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Non-Heart Beating Donors - an Untapped Resource - (full conference transcript)
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David
Talbot
David Talbot graduated from the University of Newcastle up Tyne with an MBBS in 1982. He gained an MD in 1988 and became a Fellow of the Royal College of Surgeons in 1989. His present appointment is that of consultant hepatobiliary and transplant surgeon at the Freeman Hospital in Newcastle, a position he has held since 1995.
[He starts by showing a graph (not shown) of the waiting list going up and the actual rate of donors remaining static.]
In fact in recent times the rate of donors has actually dropped. The Live Related Programme has slowly increased, but is still way off what it should be, and the non-heart beating has been pretty static, but is now starting to increase.
Now what is the difference between a non-heart beating donor and a heart-beating donor? Well you see the main differences related to primary warm ischaemia. So that is the time from the heart stopping to the perfusion of the organs with cold solution. If that is prolonged then you actually get anaerobic metabolism, so it is a bit like getting cramp when you have been running - you are actually making your muscles work harder than the blood supply running to them. So by doing it, you actually get damage to the organs. Now initially it is actually reversible, that is the blood supply comes back, or you cool the whole thing down. That change will recover later on, once you establish bloody supply. Usually, because you've damaged a little bit, the organs actually sleep, and that's when you get this thing called delayed graft function.
So the kidney goes in, and it just sits there for a few days, and then it actually starts to work. Now if you damage them for longer than that, you actually get cell death within the kidney, and when the kidney goes in as a transplant, it never actually works, and the other problem is if you have a prolonged primary warm ischaemic time, then you actually get intervascular thrombosis which is due to the fact that blood is not moving within the organ, and therefore it clots. When you actually establish the thing, and sew it in again, you get this thing called reperfusion syndrome, which is due to the fact that the blood is going in and spotting all this damaged tissue, and it actually releases a load of enzymes and the damage actually gets worse. Now the first people to perform a non heart beating donor were Damien and Casimir, in those days if you did something dramatic as a surgeon, they make you into saints. Unfortunately the chap didn't make it, but the two surgeons remained, something that doesn't actually happen these days.
What we wanted to do when we established non-heart beating donation, we took these kidneys, and initially they were patients that had actually died in the intensive care unit, but they weren't actually fully brain dead, so they couldn't be done as a normal donor. They were taken to theatre, where the machines were turned off after all consent and everything was sorted out, and then when the heart stopped the surgeon made a cut, and actually went in and removed the organs, took the kidneys out and put them into the new patient. The graft survival is excellent, 90%. What we did then was we extended it in 1994 to take people from the accidents and emergency department. These people had come in and they've had a cardiac arrest and the doctors were trying to resuscitate them and failed, and then they phoned us, and we came along and we took the kidneys out, and put them into a patient, and the results weren't very good, 45%. So the actual programme then was stopped.
Now I want to go a little through the categories of non-heart beating donors. These categories were defined from a meeting in Maastricht and category one patients were actually dead on arrival. These patients have collapsed in the street and have been down for an unknown length of time, and therefore this primary warm ischaemic time is actually not defined, and because of the unknown time since death, when you actually use these kidneys, they don't actually work well at all. So virtually no centre actually uses them. Category two's are basically the ones that have been brought in, they've collapsed outside hospital, they've been brought into the accident and emergency unit, and the team tries to resuscitate them and actually fails. Then they declare death, and we come along.So in these patients, the actual timing is quite well sorted out, and these you can actually use. We try and keep the warm ischaemic time less than 30 minutes. Category three are those patients that I mentioned in the intensive care unit, awaiting cardiac arrest. Category four, are patients that are actually brain dead that are going to be a normal donor and something happens en route, like the patient collapses, or the blood pressure collapses and you have to do the retrieval quickly. These patients are very close to normal donors.
In 1998 we introduced a retrieval protocol to try and improve the results in the accident and emergency department. What we did was we took patients that came in between the ages of 18 and 65, did a cut down in the groin, and we put a catheter in, and perfused the organs inside the body, and talked to the relatives and asked about donation and then took them to theatre and took the kidneys out within two hours. The kidneys were then cold stored, transferred to Freeman, where we added an additional step, which was machine perfusion and viability assessment, and the idea was that we do this and we could tell if the organ was a good one or not. Then we stored the organ until it was actually transplanted.
Then we needed a machine perfusion system to actually test these kidneys. Back in late 60's, early 1970's, nobody really knew how kidneys should actually be stored. There were two schools of thought, one of them was to use cold storage just within a box, and the other group believed in something called machine perfusion, where you actually place the kidney into a container and then pumped solution around it. This is an oxygen supply as well. It was all done quite cold. In Newcastle we had a system like this, and then with time people began to realise that the longer the kidney was on this machine, the worse it actually did, so we stopped using it. This machine was put into a cupboard and then we went to use it on our new programme and the cupboard was bare, somebody had actually thrown it out. So we couldn't use it. So we went to the available alternatives and this is a machine that's manufactured in America, and it cost $27.000. Every time you opened the plastics for the tops, because the kidneys are actually placed in the top containers, it will cost you $500 and we thought there was no way we could actually justify doing that, and there is no way anybody would actually give us money.
