Thank you, Dean. So my disclosures are relevant. I previously served as a consultant to Mallinckrodt. My role was primarily to help them navigate FDA approval of terlopresin in the United States and in writing the product insert for the company. I'm just going to recap some of the major recommendations from both the ASLD and the ESL recommendations as it relates to the treatment of hepatorenal syndrome or hepatorenal syndrome type acute kidney injury. Both organizations agree that the treatment of choice is vasoconstrictors in combination with albumin. The preferred drug being terlopresin administered either as IV bolus or by continuous infusion. And in settings where terlopresin is not available, norepinephrine should be given. And in cases where neither can be administered, then consideration of mitadrine plus octreotide may be considered, though recognizing that the efficacy of mitadrine and octreotide is quite low. And it's very similar recommendations in the European societies, again, recommending terlopresin primarily in conjunction with albumin as the first line therapy. Norepinephrine can be considered as an alternative to terlopresin if there's limited data supporting this practice. And again, mitadrine and octreotide is an option, recognizing the poor efficacy of mitadrine and octreotide. Current U.S. guidelines regarding terlopresin from the ASLD published in 2021, the treatment of choice for hepatorenal syndrome-type acute kidney injury in liver disease patients is vasoconstrictor-preferring terlopresin. The American College of Gastroenterology states that in hospitalized patients with cirrhosis and hepatorenal syndrome without high-grade ACLF or disease, we suggest terlopresin, recognizing moderate quality of evidence. It's a conditional recommendation. And secondarily, norepinephrine, recognizing low quality of evidence, again, a conditional recommendation to improve renal function in patients with acute kidney injury. One of the most important take-home points from my talk today is this slide. It's important to recognize that when treating acute kidney injury in patients with chronic liver disease, an increase in mean arterial blood pressure is strongly associated with a decrease in serum creatinine. And that's how we maintain therapy with vasoconstrictor drugs. This was a pooled analysis published in 2011, looking at studies comparing treatment with drugs raising mean arterial blood pressure. And you can see that over time, with increases in the mean arterial blood pressure, there's a more pronounced decrease in serum creatinine as the mean arterial blood pressure increases. And this could be used to sort of predict what type of MAP target you would need to reach in effort to reverse acute kidney injury based on the presenting creatinine. So again, in a patient with a creatinine of 3, for example, a MAP increase of 8.5 was what was predicted to be needed to return their baseline creatinine to 1.5. Turlopressin is a synthetic vasopressin analog. It selectively has greater affinity for V1 receptors, predominantly located in the arterial circulation in the splenic vasculature. This is important in liver disease. It reduces splenic blood inflow and therefore decreases portal pressures. It redistributes part of the intravascular volume to the central circulation, which is one of the central problems in the development of hepatorenal syndrome, as poor effective circulating volume. And published literature today provides evidence that turlopressin improves renal function in patients with hepatorenal syndrome and, again, is the standard of care for this condition wherever the drug is available and approved. Just to recap some of the data from the confirmed study, this was the landmark study published in the United States that led to FDA approval of turlopressin in the U.S. And remember, there were two very different endpoints that were looked at. One was verified HRS reversal. This was a compound endpoint that required two separate creatinine measurements of less than 1.5 milligrams per deciliter at least two hours apart. And in patients who are alive without requiring renal replacement therapy for at least 10 days after achieving HRS reversal. And again, you can see that there's a statistically significant improvement in verified HRS reversal. This is slightly different than HRS reversal, which is just patients achieving a serum creatinine of less than 1.5 on at least one occasion. But again, you see a statistically significant difference in outcomes in patients who are treated with turlopressin versus placebo. In this study, which was a little bit different look at things, this was an open label randomized control trial of patients with acute on chronic liver failure. This was a specific look at ACLF type patients with HRS AKI greater than or equal to stage two. And this was comparing turlopressin plus albumin versus norepinephrine plus albumin. And you can see that there was a statistically significant improvement in reversal of HRS in patients treated with turlopressin over norepinephrine. Now this isn't true in all studies that look at this, but in this specific subgroup of patients looking that had ACLF, we do see an improvement in outcomes based on treatment with turlopressin as compared to norepinephrine. This was a meta-analysis published in 2017. I just want to call your attention to two different points here. Again, turlopressin compared to placebo favors turlopressin. When you look at norepinephrine compared to turlopressin, there's really no significant difference here. But now look at turlopressin versus mitragenoctreotide, and again, this strongly favors the usage of turlopressin in this situation. When you look at mitragenoctreotide, data has consistently demonstrated poor efficacy of these agents in treating HRS. It's still what's used in many centers as the first line therapy without any clear evidence of support. There's really no role, in my opinion, for either of these agents in the management of AKI-type HRS in the critically ill patient. And again, this is data comparing turlopressin to mitragenoctreotide, and we can see that mitragenoctreotide, especially in these studies, were really no better than placebo. Some other things when we're thinking about usage of turlopressin versus norepinephrine, for example, the route of administration allows for turlopressin to be given outside