Liver Before Heart: Reversing Combined Organ Transplantation

  • 03/20/2016
Liver Before Heart: Reversing Combined Organ Transplantation
Dr Jeffrey B Geske: Greetings. I'm Dr Jeffrey Geske, assistant professor of medicine and cardiologist at Mayo Clinic. During today's trending topics video, we will be discussing reverse-order liver transplantation. That's liver transplant before heart transplant.

I'm joined by my colleagues, Dr Sudhir Kushwaha, professor of medicine and the director of our Heart Transplant Clinic, as well as Dr [Richard] "Rocky" Daly, professor of surgery and surgical director of the Heart Transplant Clinic. Welcome.

Dr Sudhir S Kushwaha: Good to be here.

Dr Geske: Recently, you've experienced successful reverse-order liver-heart transplantation. When are some times when you might think about combined organ transplant, either the reverse or the more traditional combination?

Dr Kushwaha: Well, as you know, Jeff, there are certain situations where the heart and the liver are both affected, sometimes by a systemic disease process, which requires a combined organ transplant.[1-3] Other times, when the severity of the heart failure is such that the liver ends up getting cirrhosis. We're familiar with that in conditions, particularly, where there's severe right heart failure. Then there are other diseases where there might be a concomitant liver process going on, and we're considering heart transplant because the patient has heart failure as well.

Those are the situations where we might consider doing a combined operation. We have several patients who we've done over the years who have undergone combined heart-liver transplant in the normal order, which is heart followed by liver. So, we have quite an experience as an institution in doing this. Rocky might want to comment a little bit about that.

Dr Daly: When the patients have failure in both organs, then we consider them for combined heart and liver transplant. We have quite a bit of experience. We've done about 35 cases, which turns out to be the most in the world. It's not a common operation, but there are some patients that obviously benefit from it.

The heart doesn't tolerate the ischemic time as well as the liver does. Normally, in these operations, we'd do the heart transplant, and then immediately begin the liver transplant. [The patient is undergoing] the liver transplant, then, with a stronger heart, a better heart, because we've just put it in and hopefully, that heart has tolerated the ischemic time and the surgery. Obviously, we have to select the donors properly so the heart will be good for a liver transplant. In these cases, for immunologic reasons, we considered reversing the order of the surgery to deal with the immunology.

Dr Geske: Okay. Tell me a little bit about that immunology. How do the elevated antibody levels end up affecting this process?

Dr Kushwaha: Well, transplantation has become very successful over the past several years, largely because we have very good immunosuppressives. Those immunosuppressives are good at suppressing what we call cellular rejection. In those situations, we have predominantly T cells, which can attack the newly transplanted heart and cause damage and, ultimately, rejection. But the drugs we give actually suppress that quite well, such that severe cardiac rejectioncellular rejection, I meanis actually quite rare.

Now, there are patients who have very elevated antibody levels, and these are what we call preformed antibodies. Quite often, younger women, by virtue of having been pregnant previously, will have preexisting, preformed antibody levels. Patients who have had previous transfusions can sometimes have circulating antibodies that, under normal circumstances, don't do them any harm.

But when it comes to transplantation, we have these very high levels that we can measure now and quantify using the current technology, which gives us an idea of what would happen if there were antibodies to particular antigens on the donor heart.

So if you have very high antibody levels and the donor heart expresses a certain antigen, then those antibodies will create a lot damage and cause severe rejection, which is very, very difficult to treat because these antibodieswe can try to remove them, but they always come back because the B cells that make them are still there in the recipient. It creates a situation where we are unable to transplant certain patients because we're unable to find an appropriate match for them because they have very high circulating antibodies, and we have to make sure that the donor we get doesn't express the antigens to which that patient has antibodies.

I hope that's reasonably clear. But with this concept of reverse order came about as a result of our experience with combined heart-liver transplantation. We noticed that these patients whom we have the largest seriesas Rocky just statedreally didn't suffer much in the way of rejection or even antibody-mediated rejection. I'll let Rocky comment a bit more about that.

Dr Daly: We noticed that the incidence of rejection in the patients who had combined heart-liver was much less than the rejection in the patients who had just isolated heart transplant. So, that got us thinking that this is obviously an immunologically favorable state.

We have the opportunity to collaborate with our colleagues in other areas of transplant through the transplant center here, which is a multidisciplinary undertaking. The kidney transplant team was having the same experience when they were involved with combined liver and kidney transplant. They also noticed this and noticed that the antibody titers went down: just the antibodies to that donor (not all the antibodies) didn't seem to be as high.

We had this group of patients who are young patients and have become sensitized. They have a lot of antibodies and had the need for both heart and liver transplant. Many of them are congenital heart disease patients who have developed cardiac cirrhosis from their congenital disease, often Fontan physiology. They've had multiple operations, multiple transfusions, but still, they're young peoplein their 30s and 40sand [we were] trying to find a way to help them.

