Slide 1

Dear Chairman, Ladies and Gentlemen thank you very much for inviting me to deal with this in earlier times marginal subject but it becomes now a main subject in transplantation. I have to deal with the topic marginal kidney donors.

Slide 2

I will address these 6 different topics and let me start with definitions and synonyma and if you go through the literature, there are a lot of different descriptions of the marginal donor.

Slide 3

It starts with a description in the 90s called KNW kidneys that nobody wanted. Then, definition marginal kidney donors compared to the ideal kidney donor, in the early 2000 the term of extended criteria donors to explain it a little bit more positively what it means to have a marginal kidney including 4 criteria that means cerebral vascular accident, hypertension, high creatinine and different age groups.
Then we have to deal in the following with the term SCD, this is the standard criteria donors that means everybody who does not belong to the ECD group and the DCD donor, deceased after cardiac death donors, it’s the same as the non-heart-beating donors in the American terminology. From the Eurotransplant the old kidneys with a donor age of above 65.

Slide 4

Now, several attempts have been made to categorise donors according to their risk. I think a very good analysis has been made on the material of almost 50,000 donors by Schold. He graded donors according to their risk for the first year and for the following years according to a hazard rate between 1 as a reference up to 3 and a half for the first year or later on. This includes a relatively high number of different categories to end up with this donor grading. The result of this donor grading you can see it, is related to the 5-year graft outcome.

Slide 5

The proportion in this material of around 50.000 donors was that they had donors up to grade III in the highest amount and relatively low numbers of donors between IV-V grade and you can see in the ECD the categories have been almost in the last 3 months with the result that the 5-year outcome decreases from 76.7 - 46.7 that means a difference of almost 30%. This kind of donor grading is theoretically applicable but not for clinical use so much.

Slide 6

There is another grading done by Johnston and you see form this slide it’s not practical. They tried to grade the ECD donors into 11 categories depending on the presence or not presence of cerebral vascular accident, hypertension, high creatinine and so on ending up with a summarisation of all these topics age, hypertensive cerebral vascular accident and high creatinine also in a very small proportion of this analysis.
If we go into our available donor spectrum we have we have the impression that these numbers are much higher in Europe.

Slide 7

Now, a second point, an interesting point is the limited use of marginal donors still not everywhere but somewhere.

Slide 8

Michael Cecka made an analysis of the kidney discard rates by donor age and compared the Eurotransplant data with the US registry data and you can see that according to donor age in the US there’s a very high discard rate of organs. Above 65 almost half of them have been discarded. If you compare this with the Eurotransplant data, the number of discards is much lower.

Slide 9

Now, the American colleagues are not unresponsible for their patients and the high discard rates are almost not due to the fact that they will not accept this but they are based almost on biopsy and functional data. For example, the influence of biopsies you can see the discard rates are related to the number of biopsies and in these biopsies almost the number of sclerosed glomeruli or media thickening in the vessels and you can see in the low risk group no biopsy has a much lesser discard rate as in some with these high morphological scores.

Slide 10

Even so, in cases in which marginal donors have been placed on machine pumping due to the resistant index they found there’s a high discard rate, the odds ratio goes up to 8 if the resistance in this graft is high.

Slide 11

One of the reasons to discard kidneys are the pre-implant biopsies and I would like to have the impression or the meaning of Professor Mihatsch to that they use as an index the arterio-arteriolo-sclerose index of above 25%. I learned from his talk these vascular lesions are present in donors but they do not progress to the information we got but graft survival is not affected by this difference but patient survival seems to be affected by the histological correlation of the pre-implant biopsies. Based on all this information the discard rate in the US for older and marginal kidneys is high based on biopsies.

Slide 12

There’s another completely different reason why the discard rate is going up, this is a problem of finance and reimbursement. As you know marginal donors have a longer or transplants for marginal donors have a longer stay in hospital, have a higher extent of rejection and need of treatment and so they calculated that the margin for a hospital to reimburse the use of this kind of donors is since 2005 is not yet positive.

Slide 13

Now, the problem of marginal donors has been also addressed in basic research.

Slide 14

I will show you only two examples from the work of Stefan Tullius and Johann Pratschke they did experimental data in rats comparing the transplantation of young-old, old-old, old-young and young-young rats and you can see obviously that it’s best to have a young organ and a young recipient. The old recipient has per se a risk of a higher immune reaction in a higher infiltrate and the old graft in a young patient does not improve.

Slide 15

This is also true for cell infiltrates, older grafts in older recipients have a higher number of Cd4 + T cell infiltrates that means marginally or old means not only end status it means also a functional immunological status. The same is true for hypertension as a risk factor.

Slide 16

The normotenisve donor and the hypertensive donor develop in an experimental situation much faster changes than the normotensive one.

Slide 17

What is the outcome with marginal kidneys?

