Okay, thank you for the organizers for inviting me to give this talk. I think the SLK is a really interesting topic and really sort of evolving as we speak. It's one of those situations right now that the title of the talk is Evolving Indications, but we actually have specific criteria in the United States for SLK that I think were a positive step forward. But I will provide some data and some commentary that I think there are certain situations where SLK I think is indicated where the patient is not a candidate or not yet, and there's other situations where the patient meets criteria for SLK by the U.S. criteria, but you have to kind of take a step back and say, well, while they meet criteria, does that mean we have to do a simultaneous liver-kidney? And so I still think this issue, despite having criteria, is a hot topic, well debated, well contested, and I want to give you some thoughts about where I think the field needs to go further. A lot of people say, well, we have criteria, why do we even need to discuss this? I don't think we have all the answers. I think we need to get more answers moving forward. And so this is a little cartoon, it's kind of really sort of telling, SLK is if you don't do it and the patient ends up on dialysis and very ill and may not survive, you're damned. And if you do do it, the kidney transplant community is damning us as liver transplant people, which I totally understand. And so we're still forced into this box. I think we've gotten better with criteria. But why are we even talking about this? Well, I'm just going to show old data because this is pre-MELD, but really what the early 2000s had shown that if you have a patient who's post-liver transplant on hemodialysis, their survival is infinitely better if they get a kidney transplant compared to staying on dialysis. And this is just any time after liver transplant. You can see this can be years afterwards. I think we know this, that someone has renal failure and they're five, six years out from transplant. It happens in a certain percentage of the patient population. They do really well with a kidney transplant late on. I think the real question is the early situation. But that sort of set the stage. So the early situation is we do know that if you're on dialysis after a transplant, your survival is infinitely worse than having a combined liver-kidney transplant. And so it really comes down to a survival issue here. Can we resolve that with doing a simultaneous liver-kidney compared to a liver transplant recipient who has kidney dysfunction but does not get a simultaneous liver-kidney? Well, I think if you look at the data, we'll talk about the problems with the data. But if you do any kind of head-to-head comparison, which again is difficult because they're not randomized trials, they're looking at a mixture of populations, you still see that the survival is the worst in people who have a deceased donor liver transplant who are on renal replacement versus or even have a creatinine greater than two going into transplant where the survival of a liver-kidney approximates more of deceased donor without any or mild kidney dysfunction. And then we talk about, well, how long on dialysis perhaps or acute kidney injury the patients need to be to have this benefit. In fact, even patients who are not on dialysis that have kidney dysfunction seem to benefit from a simultaneous liver-kidney transplant versus liver transplant alone. Again, the problem here, and this is the real argument, is that a lot of this data comes from pre-meld. But I don't think, to be honest, that this is too much different than the data currently. But there are really no one-to-one comparison randomized trials. So it's really hard to match patients who would go in different directions and really compare their outcomes. But there is a strong feeling that in SLK, better survival compared to someone with significant pre-transplant renal dysfunction. Of course, these data are a mixture of patients with different types of pre-transplant renal dysfunction, time on dialysis, practices in different immunosuppression regimens, which I think is also important. The other thing is the assumption is that it's sort of the other side of things is that these patients actually really needed the kidney transplant, and that's why they're doing better. I'll show you some data a little bit later that probably a good percentage of them. I mean, I think clinicians guess it right a reasonable amount of time, but not always. So where did this lead to? It's sort of before all of this, it was the center could just decide to put in a kidney transplant. It doesn't go on your liver transplant outcomes. There were certainly people who needed it, but others probably didn't need simultaneous liver-kidney. The liver transplant community wanted to protect their patient from post-transplant death, so erring on the side of doing an SLK. Unfortunately, this was taking away kidneys from the kidney transplant list. So the kidney and immunos got together and created criteria based on best available evidence, and so really how this follows is you have... if you have acute kidney injury that's prolonged for more than six weeks of a GFR less than 25, and then it can include dialysis or no dialysis, it's greater than six weeks, and you have to actually measure it every week, which is pretty common. These are... it's part of the MELD score, but you have to measure it every week to say that it is continuous. Those