of the intensive care unit. Norepinephrine in a vast majority of centers requires central line insertion and ICU-level monitoring. Turlopressin can be given by bolus infusion in a peripheral line, allowing for non-intensive care unit use. Cost considerations, turlopressin, at least at this time, is considerably more expensive than norepinephrine, but when you think about perhaps being able to keep a patient out of the intensive care unit and managing them on the floor, this may allow for cost savings in that situation. A few words about timing and special considerations for managing patients with HRS in the ICU. Early treatment is important. Early treatment is associated with higher reversal rates of acute kidney injury in patients with chronic liver disease. This is pooled data from three separate trials of turlopressin using the intention-to-treat population, and what's shown in this slide that's important is that treating the patients when they have lower creatinine results in better outcomes and better reversal rates for HRS. When you wait too long for the creatinine to increase to high levels, then we see that we lose the efficacy of turlopressin. So for example, when patients have a creatinine of greater than 5, there's really no benefit to turlopressin in this patient population, and this is one of the labeled limitations of use. You should not be using it in patients who have a serum creatinine of greater than 5 because they are unlikely to experience benefit. Dr. Subramanian mentioned that I would talk a little bit about urine output in patients with cirrhosis and in the ICU. Urine output is actually a very powerful predictor of renal function, and this was a study that was published in Pittsburgh several years ago looking at urine output and serum creatinine as both tools to predict renal dysfunction and failure, and in this slide you can see that patients who met serum creatinine stage 3 acute kidney injury but who had normal urine output essentially had the same evolution and survival as those who had a serum creatinine that predicted a low stage AKI but had stage 3 AKIs predicted by urine output. So there was no difference in these two groups in survival over the course of the study. When you see patients who have both a serum creatinine at stage 3 and urine output that predicts stage 3 acute kidney injury, we can see that these patients have much worse survival. The study looked at almost 3,500 patients with chronic liver disease in the intensive care unit, and it demonstrated that when using urine output criteria to identify acute kidney injury, 1,281 patients were found to have stage 2 or 3 acute kidney injury that were not identified as having AKI based on serum creatinine alone. Going back to Terlopressin for just a second and looking at usage on the floor, in the confirmed trial we saw that about 85 percent of patients who were treated in this study were treated outside of the intensive care unit, only 15 percent of the patients enrolled in the study were managed in the ICU, but in those admitted to the intensive care unit there was about a 50 percent reduction in overall length of stay. This was a post hoc analysis in this study, but looking at the safety events that were identified in the confirmed trial we did see some signals that had not been identified in some of the European trials looking at Terlopressin. Again data from the confirmed trial identified that both respiratory failure and sepsis were severe adverse events that were associated with Terlopressin usage as compared to placebo, and this has resulted in some of the labeling restrictions that are in place for Terlopressin at this time. Another concern for the FDA when we were labeling the product insert for Terlopressin was patients who were actually listed for liver transplantation. This was a particular concern for them on two fronts. Number one, there was concern that administration of Terlopressin if it resulted in adverse events like we saw in the previous slide, for example respiratory failure or ischemia that this may take a patient who is actively listed for transplant and because of these adverse events make them ineligible for liver transplantation. So this was another labeling restriction for patients with high prioritization for liver transplant. That means MELD greater than 35. The benefits of Terlopressin may not necessarily outweigh the risks, and for those of you practicing in transplant centers I really suggest that if you're using it in your ICU get a sense of what your transplant team wants because remember that allocation in the United States is based on the MELD score, creatinine is a significant component of the MELD score, so if we improve them with treatment with Terlopressin we may actually drop their MELD score, and this is a concern for some centers. Again this is a center-dependent concern and it isn't universal, I can attest to that. We use it all the time in our transplant eligible patients in my current institution. What are some things that are important for appropriate patient selection for consideration of Terlopressin? Again looking at three different studies evaluating Terlopressin, we saw that consistently in these studies a serum creatinine of greater than 5 or an advanced stage of acute on chronic liver failure grade 3 or higher predicted an increased risk of adverse events, but more importantly there was also an increased risk of mortality in these patients. Again ACLF patients with grade 3 or higher and in those patients with creatinine of equal to or greater than 5 had worse outcomes when they were treated with Terlopressin, so now this is a limitation of use. How should we be monitoring patients and what are the things to be looking for when considering using Terlopressin in patients with acute kidney injury? Prior to initiation we should always be assessing the patient's respiratory status and their oxygenation status. Patients have an SpO2 of less than 90 we recommend not initiating Terlopressin until this improves and if it develops while on treatment we'd recommend discontinuing Terlopressin. For patients with ACLF grade 3 this is a contraindication and should not be used, so avoid use due to increased risk of respiratory failure and if they develop ACLF grade 3 while on treatment Terlopressin should be stopped. Intravascular volume overload is also a concern. Remember that