Good afternoon, everybody, and thanks for staying on this Friday. So I'll be following up on some of Dean's comments regarding CRT and PLEX, and we'll be talking about albumin dialysis as well. So these are my disclosures. I'm a consultant for Baxter that's involved with the Mars albumin dialysis system. So from an outline standpoint, we'll, number one, review the rationale for the need for thinking about extracorporeal liver support in 2023, and I'll use the acronym ECLS. Why do we need to think about these systems? And then we'll get into discussing briefly the goals of these systems and the two forms of liver failure. You've heard a lot about acute liver failure, and we'll extend the conversation to acute on chronic liver failure. And then we'll get into some of the details, the current modalities of ECLS systems, specifically albumin dialysis and building on CRT plasma exchange, and then finally, a few thoughts about where this field could be going. So let's talk about rationale for ECLS systems. Why do we need these? So this is data from the U.S. transplant database, end of 2022, and I show you this data to highlight the tremendous discrepancy between the number of patients awaiting transplant, the wait list, and the number of organs that are available. And so you can see there's a big mismatch between the wait list and the number of transplants. And so because of this supply-demand mismatch, you have a lot of patients dying on the wait list. And the other staggering piece of data is that we're losing almost 3,000 patients that are deemed too sick to transplant, or they die on the wait list because of the multi-organ system failure, especially in ACLF. So as you look at this, and I'm sure those of you in transplant centers are seeing this as a rising meld at the time of transplant. So imagine you're a sick cirrhotic patient in multi-organ failure that you're trying to bridge to transplantation. So as you think about the scenario, this is where I think ECLS systems can be very useful, because you need strategies to either, A, facilitate hepatic recovery, and that in particular will be important for acute liver failure, as Dr. Garbel has highlighted, there's a lot of potential for reversibility back to normal function, or, as we see in ACLF, stabilizing that acute hepatic dysfunction, whether it's due to an infection, SBP, hepatorenal syndrome, as you try to stabilize that sick patient and hopefully bridge them to a liver transplant, which is lifesaving. So this is where I think ECLS systems can be very helpful as you're trying to achieve goal A or goal B with respect to managing these patients. All right, so how would any of these systems work? So let's say you have a normal liver function, you have an acute insult. It could be ALF, it could be ACLF, and then you have the accumulation of certain hepatic-specific toxins, and we'll just, we'll dissect this out a bit more. And a couple of negative downstream effects from these toxins, number one, they can induce multi-organ system failure, and those of you who take care of these patients are quite familiar with hepatic encephalopathy, distributor shock, HRS-AKI. So as these number of organ system derangements start adding up, that worsens the mortality in these patients due to multi-organ system failure. The second negative effect is the impairment of potential hepatic regeneration, and this in particular becomes important in acute liver failure, but also applies to ACLF as well. So if you were to come along and use an ECLS system to extract these hepatic-specific toxins, you can have a dual benefit as far as mitigating multi-organ system failure, thereby improving survival, even transplant fee survival, and also potentially enhancing intrinsic hepatic regeneration. And then as Dean mentioned, if you couple this with aggressive standard of care management, you can really make a difference in the outcome of these patients. Let's move on to ECLS categories. So broadly speaking, two forms, artificial liver support, i.e. there's no hepatocytes in the extracorporeal circuit. The mechanism here is very similar to renal dialysis, detoxification. And so here, this is where we'll focus most of our attention on. Number one is albumin dialysis, and we'll speak about the molecular adsorbent recirculating system or the MARS system. Number two is plasma exchange. You've already heard briefly about that from Dean, and finally, high-dose CRT. So we'll focus... So those are examples of artificial liver support. The other category, which is sort of the holy grail, is barred artificial liver support. And here you have hepatocytes incorporated into the extracorporeal circuit, and the previous few failed trials have included human cell lines and porcine cell lines. But here you're trying to mimic comprehensive hepatic function, not just detoxification, but also synthesis. You can make albumin. You can make coagulation factors. So this is currently... We have not been successful in hitting this target yet, but there's a lot of research going into this field. And a couple of examples here, some of you are familiar with the ELAD trial, which is a human hepatoblastoma cell line, which is a negative study. This is an older porcine study as well. And the few RCTs in this field have been negative to date. And I think a couple of the lessons we've learned from these experiences, it is hard to mimic hepatic function outside the body because it's so complex. And in particular, when you try to grow cells in a column outside the body, number one, it's hard to maintain cell viability for a sufficient period of time, for example, five days, so that it can support the failing liver. And number two, as you grow these cells outside the body, they seem to lose some of their cell functions, essential cell functions. So for example, the ELAD cell line lost its ability to fix ammonia, which is a problem, especially in acute liver failure. So that's sort of the extent of the bioartificial domain that I'll address in this talk just for the sake of time, but it is a work in progress, if you will. All right, so let's sort of zoom into MARS. So the principles of MARS is as follows. So when you think about albumin as a critical care provider, you think about it as a volume expander in shock that's refractory to crystalloids, for example. But in addition to