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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

    

LIVER RETRANSPLANTATION: ETHICS AND OUTCOMES

R. Mark Ghobrial, MD, PhD

Associate Professor of Surgery

Division of Liver & Pancreas Transplantation

http://www.gotomylist.com/

Thank you very much and I really appreciate the invitation to come to this wonderful meeting, which is gradually becoming one of the best meetings around in transplantation.

Before I start my talk, just wanted to ask a couple of questions to the audience.  Who would re-transplant the patient for PNF after a liver transplant?  If you can raise your hands.  Who would not transplant the patient for PNF?  Who would re-transplant the patient for recurrent hepatitis C?  Who thinks that we should never transplant a patient for recurrent hepatitis C?  So, I probably hopefully I would ask those questions after I am done and see if I can, you know, change your minds a little bit.  I never succeeded doing that though. 

Everybody is very familiar with this slide and we have seen it over and over again.  The reason that we keep talking about re-transplantation is that we are wasting organs for patients who got one chance already.  We have one pie and we have to slice the pie in many different ways, so if somebody got one slice, why does he have to have two.  We got 18,000 to 19,000 patients waiting, about 4000 livers and 5000 recipients and there are some deaths on the waiting list.  Everybody who does liver transplants is very familiar with this.  So, to be able to answer the question, should we do re-transplantation altogether or not?  And if we do it, how do we do it?  We need to go through a few steps.  Some of them are the outcomes of liver transplant.  What do we know about the outcomes?  Re-transplantation of hepatitis C recipients, does the MELD correlate with the survival after re-transplant and finally the ethics that surrounds all of this, and I did not put this slide because Dr. Langers is going to be the chair of the meeting for this session.  This slide actually shows the first work that was done for re-transplantation and it was done by Dr. B. W. Shaw from Pittsburgh at that time.  They presented several cases and the re-transplantation rate was 29%.  Most of the re-transplants were done in acute patients, HAT’s and PNF’s, and PNF’s had very bad results, about 40% survival.  Overall, altogether, it was 49% survival.  A few years after 1989, again Dr. Byers Shaw and Dr. Patrick Wood put down the same paper and they revised the numbers.  In the pediatric patients, there is about 100% survival of re-transplantations.  In the adults, it was so poor, about 53%.  Overall, one year survival was 76% and they pointed out in a primary transplant, the cost of a primary transplant was about $87,000, goes up to about $250,000; length of stay about 35 days, goes up to about 80 days. 

There was one more interesting paper that came out from Wisconsin and it came about four years after this one, and the numbers appeared a little bit better.  This was the first paper that talked about elective re-transplantation.  The patients were on the list for a while and then a year or two out, they needed transplants.  Some of them become very sick, some of them get re-transplanted, and the concept of elective re-transplantation came about and those patients that were healthy at the time that they required the re-transplant had a survival rate of 81% and this paper also was the first, which tried to find the underlying variables that would tell us or predict to us whether the re-transplant is going to be successful or not.  

    

They noted less than four organ system failure.  In other wards, intubated, may be a little renal failure and the liver is not working well.  They get about 73.9% success with the transplant.  If they get four organ system failures, it is about 10% success, in other words 90% death rate.  So, that was the first paper that said sicker patients do poorly when you re-transplant them, no matter what.  The cost of the transplant still was a little higher and going down to four years after, almost $300,000 and the length of stay was still very long.  So, where are we today?  And there have been several papers that came out from Pittsburgh and from UCLA and they all hit on the same theme and the theme is, no matter how you look at it, patients survival for all indicators, if you look at this, this is the series by Jim Markmann when he was at UCLA.  The primary transplantation has about 83%, 74%, and 68% survival of 10 years out after a transplant.  In re-transplant patients, initial re-transplant 63% survival and goes about 45% 10 years out. 

