Thank you, and good afternoon. I do have disclosures that are relevant to this talk. I've served as an advisor and consultant to Malachrat Pharmaceuticals, specifically related to FDA approval of Terlopresin. We've seen this slide before today, and I won't spend a great deal of time on it, but the EASL practice guidelines and the ASLD, the American Association for the Study of Liver, are very similar. I think one point I want to make as we're starting to talk about our approach to these patients, and as I go through these slides, I'm going to spend a lot of time talking about the importance of recognizing these patients early and initiating therapy. All of the guidelines talk about withdrawal of diuretics and volume expansion for two days, but in the confirmed trial in the United States and in tertiary care facilities where a lot of you are working, these patients have been being treated and evaluated for several days. So when they show up on your door, if they've already been resuscitated, be thinking about that, and the two-day waiting period may not be always the best approach for initiating therapy for patients with hepatorenal syndrome. Again, this has always been a diagnosis of exclusion, so you're looking for other potential causes of acute kidney injury, and once that you've determined that a patient meets criteria for hepatorenal syndrome or acute kidney injury, HRS subtype, then it's time to start volume expansion and make sure that if they meet criteria for vasopressors and they're not responding with simple volume expansion and diuretic removal, that we advance to more aggressive therapies with vasopressors and albumin. Current ASLD and easel recommendations are again very similar, but now that terlopressin is more widely available and has now recently been approved in the United States and Canada, the treatment of choice for HRS AKI remains vasoconstrictors, and the preferred drug is terlopressin, either administered as an IV bolus or by continuous infusion, though in the United States, it does not have labeling for continuous infusion. In settings where terlopressin is not available, which now is far fewer areas geographically, norepinephrine can be given, and of course in the intensive care unit where many of you are working, that may be a reasonable choice at any time, and if neither can be administered, a trial of oral mitadrine or with octreotide can be considered, recognizing that there's really weak evidence supporting the usage of mitadrine plus octreotide, but it's been the agent that we've had available to us outside of the ICU in the United States and Canada, and it's what we've been using for a long time. Current US guidelines regarding the use of terlopressin, the American Association for the Study of Liver Disease states that terlopressin is the preferred drug, the American College of Gastroenterology suggests terlopressin, and in cases where it's either not available or not approved in an institution, for example, norepinephrine may be considered. When we're thinking about management and treatment of hepatorenal syndrome type acute kidney injury in liver patients, one of the things that we've seen from several studies across different groups is that the mean arterial blood pressure increase really drives our ability to reverse hepatorenal syndrome, and looking at the right panel of this slide, you can see these are only randomized controlled trials, but as you increase the mean arterial blood pressure by various increments, you have a more likely chance of reversing hepatorenal syndrome over the course of seven days of these trials, and if you know what the baseline creatinine is, you can also come up with a predicted MAP increase required to reverse hepatorenal syndrome. If you have not been around terlopressin before, if you're from the United States where it has not been available, a reminder about terlopressin, it's a synthetic vasopressin analog, it selectively has greater affinity for V1 receptors, and these are predominantly located in the smooth muscle cells of the arterial circulation of splanchnic vasculature. It reduces splanchnic blood inflow, and therefore portal pressures, and this is one of the things that we're aiming to achieve in patients with decompensated cirrhosis. It redistributes part of the intravascular volume to central circulation, and this is the real problem in patients with cirrhosis. They have volume everywhere, but not where you need it, which is in central circulation, feeding organs. Published literature provides evidence that terlopressin improves renal function in patients with hepatorenal syndrome, and you're gonna see the term hepatorenal syndrome still staggered through these slides because that was the term that was used in a lot of the randomized control trials, even though we have evolved the definition, as Ron previously pointed out. And terlopressin now is the standard of care for this condition in places where this drug is available. This is data from the Landmark Confirmed trial. This is the study that got terlopressin approved in the United States, and in the left panel, we're looking at the primary endpoint in this study, which was verified HRS reversal. This was a multi-component and somewhat stringent primary endpoint that included improvement of the serum creatinine to less than 1.5 grams per deciliter, excuse me, less than 1.5 on two milligrams per deciliter on two separate occasions measured