hours decreases steadily.

Slide 24

At the same time the hypophosphatemia can be corrected, the phosphate values increase over 6 months treatment here significantly. As soon as you stop again, you tend to lower again your phosphate values.

Slide 25

The effect of cinacalcet on the phosphate levels is also dose-dependent. We have this 24 hour profile here with 30 mg or 60 mg of cinacalcet we nicely correct the hypophosphatemia.

Slide 26

What about the PTH values? Obviously PTH values decrease when we measure that at 24 hours slightly by about 20-30% as long as we give the drug. When we stop it, it increases again.

Slide 27

This is a 24 hour profile of patients with no cinacalcet. 2 weeks with 30 mg and 2 weeks with 60 mg and it shows that the nadir occurs here around 4 hours after taking the drug and decreasing to 60%.

Slide 28

The cinacalcet blood levels correlate quite well with the iPTH changes. These are the cinacalcet blood levels we measured with 30 mg and with 60 mg. You see here somehow a non-proportionate increase in cinacalcet levels.

Slide 29

The cinacalcet and iPTH levels fit a simple EMAX model. We plotted here the cinacalcet plasma concentrations from all these patients and the corresponding PTH values and you see here a saturation with an EMAX of about 60-70% reduction.

Slide 30

So the effects of cinacalcet provide a 60-70% decrease of PTH with a nadir occurring at 4 hours with dosages of about 30-60 mg. These cycling PTH levels correlate nicely with the cinacalcet blood levels and the dose-dependent decrease of the serum calcium levels which is quite prominent, and there is a significant increase also in the phosphate levels. So finally there are quite beneficial effects on the calcium, phosphate and PTH parameters. We don’t know what it is going to do to the bone. There we need further studies obviously.

Slide 31

To conclude, in a substantial proportion of renal transplant patients the mineral metabolism alterations do not normalise. We do have the problem of vitamin D deficiency in quite a few patients, and persistent hyperparathyroidism as well. Better control of the mineral metabolism - which we need to do also during dialysis times to prevent the problems after transplantation - is important. The lack of control of secondary hyperparathyroidism is also predicting the persistence after transplantation and this obviously could have some negative impacts on the outcomes on bone disease, on calcifications and even on graft functions. Thank you very much for your attention.