In other words, it does not matter how you look at it.  Re-transplantation looks bad.  But, there are some subgroups within the re-transplant population that may do well.  Who are these? I will attempt to define that.  This was match analysis and he looked at the 150 patients that he picked up and he matched them in all criteria, age, sex, urgency, and so forth, and re-transplantation itself was different.  So, there is about a drop of about 30% in survival in match pair analysis.  Who does better under re-transplants?  The pediatric recipients do and almost in every paper that came out that compared the results in adults versus pediatric, kids when re-transplanted always have a better survival.  The paper by Dr. Byers Shaw and Dr. Patrick Wood showed a 100% survival in re-transplanted kids, granted these were early re-transplants.  So, in the pediatric population, you are getting about 70% survival in re-transplants and in adults, it drops to about 50%.  This is no different from what Dr. Byers Shaw and Wisconsin papers have shown about 10 years before that.  So, what are we doing?  Are we re-inventing the wheel? And in someway, we are.  And it comes back again when we started classifying the patients according to UNOS status.  The patients are sick, UNOS status I patients do worse than patients who are UNOS status II or UNOS status III.  The sicker the patient, the worse the results.  Well, we have known that for about 10 years.  So, what is new?  What is new is that we have attempted on many occasions doing 2, 3, 4, or 5 transplants.  And this curve is from Jim Markmann and obviously the numbers of the patients are very small here.  I don’t want to leave the impression that we advocate three or four transplants for recipients.  In the pediatric patient may be considered a third, but for most purposes, after the second transplant, your survival really in about one year drops to about 20% or less, three transplants, four or five.  Three and four and five re-transplantation patients should be truly discouraged at the present point.  If we have some discussion, we should probably discuss only re-transplant. 

So, up till now, when I was talking, I tended to mesh in a little bit early re-transplants like the PNF’s and HAT’s and late re-transplant with the recurrence of hepatitis C and it is tough sometimes to *tease those things out with when the papers come out.  But that was a good paper that came out from Pittsburgh and they looked at the risk of this.  The probability of failure of the graft based on the days of the transplant, and it shows here that if you re-transplant somebody in the first 7-8 days after a transplant, in other words the PNF’s and HAT’s, your probability of failure is small. 

In other words, you are going to get good success.  If you attempt to re-transplant somebody in the first month, you know, 10 days to about 40-50 days out, your probability of failure is going to be very high and then the probability of failure goes down and then it flattens out.  So, the recurrent transplantation does suggest that re-transplantation for recurrent hepatitis C a year out has probably the same risk for re-transplantation of somebody for the PNF, for example 10-15 days out of a transplant.  Is that true? Does that hold?  And look at other papers, exactly the same paper, you know, this was from Pittsburgh on the West Coast.  This is the paper that followed about three years later.  And, again, if you transplant somebody in the first 8 days, you have a lower chance of survival.  If you transplant somebody 8-30 days out, it gives you the lowest chance of survival after re-transplant and re-transplantation after 30 days need chronic transplants.  These probably have the best chance of being alive, and this really blew my mind because I always thought PNF’s are okay; two to three days after that, I put the patient, the patient goes home.  We are not running that risk.  The data says “no.”  The data says that your best chances of having a good survival is 30 days out or a year out of a transplant, and the worst is between 8-30 days.  Does that hold water? Yes, it does.  That is another paper that came from New England. Roger Genkins and his group showed that very easily, the percent survival.  If you re-transplant somebody from 0 to 3 days after a transplant, you get about 60% survival.  Re-transplantation between 30-40 days have the worst survival and then your expected survival goes up.  If you re-transplant somebody after a year out, you really get good 80% chance of being alive, but how come?  Because when we go with recurrent hepatitis C, we re-transplant those patients, they don’t do well.  What’s going on here and what‘s going on here is probably the condition of the patients.