patients are a candidate for an SLK. It means they're a candidate. You don't have to do the SLK, but they're a candidate. If you have chronic kidney disease, which was talked about earlier, estimated GFR of less than 60 for more than three months, and now your estimated GFR is less than 30, you are considered to have advanced CKD, and you can be a candidate for an SLK. But I will say this is actually where I think there can be some difficulty sometimes, and you need more input, obviously, from the team, the renal imaging. These patients have to be signed off by a transplant nephrologist that they are a candidate for a kidney, which I think is important. But you can imagine that someone has a dip in GFR six months ago. You could use that, you know, and they return, and now they have a dip again, and they can get a liver kidney. So it isn't a perfect system. Of course, metabolic diseases are rare, like hyperoxyluria, HUS. Now if the real backup here is if you guess wrong, or in this case, you're not a SLK candidate. Let's say you don't meet CKD criteria or prolonged AKI criteria, you get a liver transplant alone. Two months after the liver transplant, if you're on dialysis or your estimated GFR is less than 20, which is very advanced. Most of those patients are on dialysis or near dialysis. You can be prioritized on the kidney transplant list, and this is called CALD, kidney after liver transplant, or the safety net. So I'm going to talk a little bit about those, the issues with all of these. So the question is, have we got it right with these criteria? I think what was alluded to earlier, we know that these patients have poor, the patients who have low estimated GFR is probably actually an overestimate of their true renal function. There's really no adjustment for that in the AKI CKD definitions. We have to use estimated equations. These are how patients are followed. You certainly couldn't do a measured GFR every week for six weeks. It's just not feasible or practical. But there may be some situations where if you're wondering about chronic kidney disease and someone is stable, that you could get a better estimate. The available data suggests that with GFRs less than 40, the measured GFR is probably 10 points lower than the estimated GFR. But of course, that's not accounted for in this. And so these are some of the older data on this. You can see that the iothalamate GFR in the same patient is really a lot lower than the measures that are used by creatinine base, Cockroft-Gault, the MDRDs. And we know that since MELD has been around now nearly almost 20 years, we're seeing a lot more patients with kidney dysfunction, older patients, more muscle-wasted patients. So the current criteria are based on estimated GFR. And some have proposed to raise that estimated GFR a little bit higher to account for this discrepancy, but it hasn't happened yet. And one assumption is that while you do a simultaneous liver-kidney transplant and that the native kidney function may return in these patients. So this is an argument to do a liver transplant alone. And certainly with hepatorenal syndrome, if it's very acute, this may be the situation where there's real return of kidney function. Of course, there's calcineurin inhibitor on board that may affect this. But we had done a study looking at older UNOS criteria with renal scans with our SLK, and you can actually see how much GFR is coming from the native kidney versus the kidney transplant. And as you can see, it's only a small percentage of our group had native kidney function return, and most of the GFR was coming from the kidney transplant. If we looked at the older UNOS criteria, which were guidelines for SLK before we had formal criteria, as the GFR got worse, actually the prediction for renal recovery was not great within when we tested it on our patients, and we looked at the renal scan. So that's an issue. So one of the questions is, could we have some biomarkers that it was alluded to by the prior speakers that could help you... We do have these criteria now, but maybe somebody is a candidate for an SLK or just reaching candidacy. Could we use criteria to say they have reversible to only do a liver transplant alone versus to do an SLK? Certainly a combination of biomarkers may be helpful in differentiating HRS functional renal failure from structural. We have done two... We have two papers now with some data from our center and also from a validation study at Baylor, where we took samples from patients undergoing a liver transplant alone and measured their serum or plasma. We have a renal injury panel at the time of a liver transplant. And we found two markers that was validated in a model, osteopontin and TMP1, that are actually renal tubular regenerative proteins. And we found them much higher in patients who had reversible kidney injury compared to those who had irreversible. And we developed a model, so if you're younger than 58 years old, you don't have diabetes, and you have high osteopontin and TMP1 levels, your prediction of reversible renal injury at the time of a liver transplant alone is quite high. And so this actually may help centers if patients meet SLK criteria, or even if they don't, this might be something that we can study and research to see if we can modify our current models and our current criteria. So the next thing to bring up is, of course, we put a liver kidney in, and the feeling is sort of the coin flip. Well, you do an SLK, the kidney's going to do fine. And