that volume expansion function, the other important thing of albumin is it can bind certain toxins, and specifically those hepatic-specific toxins. In liver failure, you also have sort of dysfunctional albumin. In addition to quantitative defects, you have the cirrhotic patient with albumin of two. Even that residual albumin is actually functionally deficient from a qualitative standpoint. The binding sites are not working. So you have sort of a double whammy as far as the albumin molecule working in a sick liver patient. So because of the dysfunctional albumin, it makes it mechanistically attractive. Think about using extrinsic albumin to compensate for the defect of intrinsic albumin. And therein lies the mechanism of action for MARS. So just draw your attention to this diagram here. This is just a snapshot of the dialysis membrane, of the MARS dialysis membrane. So this is the membrane itself. Here's the patient's plasma, and here's the dialysate. So as you contrast this with CRT, a couple of differences. Number one, you change the dialysate from a crystalloid solution or aqueous solution to a 16% albumin solution. And you suddenly create a diffusion gradient between the patient's plasma and the dialysate with respect to specific albumin-bound toxins. The second thing you do is you increase the pore size compared to CRT in such a way that in addition to these circular, low molecular weight substances like potassium, BUN, creatinine, you extract a second class of toxins, these triangular toxins, if you will, that are slightly larger middle molecular weight substances that will not come off with CRT and that are specifically albumin-bound that can now come off with the MARS circuit because you change the dialysate to albumin and you've increased the pore size to now be able to extract a second class of toxins. So that in a nutshell is sort of the mechanism of action of how the MARS membrane works and how it differs from CRT. So this is an interesting diagram that contrasts and highlights what MARS can remove. On the right are water-soluble substances that will come off with CRT, so you recognize urea, creatinine, interestingly, ammonia is here as well. On the left is a host of molecules that are albumin-bound that will not come off with CRT but now can come out with the MARS membrane for the reasons we spoke about. And just to draw your attention to a couple of these molecules, endogenous benzodiazepines is a class of molecules that we invoke as to why MARS is very effective in reversing refractory hepatic encephalopathy and cirrhosis. There's RCT data for that. Bilirubin, so we've actually used MARS for severe cholestatic drug-induced liver injury from antibiotics, from herbal medications, and so that's another example. And then there is some data regarding the reversal of shock in some of these patients and the invoked mechanism is extraction of nitric oxide. So just to put this in a circuit, this is regular CRT as you all know, it's a single membrane, aqueous green dialysate, removal of aqueous toxins, so water-soluble toxins. This is the MARS membrane. So just to walk you through this, the first column is what I've blown up for you. Here's your albumin dialysate. At this column, you have the extraction of both water-soluble and albumin-bound toxins, so two classes of toxins coming out of the column. And then you, and this albumin dialysate itself then gets cleansed sequentially. It goes to a regular CRT column, which removes the water-soluble toxins. And then what's left here are the specific triangular albumin-bound toxins that then sequentially pass through a charcoal column and an ion exchange column. And the rationale here is that by the time the albumin comes out of here, the binding sites are cleansed and it goes and sees the patient's blood again. And that's why it's called a recirculating system. Few logistics, it's about eight hours of therapy. These two cartridges need to be changed every eight hours, so that's sort of the eight hours of MARS therapy. And we typically do five sessions. We have actually developed the bandwidth at our center to do it continuously to truly mimic CRT. The albumin dialysate is a quick mixture of 25% albumin and saline. The blood flow is even lower than CRT. So practically speaking, if somebody in shock is on CRT, they'll easily tolerate the MARS circuit from a hemodynamic standpoint. And then anticoagulation, the various strategies for this, we have, as a center, we have started with no anticoagulation. And if we need anticoagulation, we use regional citrate anticoagulation to avoid systemic heparin. So let's move on to evidence regarding MARS efficacy. Again, it's not something that's used in many centers, but there is a lot of it is observational studies and there's improvement in jaundice and pruritus. When we have done this as well for drug-induced liver injury. There's some data regarding hemodynamic improvement because of nitric oxide scavenging. This is something I want to underline is the reversal of refractory hepatic encephalopathy in cirrhosis slash ACLF. And there's RCT level data to support this as well. And then this study coming out of a retrospective analysis from Europe many years ago, looked at very short-term mortality, 14-day survival in a cohort of ACLF. And you can see it showed that MARS compared to standard of care made a big difference in regard to short-term survival. And this raised the conversation whether MARS should be used as a BRCA transplant, especially since our patients with ACLF are getting sicker and sicker as they await transplantation. So this has started a conversation in some centers regarding using MARS as a BRCA transplant. From an RCT level data, not much data, but a few, just to summarize that, few RCTs in the field comparing MARS to standard of care have not yet demonstrated this transplant free survival benefit in both ACLF and ALF. And that's one of the critiques of the MARS circuit. But as I mentioned, if you look at non-survival endpoints, like reversal of organ dysfunction and specifically neurologic dysfunction, there's two RCTs that actually show reversal of severe hepatic encephalopathy. And this has become one of the backbones of indications at our center. This is my personal editorial that moving forward, that we may need to think about defining MARS efficacy as