CME Slides Forum - R. Mignani

A joint Congress by ERA-EDTA and ISN

TRANSPLANT, DIALYSIS AND CVD IN FABRY DISEASE

Renzo Mignani, Rimini, Italy

Chair: Joao Paulo Oliveira, Porto, Portugal

David Warnock, Birmingham, USA

mignani

Dr R. Mignani
Renal Unit
Infermi Hospital
Rimini, Italy

Ok. Thank you David and thank you to the organisers for inviting me to this meeting to speak about transplant dialysis and cardiovascular disease in Fabry Disease.

ESRD that leads to renal replacement therapy and to dialysis and transplant represent a severe life threatening condition complications of the follow up of Fabry disease. In this study based on the Fabry Registry and in the Fabry Registry report of 2008 the prevalence of patients with ESRD on dialysis and transplant was 13% in males and 2% of females.

What is surprising is that the age of onset of the beginning of ERT of dialysis and transplant was the same in both sexes. While all other ages such as the age of first symptoms, of diagnosis, of the first cardiac and cerebrovascular events were earlier in males compared with females.

Indeed, females that reached the ESRD seem to progress as rapidly as males as reported in this study from Professor Schiffmann.

The prevalence of Fabry disease among patients on ESRD has been studied by Tsakiris and Thadani in this paper based on the European and American USRDS Registry respectively and they found a similar prevalence of Fabry disease among these patients about 0.016-0.018. However, in subsequent screening studies and first of all, in the Spada study from Italy it has been found at least a ten times higher prevalence of Fabry disease among these patients due to a high number of patients with unrecognised or undiagnosed Fabry disease.

The outcome of patients on dialysis and Fabry disease is characterised by a frequent persistence of symptoms, of extra renal symptoms such as pain, abdominal pain and hypohydrosis. Hypertrophic cardiomyopathy tends to progress severely leading to a high incidence of cardiac and cerebrovascular events and to a higher mortality and low patient survival rate.

The survival of these patients has been investigated by both registries, EDTA and USRDS registry in these two studies where the 5-year patient survival rate ranged from 40-46%.
In the Thadani study, in particular the patient survival rate was significantly lower in comparison with the non-diabetic controls on dialysis but was significantly higher in comparison with diabetes controls on dialysis.

By contrast the outcome of transplant patients with Fabry disease is characterised by a long-term patient and kidney survival rate. Extrarenal symptoms tend to improve very early after the transplant even if sometimes they can relapse years after the transplantation.

No data are to date available about the progression of hypertrophic cardiomyopathy in untreated patients with ERT. The relapse of Fabry disease nephropathy into the kidney, into the allograft is very controversial in fact the graft is often free of deposits due to a normal α-Gal activity into the graft while the serum and the leukocyte activity is unchanged. The survival of these patients has been well investigated by Ojo in this study based on the USRDS registry and there were 97 transplant patients with Fabry disease present at 10 years a survival rate, a graft and patient survival rate similar to the controls. In particular the 5-year patient survival rate in the Ojo study was 82%.

About 10 years later and recently Shah analysed the survival of 197 patients with transplant from the organ procurement transplant network registry over a period of 20 years from 1987-2007. He found that the 5-year patient and graft survival rate were quite similar to the data from Ojo. However, the patient survival rate at 5 years was significantly lower in comparison with the cohort matched patients for Fabry disease but when data were censored for death, the graft survival of patients with Fabry disease was significantly higher in comparison with both controls, the cohort matched and the overall patients eluding to a higher incidence, higher prevalence, higher risk, higher significance, higher risk of death of patients with Fabry disease.

Regarding the contribution of registries to the knowledge of the natural history of patients on renal replacement therapy this paper by Ortiz that is still in preparation and I have the permission to anticipate in part, he has recruited to date 213 patients on dialysis and transplant and the prevalence of dialysis and transplant in this study is about the same as described before, about 40% of males and 2% of females are with transplant or on dialysis.

The preliminary results of this study confirm that the median age of the beginning of RRT in both sexes is the same about 39 years. In a third of patients Fabry disease was diagnosed after the beginning of RRT. The ERT is performed in 56% of males and 61% of females of the dialysis patients and in 61% of males and in 58% of females of the transplanted patients. The incidence of cardiac and cerebrovascular events is about 50% in the males on dialysis and transplant and only 20% in patients without dialysis and transplant, not yet on dialysis or transplant. In female patients the incidence of cardiac and cerebrovascular events were only 37% while in non RRT patients only 17% and in almost all of them cardiac and cerebrovascular events occurred after the beginning of renal replacement therapy.

And it is well explained in this Kaplan-Meier Estimate curve where we can see that the ESRD the renal and dialysis anticipate the first cardiac and cerebrovascular events of about 7 and 8 years in both sexes.

In the last two-three minutes I will show you some data about the effect of ERT in this category of patients and about the effect of the ERT in dialysis patients.
In this study by Pisani and co-workers from Naples they investigated the cardiac situation of 9 patients on hemodialysis or peritoneal hemodialysis and a severe cardiomyopathy as expressed by these echocardiographic abnormalities and in particular with high left ventricular mass at baseline significantly higher compared to a group of 9 healthy subjects and a group of 9 patients on dialysis without Fabry disease. In 6 of these 9 patients the progression of left ventricular mass was analysed in the period of 2 years before the beginning of ERT and after a course of therapy with agalsidase β of 2 years and they observed in this period a non significant reduction of left ventricular mass in comparison with a progression, major progression of LVM in the period before the beginning of ERT of agalsidase β.