at least two hours apart, and there was also a survival component in patients being free of renal replacement therapy. An alternative term used in some of the previous studies and also in secondary analysis within the confirmed trial is HRS reversal. This was a less stringent endpoint. It was a predefined endpoint, but it did not require two separate serum creatinine measurements of less than 1.5 milligrams per deciliter, and it did not require the survival or being free of renal replacement therapy. Again, in both of these definitions, both in verified HRS reversal and HRS reversal, there was a statistically significant improvement in reversal of HRS in patients treated with terlopressin as compared to those treated with placebo and albumin. Again, in the confirmed study, the cumulative percentage of renal replacement therapy through 90 days was overall less. It was statistically significant through day 14. This is sort of a theme that we see throughout patients being treated for hepatorenal syndrome. These drugs do improve renal function, but again, they do not improve long-term survival. The only thing that does that is liver transplantation or, if you're lucky, reversal of the underlying liver disease. In looking at patients specifically who were treated with terlopressin and then underwent liver transplantation, there was a statistically significant decrease in the patients requiring renal replacement therapy after liver transplant. So if you're working in a liver transplant center, this is an important finding because it decreases your costs and some of the resources required for treatment and management of patients after transplantation. Looking across several, excuse me, three different randomized control trials, looking at treatment of HRS with terlopressin versus placebo, we can see that both in the confirmed trial, OT0401, and the reverse trial, and in a pooled analysis of all three of these studies, there was a numerically significant decrease in the, excuse me, increase in the durability of HRS reversal. Again, the terminology here is HRS reversal, which is slightly different than what was used in the confirmed trial, which was verified HRS reversal, a more stringent multi-component primary endpoint. For an ICU audience, I really think we need to talk about the benefits of terlopressin as it relates to norepinephrine. When we look specifically at a study looking at patients only who were experiencing acute on chronic liver failure. So again, these are the sicker patients more likely to end up in the ICU. And this open label randomized control trial of consecutive ACLF patients with HRS type AKI greater than stage two, comparing terlopressin versus placebo, terlopressin versus norepinephrine plus albumin. Overall, there was a statistically significant improvement at three different time points in patients treated with terlopressin at HRS reversal as compared to norepinephrine. When we look at other studies, and that's the central portion of this figure, norepinephrine has proved to be non-inferior to terlopressin when being utilized for management of HRS. So terlopressin compared to placebo, clearly beneficial to use terlopressin. Terlopressin versus norepinephrine, and across several different studies, not much of a difference, and norepinephrine has proven to be non-inferior. When we look at anything compared to mitadrine plus octreotide, obviously norepinephrine and terlopressin are far superior to these agents. There's some other important considerations when talking about terlopressin versus norepinephrine. And for the liver community, this is one of the things that we're most excited about. And this is a major void in therapy that is hopefully gonna open up the door for treatment of patients outside of the intensive care unit. Norepinephrine typically requires central line placement and ICU level monitoring. There is at least one study performed in Stanford that demonstrated you could use norepinephrine in fixed doses outside of the ICU for HRS, but again, the vast majority of centers require norepinephrine to be given in the intensive care unit. Terlopressin may be given by bolus infusion in a peripheral line outside of the intensive care unit, and that's what makes this drug particularly attractive for management of hepatorenal syndrome, hoping to keep patients out of the intensive care unit and in a time when ICU beds are of a premium, hopefully preventing their placement in the ICU altogether. There are also significant cost considerations when you're talking about ICU versus floor treatment. However, terlopressin is significantly more expensive than norepinephrine. Few words about timing and special considerations in the intensive care unit. So again, looking at three different randomized control trials in the integrated intention-to-treat population, we can see that when you initiate treatment earlier, you're more likely to have HRS reversal, and this is one of the take-home points from this talk today is initiating treatment earlier is more likely to result in improvement. So in looking in the far left, patients who had a serum creatinine of 2.25 to less than three, you had a statistically significant improvement in HRS reversal. This held through in patients who had a serum creatinine between three and five, but once the serum creatinine goes beyond five, even though there was a numerically improvement in patient's response, this did not maintain