And I will get to this and how sick the patient is before the transplant.  And that is the key issue for the success of the transplant.  But I think the paper didn’t stop at saying that the worst survival is about 8-30 days after a transplantation.  They went on and asked a very critical question.  Which is what is the impact of re-transplantation on deaths of the patients on the waiting list and is it useful or not, and how many, what’s our percent of re-transplants?  And it is very clear, they looked here and that survival of patients with primary transplants that required the second transplant and actually re-transplantation gave primary OLT recipients an added benefit of survival up to about a rate of 35% re-transplantations.  If your rate of re-transplantation was higher, then you really start seeing worst death.  So, re-transplantation effectively is important because it gives the primary OLT candidate a better chance of survival.  But, it does take away livers from the wait list, not too much though, it drops slightly, and increases the mortality on the waiting list a little bit, but when it reaches a certain threshold, the mortality really increases.  In other words, what he is saying is that re-transplantation in a controlled fashion at a certain percentage, does gave benefit to the primary OLT recipient.  The best survival to the whole population actually is achieved by 0 re-transplantation and that is very important thought to keep in our minds as we go along.  Is re-transplantation a good procedure to do?  Is it costing us a lot or is it costing us less? And the answer is, it is costing us a bundle.  The mean hospitalization doubles.  The mean of your stay is about 10 times higher for a re-transplant than the primary transplant.  The cost of charges is almost 300% more.  If this was costing us $250,000 seven or eight years ago, it can go up to $500,000 to $750,000 for a re-transplant case.  Really, today we ought to think of outcomes, not just the patient and graft survival but also in terms of cost analysis and cost-benefit analysis. 

    

So, I come to the question that really, you know, probably got that lecture in people’s mind or ask me to talk about it is re-transplantation in hepatitis C.  What do we know about re-transplantation with hepatitis C.  Actually, very, very little.  Why are we so worried about re-transplantation with hepatitis C, because all the papers tell us that 8% to 31% of patients will develop recurrence in 5 to 7 years and a good proportion of them, about 10% a year will develop cirrhosis.  There is a graft failure in 10% of the patients by the 5th year and therefore you are going to see an increased requirement of re-transplantation.  So, all this predicts an increased incidence or at least increased requirements in re-transplants in the long term and everybody is, look, we are holding our breath, we are holding our breath, and we want to see want is going to happen, but I have to tell you that most of the re-transplants in patients with hepatitis C are not done because of recurrent hepatitis C, they are mostly done because of PNF’s and grafts failures and so forth.  That is the paper by Hebo Rosen when he was at UCLA and he looked at the causes of re-transplantation.  Only 4% of the patients underwent re-transplantation for recurrent hepatitis C.  So, what is going on?  What really is going on, came about in the recent paper that came from Nebraska and they were able to show binary numbers going into the UNOS registry.  Re-transplantation of patients with hepatitis C is actually if anything, it is steady and with some decline along the time.  So, from 1997, there is a little increase, and from then onwards, there is no increase in the percent of patients with hepatitis C undergoing re-transplantation.  And sometime you have to ask yourself, is it perception or is it reality?  The reality is the hepatitis C recipients like every other group have okay results or reasonably good results.  You know, after one transplant, those who would require re-transplants, would have a lower survival and the numbers are no different from transplantation for other indications.  The patient survival with one transplant is 85%, 81%, and 75% in five years.  Re-transplanted patients for any cause, whether it is recurrent hepatitis C, PNF, or HATs, it is about 63% to 58%.  When we looked at our data of re-transplantation in patients with hepatitis C, is it different between hepatitis C and non hepatitis C patients.  And we looked at also the general UNOS and there were no significant changes or differences, this was in 1997.  In re-transplantation for hepatitis C, for recurrent hepatitis C, or transplantation for hepatitis C patients. All the numbers were the same and the most critical factor that determined the survival of those patients were how sick they were before going into the transplants, into re-transplants.  The numbers are small, but again, a lot of series have some numbers, but they are all small.  Those patients that underwent re-transplantation for recurrent hepatitis C, as non-urgent recipients, did extremely well and about three years out, they had a survival rate of about 85%-90%.  Those patients that were transplanted as urgent UNOS patients when their bilirubin was 30 and creatinine was 5, they really did very poorly.  Having said that, I will have to tell you that at least two other papers that said that re-transplantation for recurrent hepatitis C has worse results.  Where are those two papers?  This paper actually was from Mount Sinai and they can tell you that you know, if you re-transplant somebody with recurrent hepatitis C, they have poor survival than re-transplantation for all other indications.  They selected those patients who underwent re-transplantation in 90 days after the initial transplants, so they can exclude the acute causes.  So, read, recurrent hepatitis C has a worse survival compared to non hepatitis C, that is the Mount Sinai experience, but this difference is not significant.  And when they went to look at the fact that predicted survival, it was the serum creatinine, the age of the recipient, the number of blood products, and all those things correlated with how sick the recipient was before getting a re-transplant. 