We remember in the early days we actually built one of our own, and that had worked reasonably well. It had wheels on the bottom so it was mobile, but obviously that had been thrown out long ago. But we thought well if we could do it then, surely we could do it again. We also had a very enthusiastic Pam Buckley, whom I'm sure a lot of you know, who originally was a dialysis nurse and said she was sure we can do something with some dialysis tubing, and dialysis machine, so that's what we did. We used a dialysis pump, which basically had two pumps, pump 1, and pump 2, with a cooling unit, which basically was a stainless steel coil, and then the fluid was pumped around between them with the kidney in the middle, and the fluid ran into the kidney and then sucked up, there was some sampling ports, a pressure transducer, and there was a third pump which we actually bought from a garden centre, which was not sterile and it would actually pump the fluid from a slush around the heat exchanger. This cost about £25, the actual dialysis machine was free because nobody was using it anymore - it was condemned - and the most expensive thing in this was the solution which cost about £90 for a bag and the pipe work was actually customised for us for £20.
You take the kidney out and prepare it, put a special clamp on it, which is connected to the pump system. Sometimes the kidneys actually have more than one blood vessel so you have to simplify it by bringing the two vessels together; otherwise you can't be machine perfusing the whole organ. Then we measured the level of Gluthathione S Transference (GST), an introduced enzyme mass which is produced by most organs of the body, particularly the kidney. If you've got a kidney in a close circuit and it's been pumped, then if you take the solution off that close circuit, the enzyme level is actually related to the degree of damage. So if you've got a really damaged kidney you'll have a high level of GST. This offered a good way of telling which one was too damaged, so we introduced a cut off saying the GST level had to be less than 200. The other thing that was known about was that the resistance of flow had to be shown to be falling for the perfusion characteristics to be good. So when we did this, we had brilliant results. We felt quite happy with ourselves. The machine perfusion itself, however, does do some damage.
Where we found dropping resistance, and a low GST was the important thing, we now know there are several things to look for. We have introduced the perfusion flow index, which basically means that the flow per millimetre of mercury has got to be good, which means we can avoid using excessive pressure to pump the kidneys and therefore we minimise the chance of actually damaging the kidneys. The temperature has to be low, and we have to have a low weight increase, and also the GST has to be low.
This is the state of affairs (diagram not shown), since 1998 giving the total numbers. We've had 71 donors over this time, producing 142 kidneys. Out of the 142, 90 kidneys have been transplanted, and 50 have been discarded. Category 3's are the best donors, and there are 11 discards and 46 transplants, so it's roughly 1 to 4. If you have that sort of donor, you don't throw many kidneys away. But if you have a donor from the accident and emergency department, you see it's roughly 50/50 because these kidneys have been damaged far more with the initial insult. The primary warm ischaemic time is about 20 minutes, secondary which is the time it takes to sew the thing in, and then the cold ischaemic time, we like to keep this under 24 hours. And you see the actual kidney survival rate, and the patient survival rate, are about 90% for the first year and the same for the third year. We are quite pleased with these results.
The other thing to notice is that the delayed graft function rate is quite high, so most of the kidneys, when they go in, sleep initially before they actually start to work. What we've done here is we've compared a group of non-heart beating donor kidneys to the heart beating normal kidneys. There is quite a significant difference between the sleepiness rates initially. And therefore the actual hospital stay is slightly longer if you have one of these kidneys, 25 days as opposed to 21 days, but the graft failure rate is very similar between the two. There was some worry about the quality of the kidney that you have got, in other words the kidney might be working, but the quality of function wasn't very good, so we actually compared creatinines and also urea, and at the discharge the creatinine was a lot worse than kidneys from the ordinary donors. What happens by three months, it's exactly the same. So the kidney has actually recovered from this insult, and both sets of curves run along exactly the same.
One of the other problems about using these kidneys are you actually don't use a lot of kidneys, so a lot of kidneys are returned to the body from whence they come. For us, it's the order of about 33% not used, in Leicester also 30%, Spain 30%. The Americans use very young donors, excellent donors, because they have a lot of shooting. The quality of their organs is much better than we get. In Japan, where they have a big problem with the actual concept of brain death, what they do is they have somebody who is brain dead, and they go along and see the patient and put the cannulas in when they're actually brain dead but they don't touch them after that until they actually have a heart attack and the heart stops. Then they start to perfuse them, so these are very good quality donors. Their discard rate is very low.