statistical significance. And again, there's a limitation to this analysis. This is HRS reversal, which was a surrogate endpoint using a single serum creatinine measurement of less than 1.5 milligrams per deciliter, not the multi-component endpoint that was used in the confirmed trial, which garnered terlopressin approval. This also highlighted one of the limitations of use, so this will be in the package insert. Patients with a serum creatinine greater than five milligrams per deciliter are unlikely to experience clinical benefit, and therefore this is a population in which we do not recommend usage of terlopressin. To piggyback onto what Dr. Subramanian mentioned a while ago, I think all of us in the intensive care world realize the importance of urine output as it relates to renal function in patients with any type of acute illness. This was a study specifically looking at the importance of urine output in a series of patients admitted to the ICU with cirrhosis. This occurred in Pittsburgh. And patients are stratified on the basis of KDGO criteria, whether they had kidney injury stage three based on serum creatinine, but normal urine output, serum creatinine normal, but urine output criteria. And you can see that those two patients, those two groups of patients are very similar. Highlighting again the importance of urine output in this patient population, even though the liver guidelines do not use this yet. So in this specific study, there were 3,400 patients who had chronic liver disease evaluated in the ICU. And when using urine output criteria alone to identify AKI, there were 1,200 patients that were found to have stage two to three acute kidney injury that were not identified when using serum creatinine criteria alone. So for those of you in the ICU, don't give up on urine output. The liver community just hasn't quite caught up with us yet. Mentioning again the importance of terlopressin and some of the advantages this drug may give us, the unconfirmed trial in the United States, terlopressin was used outside of the intensive care unit 84% of the time and only 15.6% of the time was used in the intensive care unit. In those patients who were in the ICU, terlopressin was associated with a 50% reduction in ICU length of stay. And this is also, I think, an important consideration when we're talking about the benefits when we really analyze the costs associated with this new medication. The confirmed study did identify some important safety concerns, and these are highlighted in the package insert in the terlopressin packaging. And two that were particularly important were the development of circulatory overload and respiratory failure. The most common adverse events were abdominal pain, nausea, diarrhea, but respiratory failure, and this was as defined by the primary investigator at each site, so there was not a specific oxygen requirement nor PA2 that was required. But again, we saw a significant signal for patients that did have respiratory failure, and this has led to some specific package recommendations in the product labeling. So there are some very specific groups in whom we know that terlopressin and albumin administration is more likely to result in fluid overload and respiratory failure. These are patients, again, with a serum creatinine of greater than five milligrams per deciliter, patients with ACLF grade three, and we've seen previous slides that help you stage that, and patients with a clear evidence of vascular congestion or pulmonary vascular congestion at time of initiation. This is also in the package insert, and it's an area that's somewhat controversial in the liver transplant community. Remember that in the United States, organs are allocated on the basis of the MELD score, and serum creatinine is a major component of the MELD score calculation. So a patient with a high MELD score more likely to get transplanted earlier. So within some transplant programs, there's conversation about maybe we don't wanna be using in terlopressin in patients who are actively listed for transplant because this may lower their MELD score and thus decrease their risk of getting allocated an organ. This also resulted in this being mentioned in the package labeling, terlopressin-related adverse reactions such as respiratory failure or ischemia could potentially make a patient ineligible for liver transplantation if listed. And so this is one of the considerations as well. You don't wanna cause a patient something that may make a transplant team averse to performing a transplant. And so for patients with high prioritization for liver transplantation, high MELD score greater than 35, the benefits of terlopressin may not outweigh its risk. So this'll be a conversation for people within their transplant centers. So looking at the selection of appropriate patients for terlopressin, again, this is the intention to treat pooled analysis from three separate trials. Patients with ACLF grade three were much more likely to have adverse events than patients with lower grade ACLF and also patients with baseline serum creatinine of greater than or equal to five milligrams per deciliter more likely to have adverse events. So terlopressin should only be used in patients with creatinine less than five and ACLF grade less than three. Prior to, during treatment, patients must be monitored carefully for respiratory failure. The package labeling actually recommends continuous pulse oximetry