Slide 18

There are large data from registries like from the US and if you compare the 3 categories death after cardiac death the straight line, standard criteria the best one and ECD is the group with the highest risk for long-term inferior graft outcome.

Slide 19

Now the hazard rates for transplantation if you use in a re-transplant a non-ECD donor, the patient has a benefit concerning his survival compared to the waiting list but if this patient gets an ECD transplant, the effect of his prognosis compared to conventional therapy that means dialysis is almost not yet established.

Slide 20

This is you can see it for a long time if you compare the extended criteria donors with conventional treatment, there is no effect if you are using ECD donors in re-transplants but there is a big effect if you are using non-ECD that means young and non marginal organs. That means in summary that the transplantation of ECD or marginal donors carry a risk for the recipients for failing grafts.

Slide 21

Now, these organs are there and we have to use them. So, how can we optimally use this?

Slide 22

I think an important basis for this is again an analysis of Schold and Meier Kriesche in which they analysed the prospected life years from the time of ESRD in different age categories. You can see they compared living transplants, standard donors, ECD donors on dialysis. If you are early after start of dialysis within the first two years, there is a difference with respect to the donor. If you are longer on dialysis and you are aged, there is no difference. That means if you are older or if you are staying longer on dialysis, you can accept such kind of donor because a younger or a living donor transplant is not so much of benefit for you compared to this kind of a graft.

Slide 23

This is also true for patients with diabetes with shorter projected life times. But it’s the same if you are staying long on a waiting list and if you are older, you should accept these kinds of grafts.

Slide 24

If you are younger or if you are staying only a short time on a waiting list, you should wait for better transplant.

Slide 25

This shows you that the use of older recipients is still not adequate. People above 65 have a higher risk of not receiving a graft as long as they live and if you correct this for death on the waiting list, still there is a discrimination of older recipients. Also the data showed that older recipients may benefit from a marginal kidney transplant.

Slide 26

Now, further aspects in research and practice.

Slide 27

And with respect to a prospective approach, you know I have worked with Eurotransplant in a prospective age-matching figure in elderly kidneys that means that we put donors above 65 in recipients above 65 but with a special approach with no HLA matching and aiming for very short ischemia times.

Slide 28

I will show you only very shortly the results which show you that the use in dark, the old for old category compared to older grafts that are transplanted in younger recipients and younger grafts that are transplanted in older recipients first of all you see the donors of the old for old program have also been in the mean 70. The donors of the younger category have been 45 that means it’s the best, you have a young graft if available, if not you should use a short ischemia time because the old donors in old recipients have no inferior outcome, if compared to a conventional kind of treatment. If you look at the patients the recipients have been 68 years and the recipients in this group have been 64 that means again a young graft is of benefit for an old recipient but if you are using old kidneys in younger recipients, there is no improvement which underscores the need for prospective also matching of donors and recipients.

Slide 29

Now, to summarise I think there’s no chance to avoid the use of marginal donors in the near future because of organ shortage. We need investigations which haven’t been addressed so much concerning the preservation in extended criteria donors, Pump versus cold storage. We have to investigate preservation solutions. So far we have been using the same from age 1-100. We should use or we should aim for anti-inflammatory protocol in these old donors with respect to the findings in the experimental data and perhaps we should change our clinical practice in attempts to shorten cold ischemia time in ECD donors. We should have a better matching of donor quality and recipient needs and we should develop an applicable scoring system for ECD donors to give the patient and our colleagues better advice on how to use them.

Slide 30

Thank you very much.

Slide 31

Chairman: We thank Doctor Frei for this very nice presentation. Now, we have time for two questions. Yes please. Would you please identify yourself and your country?

Question: Yes Diego Cantarovich, North France. You didn’t mention dual kidney transplantation, so I should understand that you are completely against it or why?

Prof. Frei: Dual kidney transplantation because this is only a very small fraction of these marginal and elderly donors nowadays in the range of 1-2%. There are data that dual kidney transplantation may add GFR rate, on the other hand you should imagine this is a significant extension of the operative procedure. You should have to put in elderly recipients with a calcified iliac access double kidneys, double anastomosis, double urethral anastomosis. It’s a bit too much surgery for all patients that’s my impression.

Question: So you’re against it.

Question: Hello, can I ask you a question please?

Prof Frei: Yes please.

Question: I’m Doctor Sarin from the Apollo hospital in India. Sorry, I came in a bit late. What do you have to say about diabetic donors? I don’t know whether you dwelt on that? Diabetic donors especially who don’t have any retinopathy, who don’t have microalbuminuria, who don’t have any evidence of target organ involvement. Can we consider them marginal donors, yes or no?

Prof Frei: Diabetic donors almost from younger age groups and with these criteria you have shown are good donors and they should not be considered as marginal donors. There is a lot of evidence available that in a non-diabetic environment these kidneys from diabetic donors behave very well and the diabetic signs, the thickening of the basal membrane is reduced after some years.

Chairman: Ok thank you.