We want to introduce another study because one of the reasons why you don't use kidneys from these donors is you get this intravascular coagulation because the heart isn't actually working, so you get clotting within the vessels. Streptokinase is a thrombolytic, in other words in dissolves clot, so we developed a project. We actually took pigs which would be used for another experiment, not ours, and they were surplused to requirement and they were actually dead. Then we went and put a catheter in and actually started to perfuse them 60 minutes after they had actually died. And we used streptokinase in this situation. By doing that, we found that the quality of the kidneys was much better if you used this thrombolytic.
This is the temperature (diagram not shown), which relates to the quality of the perfusion, so if your perfusing really well you're using a lot of cold solution and therefore the temperature will be lower. And therefore it is better for streptokinase, the pressure required to perfuse is lower, the enzymes that you're producing is lower and the resistance to flow is lower. Therefore thrombolytic is a good idea in an animal model. So then what we did was we actually went on to do it as a human study where we'd actually give the streptokinase or not in a blindfold fashion to ordinary donors, and we had about 15/16 in each group. They all got heparin as normal, and then they were machine perfused afterwards. Where they came from is exactly the same, so the same incidents as category 2 category 3, the donor age was the same, the donor creatinine was the same. Then the outcome, the streptokinase kidneys looked much better, so they were pale when they came out, as opposed to the non-streptokinase group which were largely mottled, the colour of the effluent was much better, the enzyme levels were much better, the streptokinase group and the perfusion was much better, and the actual proportion that were transplanted, 63%, as appose to 42%, was not significantly, but was obviously higher with the streptokinase group so we were quite pleased with that, and now we routinely do it.
Another problem that we've sort of alluded to was that the creatinine takes a while for it to drop after the transplant. It comes down after about 30 days. One of the things that influence this drop is the sort of immunosuppression you get. Ciclosporin and Tacrolimus are not particularly good, so we have actually done trials with Leicester to compare this, but the results will be announced later.
So when we started which was mostly from 1998, Leicester was working and St George's were working in the field before but it stopped. What's happened is the UK Transplant is promoting this sort of approach, because you actually do get a lot of donors this way. There are more and more centres doing this, St Georges have started again, St Mary's, Kings Hospital London, Bristol, Cambridge, Oxford, Leeds, all these places are starting again. In the future Nottingham wants to start, and there was some problem in the law in Scotland, because it is slightly different, but that looks like that is going to be sorted out, in which case Edinburgh and Glasgow will be able to start too. We have actually started now to explore the aspect of using a District Hospital, and Sunderland are quite close to us and are quite keen, they have a large A&E Department there, so from January we will be starting a donor programme there so hopefully we will have lots of kidneys for everybody.
Another thing that is happening in the future is, rather than having our Heath Robinson affair,'Organ Recovery Systems' (which is another Company), has produced this Perfusion System (Photograph not shown), which is much simpler than the American version, much cheaper, and I think much better than our Heath Robinson approach.
So in conclusion, if you're careful, you can actually use kidneys from non-heart beating donors which give excellent results, and they're very comparable to kidneys from ordinary heart beating donors. Category 2, these are the ones from the accident and emergency department, are very labour intensive, because you've got to drop whatever you are doing and you've got to dash over and do the necessary in the accident and emergency department. You need machine perfusion in this situation, and you need enzyme analysis to determine which kidneys are good and which kidneys aren't so good. The viability testing, I feel, is an evolving process; I don't think we've still worked it all out just yet - we can say if a kidney is damaged, but what we don't have is some test which tells us how well it is, so hopefully one day we'll come up with something for that. Your graft quality can be improved, by manipulating the organs, by using thrombosis, by using agents that you're adding to the system. We use perfusion because the kidney's been starved of oxygen for a while, its usually a little bit worse and it may be that its actually improved by machine perfusion.
Sleepiness within the kidney, known as delay graft function, is common in the organs from non-heart beating donors. With the best donors, if you're really careful, can be sure they aren't actually going to be sleepy, and have delay graft function, and in these situations, you can actually use these donors, for liver, lung and pancreas, and we've done two lung pancreas, we've done about three livers and Kings Hospital in London has done about 20. The thing is, you can't afford to have delayed graft function with the liver because if you do, then the patient who receives that organ will actually die, but with a kidney you can actually keep them going long enough with dialysis and let them pick up. So you've got to be reasonably certain before you use the liver.
And the other important thing to say is there is a lot of people involved in this work, the research fellows here that have been focusing on this. Pam Buckley was the original enthusiastic transplant co coordinator, and now there are more enthusiastic coordinators, and we couldn't work this system without the coordinators. Scientists, Bryan Shenton and Dave Mantell, Bob Pearson and Chris Connell, are vital, and my colleagues for also putting these kidneys in.
Thank you very much.
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