for patients being treated with terlopressin. And risk factors that may predispose a patient for respiratory failure are hypoxia. So if a patient has oxygen saturations less than 90%, terlopressin should not be initiated if it's already present. And if it develops while on treatment, terlopressin should be discontinued. Similarly, patients with ACLF grade three, prior to initiation, terlopressin should not be used and should be avoided due to the significant risk of respiratory failure. If it develops during treatment, so you have progressive organ failures, avoid use and discontinue use. For patients that have evidence of intravascular volume overload, use with caution, reduce, discontinue usage of albumin or other fluids. You may want to consider judicious use of diuretics. And for patients that develop volume overload while on therapy, terlopressin should be discontinued and albumin and other fluid administration should be stopped. A couple points about this. So as I mentioned, terlopressin's been around for a long time. These respiratory events were not really identified in a lot of previous trials with terlopressin. During the confirmed trial, when respiratory failure occurred, had a median onset of five days and an average onset of 7.5 days. So these patients were receiving considerable amounts of albumin during this trial and this is one of the reasons I think that we saw some of these safety concerns. Dosing administration. If you're familiar with the trial data, the dosing is typically one milligram of terlopressin. United States labeling requirements because of the salt component required it to be labeled as terlopressin 0.85 milligrams. This is equivalent to the one milligram that was used in the trials and so a treatment dose is still going to be one vial. This is not a dose difference that was published in all of the randomized controlled trials. So for days one to three, the initial dose of terlopressin is 0.85 milligrams or one vial every six hours. The serum creatinine should be measured so you can use this as a comparison for response to therapy. On day four, the serum creatinine level should be compared to the baseline and if the serum creatinine is decreased greater than 30% from baseline, terlopressin may be continued at the same dose. If the serum creatinine is decreased by less than 30%, terlopressin may be increased to 1.7 milligrams or two vials every six hours and if the serum creatinine is not improved, it's either at or above the baseline value, discontinue further use. Terlopressin may be continued or should be continued until 24 hours after the patient achieves the second serum creatinine of less than 1.5 milligrams per deciliter. All of these topics usually result in the questions about when should we be using renal replacement therapy. This is going to be highly variable depending on your center and who you ask. Easel practice guidelines still recommend that renal replacement therapy should be considered on a case-by-case basis. Initiate if there's a reversible cause of liver failure in patients who are actively listed for transplantation. In a consensus meeting published in the United States in Journal of Hepatology, we recommended that in patients with evidence of worsening acute kidney injury, worsening volume overload despite diuretic therapy or worsening acid-base status, then renal replacement therapy should be continued. Again, I think this is really where's your patient at in the continuation of resuscitation. Are they arriving to your center already having failed aggressive therapy? We might be thinking about initiating renal replacement therapy much quicker. Liver transplantation remains the only definitive treatment for hepatorenal syndrome and AKI type HRS. Timely transplant is optimal for renal recovery and there are cases where we would consider simultaneous liver kidney transplantation if the acute kidney injury is persistent or sustained. This is defined by UNOS and OPTN as follows either one or both on dialysis at least once every seven days. The creatinine clearance or GFR is less than 25 milliliters at least once every seven days. There are still some unresolved questions when we're talking about HRS type acute kidney injury. What are appropriate albumin stopping points and duration of albumin? Should we be looking at serum albumin levels to guide therapy? What are the maximum dose limitations for albumin? Remember a lot of these are weight-based dosing strategies. Should patients with suspected HRS be moved to the ICU for norepinephrine treatment? This is something that we haven't always done aggressively and when should we be utilizing a renal replacement therapy? These are all unsolved questions. Take-home points, HRS type acute kidney injury carries a very worrisome prognosis. Always be thinking about hepatorenal syndrome in cirrhotic patients. They must have ascites. This is a requisite in acute kidney injury. Increasing mean arterial blood pressure is critical for management. In the ICU we should be being aggressive. Urine output is a powerful predictor for acute kidney injury in cirrhotic patients. So in the ICU we can still use it even if it's not part of the guidelines. And at the end of the day, transplantation remains the only definitive treatment for hepatorenal syndrome. Thank you for your time. Thank you.

hepatorenal syndrome

HRS AKI

terlipressin

norepinephrine

early initiation

liver transplantation