Slide 1

First of all I’d like to thank the organising committee and Professor Lameire for this kind invitation and for giving me the opportunity to give this talk here but he also gave me a very difficult challenge because he asked me if I could show mostly histomorphometric data in post-transplant patients and there is basically no histomorphometric data in post-transplant, so it was really a challenge and that is actually why the title is like this because I told Professor Lameire look just put open title because I’ll see what I can do but after all I was able to find some data so what I’ll try to do is to tell you my story. This is to focus the problem because I think the problem is huge. What we have we invest a lot of resources trying to rehabilitate our patients with transplantation and then these patients fracture their bones and have an incredibly high risk of fracture. So, we’re not doing certainly a good job on treating or on preventing these bone diseases.

Slide 2

This is data from Chicago actually from Doctor – who is probably in the audience that he published years ago and what he did he compared this population of transplanted patients with a non-selected non-institutionalised group of patients, a large cohort of patients in the United States that were used for the National Health Institute Survey of 1994 and with that these are more or less the demographic characteristics of his group of transplanted group of patients, more or less months after transplantation here but what he found is that compared to the general population the relative risk for bone fractures is much increased in kidney transplants, these are females and males, obviously with females with a higher risk mostly in post-menopausal ages but even higher rates of higher risk of fracture in kidney-pancreas transplantation.

Slide 3

This is probably not specific for kidney transplantation actually the rates of fracture are even higher in the heart, liver and lung transplantation. This data has now some years but several other studies have confirmed this increase in fracture rate, there are several publications mostly within 2004 and as you can see, the range of incidence is huge and I believe that’s because different times where patients are observed after transplantation and also probably different ways of reporting the fractures.
In any case, I think very important to take from this slide is that these two observations here and here that in this study one third of the patients had no bone mineral density criteria for osteoporosis and here at low bone mineral at femoral neck was not associated with prefractures meaning that the information that we are getting from BMD maybe is not the most helpful or the most adequate for these patients and that defending a little bit the use of bone biopsy and bone histomorphometry in this population.

Slide 4

These are some BMD studies. This is a classic study always shown in these meetings. Probably most of you know this slide but it was probably the first good piece of evidence showing the fast decrease in bone mineral density. These were 20 living donor recipients and the fast decrease of BMD in the first 6 months and then a slow down, still a significant increase but a slow down along the year and half post transplant that this cohort was prospectively observed.

Slide 5

In any case, I believe this study provided us also with very interesting information because here Doctor Carlini actually from Venezuela I believe, what he did he looked at BMD and histomorphometry in 25 asymptomatic men apparently with good renal function I’d like to say normal after bone transplantation 7.5 years of renal transplantation. What he found and this is the interesting finding is that BMD at lumbar spine and femoral neck was low in both groups but actually improved at both sites with time approaching normal levels after 10 years post-transplantation.

Slide 6

The result from this study in terms of bone histomorphometry what he found was that bone resorption, osteoid volume and osteoid surface were greater than normal range but with a decreased bone formation rate and mineralization surface and delayed mineralization time. Again, these lesions were more severe in patients after 3-4 years of transplantation but they improved with time approaching normal values after 10 years. Again, the same with trabecular bone volume which was low after 3-4 years, whereas the values were normal for patients that had longer time post-transplant. So this gives us a little bit of information on the natural history of bone disease maybe but I have some more information.

Slide 7

Also what they tried to do again to look and to find out the usefulness of BMD looking at what type of bone change, of bone disorder these post-transplant patients have, they tried to make some correlations initially they studied parameters and they found that BMD at the lumbar and femoral neck correlated with trabecular bone volume and resorption surface. But there was no correlation between BMD and either site with dynamic histomorphometric parameters.

Slide 8

Another study with bone histomorphology also tried to look at this issue on the usefulness or the help of BMD in these patients and again these are 45 patients with 107 months of long-term post-transplant were evaluated with bone biopsy and BMD. Again, the patients that had normal in terms of histology, normal histology had a tendency to have better BMD but again, the other types of diseases, bone diseases found there was basically no help and no correlation with bone histomorphometric data.

Slide 9

Moving a little bit ahead and looking at the bone in an earlier phase, this means early post-transplant. This paper from Doctor Rojas was very helpful and actually a very interesting paper. What they did was they looked at 20 patients with this mean age and the bone biopsy was then actually early after transplantation and 12 patients were able to obtain a bone biopsy on the day of transplantation. These are the phosphorous levels pre and post transplantation respectively and the PTH levels pre and post transplantation. These are the histological diagnoses of this group of patients.

Slide 10

Interestingly in the 11 patients that were able to have the 2 bone biopsies on the day of transplantation and after transplantation showed that there was a decreased of osteoid surface, a decrease in osteoblast surface and an decrease in the fibrosis after transplantation.

Slide 11

Now again, when they looked at the dynamic parameters what they found they were mostly below normal range, the mineralization surface was low, the bone formation rate was low and the mineralization lag time was increased. This is data only from 11 patients that underwent double labelled tetracycline in the post-transplant biopsy.