The question is, are we waiting too long for those patients before we re-transplant them and most of the deaths in that series occurred in the first 90 days and not because of recurrence of hepatitis C, only one death came because of recurrent hepatitis C about a year-and-a-half out after re-transplant.

Hebo Rosen went and said, I am going to look at this question in the UNOS database and he came out with that paper which actually was discussed widely and he said that re-transplant in hepatitis C recipients have worst outcomes, 57% and 54% in five years.  Re-transplantation in non hepatitis C recipients have better outcomes.  But, again, on multifactorial analysis, he found that it was the serum bilirubin and serum creatinine that made the difference and not the recurrence of hepatitis C.  This question was taken actually again by the group in *Omaha and they asked the question, why we are getting so many different results when we look at the UNOS bases and single center experiences.  Does re-transplantation for recurrent hepatitis C, is it different from non hepatitis C patients or not, and here is the result.  Re-transplantation based on the UNOS data for hepatitis C gives us a survival of 61% and 45% in one and five years.  It was similar to re-transplantation for all other indications with two exceptions.  Hepatitis B patients did better after re-transplantation and patients with autoimmune hepatitis did better after re-transplantation.  The results of re-transplantation for hepatitis C was equivalent to all other indications.  So, what does that tell us?  It tells us really that hepatitis C or re-transplantation of hepatitis C, the results are not as bad as we thought they were.  They have another question, how sick the recipient, does the MELD predict to us survival after re-transplant and the answer is “yes.”  There is correlation, but the correlation is perfect and again this is the paper from Nebraska.  If you re-transplant somebody with MELD score less than 10, their survival is excellent.  If the MELD score starts going to about 21 to 25, the survival drops and if you draw a line here, if you re-transplant somebody with MELD greater than 25, their survival at 1 or 5 years is less than 60%.  What does that mean?  It means that re-transplantation of a non-sick recipient would give you good results, both short and in the long term, much better than when you wait on those patients for a longer time. 

So, can we count only on the MELD to tell us whether we are going to get good outcomes or not.  So, I looked up a couple of other papers.  One of them was from Pittsburgh.  And you can see here in the Pittsburgh series, they included donor age, the donor gender, the recipient age, mechanical ventilation preoperatively, creatinine, bilirubin, and immunosuppression.  So, the factor is that predicted by the MELD are here.  But, there are other factors that relate to donor organ and the recipient that also predicts survivability.  And this is the same thing from the Markmann series from UCLA, the MELD can predict and weighs on the outcome, but there are also other factors like the age group of the donor and the recipient that may weigh heavily on the survival after.  So, what we try to do at UCLA is to come up with a model that is all inclusive, to be able to tell us accurately whether that patient will survive or not.  And the factors we found was the donor age, the recipient age, the recipient creatinine, the recipient bilirubin, the protime, all the factors are on the MELD.  However, the length of the cold ischemia time did make a difference, the length of warm ischemia time was important and whether the patient had the re-transplant or not.  How does this model hold?  This model can give us five, you know, we can stratify the patients based on those criteria into five quintiles.  The lowest quintile, the patient really has horrible. 