actually, mostly that's true, but the kidney is susceptible to immune-mediated injury, even with the placement of a simultaneous liver graft. So this is one of the questions when you're deciding between SLK and liver transplant alone. I think the feeling is, well, put the kidney in, you're not going to have a problem with the kidney. But in fact, the assumption really is that the liver, because it's tolerogenic, it's going to protect the kidney graft against antibody-mediated and acute cellular rejection. In fact, that may not necessarily be the case in some cases. So data from Baylor actually showed that acute antibody-mediated rejection was associated with class 2 DSA. If you have a class 2 DSA, you're at higher risk for antibody-mediated rejection with an SLK. And the renal allograft survival with class 2 DSA is worse. So these are just correlations. We did some work on looking at our SLK population and found that about 20% of patients who had an SLK, and we were starting to do some protocol kidney biopsies on these patients in this era, and now we're doing them regularly, we found that up to 20% have rejection of the kidney graft from a clinical perspective. I would say more than half of these are borderline rejection, but I think some of the transplant nephrologists feel that that's important. And those patients who had rejection of the kidney graft had worse outcomes of GFR in the long run. So I think there is something to be said here that the kidney is not totally protected. Now I think this has led to an increase in the interest in using more potent induction therapy, more akin to a kidney transplant in the liver kidney population. And you can see that increasing over time. This group did a nice study looking at UNOS data and comparing actually no induction therapy versus lighter induction IL-2 receptor antagonists versus antithymocyte globulin, which is more potent, and actually found that the antithymocyte globulin led to worse outcomes, and probably not related to the kidney, but more immunosuppression outcomes. But actually the IL-2 receptor antagonists trended towards slightly better than the no induction. And we wrote an editorial on this just claiming that I think patients who are maybe at higher immunological risk, maybe who have antibodies pre-transplant should get induction with IL-2 receptor antagonists. I think this really needs to be studied. So finally the safety net, let's say all else fails but you can't do an SLK, you're actually not a candidate for it but you're close to it, but you have this safety net and it's sort of I think a little bit of a misnomer because I think it has some holes in it. And so what this means again is that a recent liver transplant recipient, and this can be actually somebody who doesn't have any kidney dysfunction going into the transplant and has it afterwards. So actually they don't even have to have met SLK criteria, but most of these patients will be SLK or would not have met it before but sort of had some dysfunction going into the transplant. If you're two months to a year after the transplant, again your GFR is less than or equal to 20 or you're getting dialysis, you get prioritized on the kidney transplant list. I think this is certainly kind of a balance, right? I don't want to use the term quid pro quo, but I think it's kind of true between kidney and liver. And so this was sort of the kidney side saying we have this safety net and the issue is of course they may not survive the two months if you're on dialysis. Well I think some will say well that's not the kidney dysfunction, but certainly there's a contributor. The other thing is we really don't have data on kidney after liver transplant outcomes. I think some centers have done it. We will see more data with this new policy, but it still is the data, the existing data are not very robust and actually support some concerns with doing kidney after liver. There can be technical issues. You're re-immunosuppressing these patients once again and you actually probably have to really re-immunosuppress them because you have different liver, different kidney, different HLA. It's not the same as SLK. So just in conclusion, I think we have criteria but they're not perfect. I think we have to take the current criteria and really make the best decisions for our patients. But I think we can optimize it. The biomarkers, hopefully with development of these models, can help us predict patients to proceed or not with an SLK in those who meet criteria. It can be helpful because I think patients who meet criteria, not all of them need it still. And it can also be helpful for your post-transplant immunosuppression, post like renal sparing regimens to really be more aggressive or not aggressive on top of that. I think we need to do more studies. We really need more kidney after liver transplant data to really determine this safety net. How really is this really working? What are the outcomes, the rejection of the kidney, the survival? Is it really saving the patient's life? And we really need more immunosuppression studies, which are challenging to do in SLK because they're not high numbers. But certainly, I do think a select patient with SLK have higher risk for T cell mediated and antibody mediated rejection, probably need to be more optimized and moving forward. So questions maybe at the end. So thank you.

simultaneous liver-kidney transplant

patient criteria

kidney rejection

induction therapy

post-transplant outcomes