these patients are receiving, can you go back a slide? Also receiving albumin and it's important to really carefully monitor the albumin use in these patients. For patients who are developing signs of intravascular volume overload Terlopressin should not be initiated until this has been corrected and for patients who clearly are developing more signs of vascular volume overload or pulmonary edema while on treatment we recommend reducing the dose or discontinuing administration of Terlopressin until the volume overload has been addressed. It's important to note that during the confirmed trial so people aren't, it's not that this isn't a concern but recognize that when respiratory failure occurred in patients in the confirmed trial it had median onset of at least five days of therapy so this isn't something that's happening right away and the average onset of 7.5 days with a range of 1 to 67. So there was something that was identified in the confirmed trial patients were getting a lot more albumin in this trial than in a lot of the European studies and so this is clearly an issue in patients developing respiratory failure watching how much volume they're getting and how much albumin they're getting and paying very close attention to this can help prevent respiratory issues. How do we administer Terlopressin? So if you read the studies Terlopressin in all of the studies was dosed at one milligram or two milligrams but in the U.S. labeling we're required to label it differently due to the SALT rule so the 0.85 milligram dose is one vial and it's equivalent to the one milligram dose that was reported in the trials. The initial dose is 0.85 milligrams every six hours. It's important to record the baseline creatinine on day one because you're going to be using this to evaluate response to therapy and whether or not to continue the drug. At day four the serum creatinine should be reassessed and compared to the baseline as to where you started therapy. If the serum creatinine is decreased by greater than 30 percent from baseline then you can continue Terlopressin at the same dose 0.85 milligrams every six hours. If it is decreased but less than 30 percent from baseline then increase Terlopressin to 1.7 milligrams or two vials every six hours. If the serum creatinine is unchanged or has risen this is an indication to stop Terlopressin as there's going to be no benefit. Therapy should be continued until 24 hours after the patient achieves a baseline creatinine that's close to their original baseline within 0.3 milligrams per deciliter or for a maximum of 14 days. Starting points, acute kidney injury reversal defined as when the serum creatinine is within baseline of the patient's known baseline or the lowest anticipated serum creatinine possible. If you initiate renal replacement therapy, if you need additional vasopressor support, day four serum creatinine is unchanged or rising, the patient undergoes liver or simultaneous liver kidney transplant after 14 days of therapy or if the patient develops contraindications like those that I described above. A common question that comes up when we're talking about hepatorenal syndrome and patients with volume overload, can you give these patients diuretics? And remember that when you're talking about diagnosing HRS oftentimes you have to have withdrawn diuretics and volume expanded the patient. For patients that have been volume expanded, so they've been receiving albumin or other fluids for several days and they're demonstrating signs of volume overload, it is not unreasonable to consider a trial of diuretics in these patients. You should not try diuretics in patients who you think have hepatorenal syndrome but have not yet been appropriately volume expanded. What about when renal replacement therapy should be used? I think this is always a little bit controversial as well. The easel practice guidelines suggest to consider this on a case by case basis. Initiate if there's a reversible cause of acute liver decompensation and a patient that's listed for liver transplantation. In the United States there was a consensus group that met several years ago and the outcome of that meeting was suggesting that patients with evidence of progressive acute kidney injury, evidence of progressive volume overload with greater than 10% total body weight increase despite diuretic therapy or progression of acid base abnormalities, then renal replacement therapy should be initiated. And the AGA practice update suggests that continuous renal replacement therapy is preferred over intermittent forms of renal replacement therapy. This is particularly true in acute liver failure which is not the topic of today's talk. And all etiologies of acute kidney injury if they are eligible for liver transplantation should be considered for renal replacement therapy. Lastly, definitive therapy. Liver transplantation is the only long term answer for patients who develop HRS. Timely transplantation is important for optimal renal recovery and to ensure that they don't end up needing a kidney transplant down the road. We consider simultaneous liver kidney transplantation if HRS AKI is persistent. Persistent acute kidney injury is currently defined as a patient who has either one or both for at least six weeks. Patient's been on dialysis at least once every seven days or CRRT where the calculated creatinine clearance or GFR is less than 25 milliliters at least once every seven days. Take home points acute kidney injury type paddle renal syndrome type acute kidney injury carries a very worrisome prognosis. Always be thinking about a paddle renal syndrome in patients with cirrhosis and ascites. That's a requisite. Patients who have AKI in the setting of liver disease increasing the mean arterial blood pressure is critical for management and in the ICU we should be aggressive. I believe there's no role based on not just my opinion but also on data. There's no role for miniature noctreotide in the critically ill cirrhotic with HRS type acute kidney injury. Urine output is a powerful tool for predictor of acute kidney injury in cirrhotic patients even if our definitions haven't quite caught up to that and at the end of the day transplantation remains the only definitive therapy for patients with advanced kidney disease and liver failure.

hepatorenal syndrome

terlopressin

acute kidney injury

liver transplantation

albumin