Some years later in our Nationwide Italian Collaborative Study we analysed the cardiopathy and the allograft function of 16 dialysis patients and 17 transplant patients treated with ERT. Almost all of them were treated with agalsidase β and only 3 of them with agalsidase α and almost all of them at baseline have a severe cardiomyopathy expressed by a high left ventricular mass index. After good therapy of 3 years we observed a non-significant worsening of LVM in 7 dialysis patients while in 11 transplant patients the LVM tended to stabilise after 3 years of treatment with ERT.
In transplant patients the allograft function expressed by the serum creatinine and creatinine clearance show after 4 years of treatment a stabilisation of allograft function with a slope of serum creatinine of 1.92 ml/min/year.

A global 6-year follow up of these patients documented a high number of cardiac and cerebrovascular events in the group of dialysis patients. Of the initial 16 dialysis patients during this 6-year follow up 6 died and 6 out of 8 on the waiting list were transplanted. So at the end of the follow up period of observation only 4 people, only 4 patients were still treated with ERT.
By contrast in the transplant group only 3 events could and of the initial 17 transplant patients only 2 went back to dialysis and one stopped therapy. So at the end of the study, of the follow up 14 patients were still on ERT.

More recently in this study based on the FOS registry data the clinical characteristics have been analysed of 27 patients with transplant of the registry and here you can see with this line the cardiac characteristics of these 27 patients that were quite mild, less severe in comparison with the same characteristic cardiovascular parameters of our cohorts of patients, even if the prevalence of cardiac and cerebrovascular events in our cohort was less prevalent in comparison with the FOS group. 27 patients of the registry were treated with ERT and in particular with agalsidase-α and after 2 years of treatment they showed a slight decrease of GFR with a slope of GFR of 3.5 ml/min/year.

So in conclusion all these studies and the limited experience acquired to date on this issue confirm that still now lights and shadows persist on this issue and in particular about the progression of cardiomyopathy in both dialysis and transplant patients with or without ERT.

In this way the emerging question is what are the compelling indications for giving ERT in Fabry disease patients on dialysis or with transplant? It is one of the questions that we will try to answer during our workshop that will be held in the Fabry Nephropathy Meeting that will be held in Bergamo next week and where I invite you to participate.

Chairman: Thank you very much you were right on time as were the other 3 speakers. We can take a few questions. Michael.

Question: Thank you, Michael West from Halifax Canada. Thank you for this presentation. It was very interesting. The data you showed us about cardiomyopathy in those patients receiving enzyme therapy on dialysis is very compelling I mean you really don’t see the benefit, they continue to worsen in cardiomyopathy. We had a similar situation, one of our patients died aged 49 after a year and a half of agalsidase therapy, 3 months after transplant because he had severe cardiomyopathy that he acquired during a period of time on dialysis. So knowing that is it worthwhile putting these patients on dialysis? Shouldn’t they all receive a kidney transplant? Should we not give them some priority? Because dialysis looks like it’s an inferior therapy to a transplant for a patient with Fabry disease on ERT.

Question: Just one question, Fabry patients on ERT do badly on dialysis, cardiomyopathy so why should we put them on dialysis? Why shouldn’t they all get some priority to get a transplant?

Dr. Mignani: Yes of course. It’s a very important issue because it’s one of the points that is in discussion and to perform transplant before dialysis and avoid the problem that dialysis patients have about the cardiopathy. In the Shah study I want to underline that almost all patients on transplant are pre-emptive transplants or living donor transplants, so this is why we have to stimulate the performing of a transplant before dialysis and avoid this situation. As we know, dialysis with several problems such as anaemia the hyperparathyroidism, the chronic fluid overload is much worse for patients with Fabry disease, so it’s better to avoid this.

Chairman: Michael I would suggest that we see the same problem though with our diabetic patients the ones who are transplanted do better than the ones that go on dialysis but there’s a big selection bias. I think the answer is let’s stop progression, let’s control the proteinuria, let’s give them ERT, let’s keep them from getting worse, so we don’t have to talk about these issues. I think what’s very interesting in the transplant experience and Shah’s report and your report is that you can take the kidney off the map. It takes 40 years to get kidney failure, so you would be 80 before your kidneys failed again before Fabry occurred. I don’t think it does in the transplant kidney that’s not the point the point is I think we do have people with a high burden of disease and we’ll be seeing cardiac events, we’ll be seeing stroke in those patients. So we have to be very careful about giving the best care we can and I think that’s your point and I agree with you completely. Ravi we’ll let you have the last point.

Question: Thank you why do you think the graft survives longer in the Fabry patients compared to controls, to others?

Question: Some of the studies seemed to suggest that that the kidney actually lasts longer in a Fabry patient compared to others.

Dr. Mignani: Yes, but I don’t why, this is still to be investigated in particular because there are several parameters to investigate such as the effect of the immunosuppressive therapy on transplant but I don’t know why there is this difference.

Chairman: Ok I think we should close the session. The plenary is coming up. I want to thank everyone for your participation. I also really appreciate the plug for the satellite next week. If you’re interested, if you would like to participate it’s still possible contact me. Either send me an email at Fabry at uab.edu or come see me right now and we can make an arrangement. Thank you very much.