a BRCA transplant rather than looking at transplant free survival only. So based on all of that, how are we using it at our center? We used to use it a lot in ALF, but based on the CRT data that you saw, we've moved away from using MARS in ALF and using purely hydroCRT. We are experimenting with BRCA transplant in ACLF. This is the backbone of indications of refractory HE in decompensated chronic liver disease slash ACLF, including preventing intubation or facilitating extubation. We've used it for many cases of cholestatic drug-induced liver injury. We're talking about biter wounds of 50, 60 that normally will not reverse with supportive care. This is more of a homeopathic indication, refractory itching in PSC or PBC. And then this is the other thing that we are experimenting with is alcoholic hepatitis. As some of you may know, there is a shift in the paradigm as far as transplanting fresh alcoholic hepatitis. So we are thinking about using MARS as a bridge to transplant in this specific patient population. And then recently, just for any of those interested from a nephrology standpoint, we've actually recently written about reversing mild cast nephropathy in a severe case of severe jaundice-induced AKI. Switching gears from MARS to hydroCRT, again, for the sake of time, I'll zip through this since Dean has already spoken about this, but this is using hydroCRT to reverse severe hyperammonemia in ALF and specifically bringing the ammonia down to 150. And you can argue in the younger brain, even less than 100. And as Dean has already spoken about, there is accumulating data regarding the utility of CRT and hydroCRT in reversing hyperammonemia and having both survival benefits and neurologic benefits. And then for those of you who were there in the session for our liver guidelines, we've actually suggested that in patients with acute liver failure, CRT should be, or hyperammonemia should be an independent indication for CRT apart from all the other indications that we usually use CRT for. Moving on to PLEX, the rationale for PLEX is as follows. In the setting of acute liver failure, there is a cytokine storm because of severe hepatic necrosis, and that can then cause multi-organ system failure from a neurologic standpoint, from acute lung injury standpoint, renal dysfunction. So it makes it mechanistically attractive to use plasma exchange as a cytokine sink in order to mitigate the multi-organ system failure. And so this is, again, I'll capsulize this slide as well, but this is the RCT that Dean had showed in the previous talk about this is the first instance of an RCT showing a transplant-free survival benefit in an ALF cohort. And this is a lot of FFP. You need a very supportive blood bank. This is eight to 12 liters of FFP with a mean of two to three sessions. And this is the transplant-free survival data that Dean had already shared with you that showed benefit. And the one sort of amazing thing every time we do this is that there's a dramatic improvement in mean natural pressure, especially after session one, which supports the theory that this is acting like a cytokine sink and mitigating the hypotension that can cause multi-organ system failure. And just to sort of also mention that there's a more recent study that scaled down to regular volume plasma exchange and demonstrated that it maintained the same efficacy. And so what we've done at our center is scaled down to regular volume plasma exchange for ALF as well and avoiding excessive FFP and all the negative side of potential side effects of FFP. Let me just sort of share this one last sort of a case with you. This is one of those first times we co-administered PLEX with CRT. And this was actually a few years ago, a 30-year-old female who actually was a Korean Airlines flight attendant passing through Atlanta, found down in a hotel room with severe herbal hepatotoxicity. It was a weight loss supplement. And she presented to a community, sort of a county hospital in extremis. So grade four hepatic encephalopathy, ammonia 500, intubated on arrival, severe full pressure shock, liver was not doing well, INR was 7, pH was 6.9, so there's no lactic acid clearance. So we transferred her to our center and we started high-dose CRT to target the metabolic acidosis and target the hyperammonemia. For the first time, we co-initiated a plasma exchange to a second catheter, it's good to be 30 years old, I guess. And she tolerated pulling blood from two circuits and within 24 hours, ammonia is down to 150. We corrected the metabolic acidosis and this is what is remarkable. Dramatic improvement in shock, broken down to norepi of 0.05. And she was on max norepi, epi, vaso, angiotensin II, methylene blue. And the cool thing about this case is we actually bridged her transplant. Within 48 hours, once we brought her into the window for transplantation, we actually transplanted her. She's now five years out from transplant back in Seoul. So when you think about this phenotype of a patient, prior to the CRT plex strategy, that patient would not have survived. They would have predictably herniated. But CRT has been a game changer for us as far as being able to stabilize hyperammonemia and neurologic dysfunction. And then the plex is a great add-on with respect to stabilizing the hemodynamics. So just to finish up and to think about future directions, number one is to highlight the efficacy of aluminum dialysis and the treatment of refractory hepatic encephalopathy and decompensated cirrhosis. The role of high-dose CRT in the management of hyperammonemia in acetylobephalia. The emerging role of plex in acetylobephalia, including hemodynamic stabilization. In fact, there is a clinical trial right now looking at ACLF using albumin plasma exchange as well. I've shared with you the strategy of co-administration of plex with CRT may provide synergistic benefit. And then these are just future areas of investigation, including bioartificial liver support and timing of plasma exchange. And then finally, as I've mentioned, I think as we think about the future, in addition to looking at survival benefit as your definition of efficacy, we should look at the benefit of these systems as a bridge to transplant. Thank you for your attention.

extracorporeal liver support

albumin dialysis

MARS system

hepatic encephalopathy

plasma exchange