We had very little success with just reducing the antibodies [using] various medical means, which is consistent with other reports. It occurred to us that we might consider transplanting the liver prior to putting the heart in, and that might, as Sudhir said, reduce the antibodies. So we proposed doing that.

Dr Geske: What sort of technical challenges did you run into now that you've identified this issue and you've come up with a novel solution? As you began to approach it, what are some of the considerations in that regard?

Dr Daly: From a surgical standpoint, it's intimidating because if the patient has had multiple cardiac surgical procedures and then we're considering doing the liver transplant while the heartwhich has also been procured from the same donoris just kind of waiting on ice in the corner of the operating room, the ischemic time for the heart gets very long. Then, we still have a heart operation where there are multiple previous surgeries and, you know, pretty massive adhesions and a long dissection.

We have to work carefully with our liver surgeon colleagues, and work back and forth. Ideally, we do as much of the cardiac dissection as possible without having to go on bypass. Then, they come and do as much as they can do, and they actually remove the liver while the organs are in transit, so that as soon as they arrive, they can sew the liver in, which is a little different from what they normally have to do.

Dr Kushwaha: So timing is everything.

Dr Daly: Timing is everything. It's like this choreography that has to happen because the patient won't tolerate hepatectomy for a long time. On the other hand, we don't want to have the organs sitting in the corner while we're still working. We want to be really, really ready for them when they arrive in the operating room.

Dr Kushwaha: We end up being limited, I suppose, by having organs that are close by. Some of the organs we might take from further afield, because of the ischemic time, as Rocky already mentioned, is a limiting factor. We're really confined to having fairly local donors for this sort of situation, wouldn't you say, Rocky?

Dr Daly: Yeah, we need donors that are not too far away and, obviously, vigorous enough to tolerate what's going to be a longer-than-usual cardiac ischemic time. The other challenging thing is that we don't know how effective the liver will be, to what degree it will remove antibodies, for some of these patients who have massive levels of antibodies.

We have some criteria that we've developed to try to select patients with situations where, at least, the liver has a chance. We do that with prospective cross-match, which we accept as positive.

Dr Kushwaha: Yeah, we try to limit the degree of mismatch, to put it in simple terms. I mean, you can get high degrees of mismatch and low degrees of mismatch, and we try and minimize so that we get the best match possible in terms of antigen and antibody matching.

I'm thinking back to the first patient we did. She had a lot of circulating antibodies, very high levels. But in fact, the major mismatches were in only three antigens. That allowed us to limit the exposure to the donor liver. We were very concerned. We went into this with some trepidation, obviously, because the price of failure would have been a bad outcome for that patient. We thought about it and formulated this strategy, and we minimized the degree of mismatch. Luckily, the appropriate donor came up. Actually, the donor was at Saint Mary's, our institution, so that also minimized the ischemic time issue, which Rocky was just talking about.

Dr Geske: Okay, it sounds like a lot of moving pieces between the antigen matching; having the organs close enough to have the timing right; and minimizing the ischemic time. What's the Mayo experience been like so far, and where do you see it going next?

Dr Daly: Well, we've done four cases so far. They've all been successful. We are still limited by some patients having a much higher reaction and a prospective cross-match where we haven't been able to always do the surgery. We have a kind of limit. We accept a positive cross-match, but we won't accept a positive cross-match that's extremely high because that tells us that, perhaps, the antibody activity is more than the liver will deal with. So, we've developed a protocol where we will accept a positive cross-match up to a certain level, a channel-shift level.

Whether we could expand that, I don't know. At some point, we'll have a problem; and as Sudhir said, the patients will be the people who will suffer from pushing the frontier maybe a little bit too hard. So we're being careful with that. There aren't really data to help us.

The limiting factor is getting the donors. The limiting factor, of course, in transplantation is having donor availability. We have a large heart-transplant waiting list. We have a number of patients on the waiting list, waiting for this procedure, and it's very challenging and disheartening.

Dr Kushwaha: The wait time can be very lengthy, unfortunately. It's very difficult for these patients, and we really feel for them because, they're very limited because they have such severe cardiac failure and liver failure as well. But there's nothing we can really do to speed the process up. As Rocky said, perhaps we could consider changing our criteria, but then we're also exposing a greater degree of risk as well.

Dr Geske: Great. Well, I'd really like to thank you both for joining me today. It's been fantastic learning about some of these new groundbreaking approaches to both heart and liver transplant or liver and heart transplant, as it may be in this case. I'd really like to thank you both, Rocky and Sudhir, for a fantastic discussion. I'd like to thank you, as well, for joining us today on this Mayo Clinic on Medscape topic review. Thank you so much.
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