There are always 20% of the patients have horrible survival and I have to tell you that most of those patients were the ones that underwent re-transplantation.  If we look at that model, the model predicted survival accurately.  If you compare the risk predicted by the model compared to the observed survival in the first, third, and fifth quintiles.

In summary, if you classify the patients into five categories, five being the highest risk, this is the model predicted risk of deaths versus observed risk of deaths, and it is identical at every stage.  So, what does all that mean?  And it means that we can predict exactly the death or the survival of the recipient based on the MELD criteria, in addition to the age of the donor and the age of the recipient.  For example, if you look here, a recipient who is 20 years of age, gets a 50-year-old donor and his MELD is 10, and his survival is going to be about 89%.  In the opposite spectrum of the curve, the recipient who is 70 years of age, gets a 50-year-old recipient for the re-transplant.  If his MELD is 15, he has one year survival of 60%, and horrible survival if his MELD gets worse.  So, the question is where do we draw the line and that is a very important answerable question.  You consider survival of 60% or worse, is this hard to draw the line and we have always struggled with that in re-transplantation.  And the struggle is between two principles, the urgency of need or justice, should you re-transplant patients regardless of how sick they are, regardless of the outcome, or the efficiency of organ use, which is the efficacy for scarce organ resource.  And I looked a lot and there was one paper that was written many years ago and the paper’s title was very challenging, and what it said, it talked about re-transplantation, the title of the paper was Rationing Failure.  The ethical lessons of re-transplantation of scarce vital organs, and after about eight pages reading through this paper, I was more confused, you know, at the end of it, more than the beginning, and it basically keeps going back and forth about the two principles.  To turn a dying patient away because of a lower chance of survival violates our duty to help the most urgently ill patients.  That is the justice, but if we ignore our duty to distribute scarce organ resource and ways that increase the benefits, and that is the question of benefits or outcomes.  And that is a critical question, that how can we strike the balance between both. 

I will give you three or four scenarios and I will end up after this slide to see what would you do.  One easy way is saying we are not going to be transplanting anybody because if we don’t, then we are really getting most benefit.  But, this way, we are really not fulfilling our obligation to a dying patient.  So, we have to do the re-transplantation.  So, the simple thing is to go and say, what is the final MELD score and the Nebraska paper suggested that a MELD score of 20 is excellent.  If the patient has MELD score of above 20, we should not re-transplant him.  However, we know that MELD alone cannot do it.  You get a very sick patient with a MELD score of 40.  If you give him a 16-year-old liver, he has an 80% chance of survival, so you cannot use the MELD alone.  So, what can we do?  We should re-transplant the patients before they get too sick, in other words, what we do with *HCC, we should apply for re-transplantation, why treat them differently.  If the patient is going to be a re-transplant candidate, give him 20 additional points, so he gets transplanted at the lower biological MELD than the primary transplant, or we come and say, no, we are going to adopt an outcomes model for re-transplantation. 

If we predict a good outcome for that patient, then we re-transplant him, but this really ethically also unacceptable because we are holding the re-OLT candidates to the principle of outcome while we are transplanting the primary OLT candidates based on the prevention of deaths. 

So, anyway you look at it, it is a dilemma.  And I will leave you with those talks and basically re-transplantation today remains an issue, as it was about 15 years ago.  We continue to see poor survival outcomes and increased utilization.  The results of re-transplantation in hepatitis C patients seemingly is worse, but in some basis, it is equivalent to other non hepatitis C patients.  The high MELD scores correlate with poor outcomes and the cutoff that is suggested by the Nebraska paper, which is an excellent study, is about 20.  There is an urgent need to balance urgency and efficacy in distribution of organs to re-transplant recipients, but don’t ask me how we can do that.

 

 

 

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