Slide 12

A very interesting finding they looked at apoptosis in every bone biopsy that was done, they didn’t find by using the method to know, they didn’t find any apoptosis in the pre-transplant bone biopsies but they found apoptosis in 9 of the 20 post transplant biopsies.

Slide 13

When they looked at these patients, they found that patients which showed apoptosis had less osteoblasts and also they found that patients with apoptosis had lower serum phosphorous and actually serum phosphorous also correlated quite well with the number of active osteoblasts meaning that the lower serum phosphorous, less active osteoblasts were present in the bone biopsy pointing to a role of hypophosphatemia in some of the findings presented in these bone biopsies. But also they found that the pre-transplant PTH and the post-transplant PTH also correlated with a number of osteoblasts and here it looked like the PTH had a protective role, the higher the PTH, the more osteoblasts were present meaning that again, it looks like high levels of PTH were able to preserve a better osteoblast number.

Slide 14

So in conclusion, what these authors concluded, I didn’t show data for questions of time I want to keep my 18 minutes time that was given to me, post-transplant bone disease starts early after transplantation. Early osteoblast apoptosis and osteoblastogenesis are involved and possible mechanisms include hypophosphatemia, glucocorticoids and pre-existing bone disease data that I did not show. Again PTH seems to play a protective effect by preserving osteoblast survival.

Slide 15

This other study is also very interesting and I believe it’s the only piece of information regarding this condition. They looked at patients with adynamic bone disease. This data comes form Brazil, from the group of Doctor – I believe there are probably some representatives in the audience but what they did they looked at 13 patients with biopsy proven adynamic bone disease and they were prospectively studied 1 year after that. So these were patients that had a biopsy at the time of transplantation, close to time of transplantation and then 1 year after. Bone histomorphometry was done and BMD was performed in the first and 12 months post transplantation. This is some demographic – but I want to call attention for this iPTH levels and these are iPTH levels at baseline and after 12 months post-transplantation and also for the phosphorous levels to show attention that despite these PTH levels well within the range of KDOQI again all these patients had adynamic bone disease, presented adynamic bone disease.

Slide 16

What we saw in terms of BMD there was a decrease in lumbar spine BMD with increase at femoral neck.

Slide 17

But the old patients recovered, most of the patients recovered. There was a marked increase in the bone formation rate in these patients 1 year after transplantation.

Slide 18

So to summarise this piece of data also again baseline adynamic bone disease was present in all patients and 5 patients had positive aluminum staining. The second bone biopsy was done in 12 patients. Bone histomorphometric dynamic parameters improved in 9 of these 12 patients, actually in 6 of those 9 was normalised. Again in 3 patients there was no bone mineralization. There was no aluminum after 12 months.
So the conclusion from this study is that adynamic bone disease even with reduction of PTH levels may actually partially or completely recover after successful renal transplantation.

Slide 19

To finalise there is also this and I think this study will help us a lot in the next presentations because I think it gives some insight and some thought to look at this disease. What they did they biopsied 17 patients that had a kidney transplant for more than 6 months but with persistent hypercalcemia and with persistent secondary hyperparathyroidism. They put patients on therapy, bisphosphonates, calcitonin, cinacalcet and so on and they submitted these patients to bone biopsy after double tetracycline labelling.

Slide 20

This was the diagnosis and I think this is very disturbing finding but they found that only 9 patients of these hypercalcemic patients had high turnover disease, while 8 patients had actually low turnover disease. There was no major difference, there were actually no significant differences. A small group, no significant difference in the steroid dose, no difference in the post-transplant time or time on hemodialysis pre-transplant.
I should call your attention to the fact that none of the patients had marrow fibrosis or woven osteoid, features of severe hyperparathyroid bone disease.

Slide 21

Again looking at some of the data in these two groups of patients I would like to just draw your attention to the fact that these are the mean PTH of patients with low and high bone turnover as well as the GFR serum calcium and actually there are no major differences. One thing to point out is that these patients had a low fraction excretion of calcium and the authors in discussion point to these findings as a possible independent cause of hypercalcemia in this group of patients.

Slide 22

To summarise or to discuss I guess it’s important to think at least that patients with post-transplant hypercalcemia and persistent hyperparathyroidism can have either increased or decreased bone turnover and in these patients some of these patients with parathyroidectomy or medical treatment to suppress PTH can further increase risk of fracture in a consistent number of patients and so we should consider less aggressive therapy for the patients with low turnover and maybe we should think that bone biopsies should be obtained before initiation of therapy in these patients.

Slide 23

So this was my final slide just to try to summarise my talk and I think this is important what we are discussing here is that we have a significant increase in fracture risk and we can’t forget this in patients receiving kidney transplant that what we are looking at and trying to resolve is impaired osteoblastogenesis and early osteoblast apoptosis may play an important role in the pathogenesis of post-transplant bone disease. The bone alterations after long-term renal transplantation consist and have characteristics of mixed bone disease in which features of high turnover – with altered bone formation and delayed mineralization. Adynamic bone seems to improve after renal transplantation. Patients with post-transplant hypercalcemia, persistent hyperparathyroidism have either increased or decreased bone turnover. Thank you very much for your attention.