Good afternoon now, everybody. My name is Don Rocky, and on behalf of the Portal Hypertension SIG, it is a great pleasure to welcome you all and to introduce our speakers this afternoon. This is the first Portal Hypertension webinar of 2023, and we hope to have another one or two coming later. For today, leading off will be Dr. Pratima Sharma, a transplant hepatologist and health services researcher at the University of Michigan. She is currently serving as the medical director for adult liver transplant, transplantation there, and her specific research interests are in the area of liver allocation policies, kidney dysfunction before and after transplantation, and outcomes of simultaneous liver kidney transplants. So she's going to start off by tackling AKI in patients with cirrhosis, and then after Dr. Sharma, Dr. Wang is going to speak, and she's going to focus on the use of turlepress in an AKI hepatorenal syndrome. So as many of you know, I'm sure Dr. Wang is from the University of Toronto and is a hepatologist there at the Toronto General Hospital, where she is professor of medicine and has been active in the care of patients with cirrhosis for many years. She does research in the pathogenesis of portal hypertension, ascites formation, liver-kidney interactions, including the hepatorenal syndrome. She has received more awards than we have time to review, but I would point out that she was the first author of the landmark New England Journal of Medicine study on turlepress, and published just two years ago, and she has been a member of multiple writing committees that have developed guidelines for the management of refractory ascites, renal failure, and ACLF. So with that, just one housekeeping note, we will take questions at the end, so chat your questions. I'll try to get those organized, and we'll get those to our speakers, and without further ado, Dr. Sharma, please take it away. Thank you, Dr. Rocky, for your kind introduction, and I would like to thank ASLD Portal Hypertension SIG for this opportunity, and it is a real honor to share the stage with Dr. Wong. So I'm going to focus on an overview of acute kidney injury in patients with decompensated cirrhosis, and as Dr. Rocky said, Dr. Wong is going to take a deeper dive into turlepressin and albumin use. So I don't have any disclosures. We are going to learn a little bit about the epidemiology of AKI in patients with cirrhosis, the pathophysiology, as well as diagnosis, and I will focus on non-pharmacological management. As we know that the spectrum of kidney disease in patients with cirrhosis varies from normal renal function to full-blown renal failure requiring renal replacement therapy in some of the patients. It can be reversible or irreversible patients requiring liver and kidney transplant. It could be acute, chronic, acute-on-chronic. It is very important to characterize a patient, what kind of AKI they have, and it's mainly pre-renal, renal, and post-renal. In the study of 400-odd patients, this is an older study, they found only one patient had post-renal cause of acute kidney injury. Before we take a deeper dive into diagnostic algorithms, let's just review a few of the definitions as some of the definitions have changed, and also the definition of HRS has evolved over the last 20 years. What is baseline creatinine in a patient? If we don't know the baseline, we would not know whether a patient has AKI or not. The baseline serum creatinine was defined as serum creatinine obtained in the last three months. If you have more than one value of serum creatinine in the last three months, then use the closest value to the admission as the baseline creatinine. If somebody does not have any previous serum creatinine into the chart or in the system, then use the serum creatinine on the day of admission as the baseline creatinine. The definition and stages of AKI are mainly based on RIFLE and Aiken criteria, and AKI is defined as increase in serum creatinine greater than 0.3 milligrams per dL within 48 hours, or 50 percent increase in serum creatinine from baseline within the prior seven days. The RIFLE criteria has serum creatinine as well as urine output criteria. There was a survey which was performed in 2012 in preparation for the SLKT, Simultaneous Liver and Kidney Transplant Consensus Conference, and in the survey we found that most of the physicians in the hospital use serum creatinine criteria, and very few people use the urine output criteria. The stages of AKI are risk, which is stage one. Stage one is further divided into stage 1A if the serum creatinine peak is less than 1.5. Stage 1B as if the serum creatinine peaks greater than 1.5 within the realm of those definitions, which are here in the middle. And stage two is injury, which is serum creatinine increased by two to three-folds from baseline. Stage three is failure, which is serum creatinine greater than three-fold from baseline, and also greater than four milligrams per dL with acute rise of 0.5 milligrams per dL or initiation of renal replacement therapy. It is very important to characterize what kind of AKI a patient is having. So this was a review which was published in 2008, where they looked at all the hospitalized patients with cirrhosis. The incidence of kidney disease or acute kidney or kidney injury was around 20 percent. But if you look at the recent literature, it has increased over time, especially with the increase in number of patients with chronic kidney disease with the rise of metabolic-associated liver disease epidemic. So in this review found that majority of the patients had AKI, and only one percent had chronic renal failure. Of those who had AKI, two-thirds had pre-renal physiology, and a third had intrarenal or ATN and glomerulonephritis as the cause of their kidney injury, and less than one percent had post-obstructive uropathy. Of those who had pre-renal etiology, two-thirds were volume responsive, and one-third were volume non-responsive, and they were further characterized as type 1 and type 2 HRS, which is a definition of past. And we will learn a little bit more about what is the current definition. So this is also a very nice study, prospective study, which was published in 1993. In this study of 229 non-ezotemic patients with cirrhosis, the incidence of type 1 or one-year cumulative incidence of type 1 HRS was 18 percent, and five-year it was 39 percent. Again, there are two subtypes of hepatorenal syndrome historically, HRS type 1, which is more acute and had worse prognosis, and HRS type 2, which is now called HRS and AKI, which is basically defined as a gradual decrease in the glomerular filtration rate. So again, this is another study which is also from 1975, and this hasn't changed in the setting of patients who develop HRS. The survival is abysmal, and this is in the absence of any treatment. Again, so HRS type 1 was historically doubling of serum creatinine to greater than 2.5 milligrams per dl within two weeks, and now it is called HRS AKI. So again, the absolute increase in serum creatinine by 0.03 within 48 hours, urinary output less than 5, or percent increase greater than 50 percent based on last serum creatinine. And this is mainly in the absence of any improvement to diuretic withdrawal or fluid challenge, absence of shock, no current or recent use of nephrotoxic drug, and no structural damage to the kidney. So mainly it's a diagnosis of exclusion. So the take-home point is pre-renal physiology diagnosis of exclusion with rapid increase in serum creatinine based on the RIFLE criteria. HRS 2, which is previously gradual decline in EGFR and a cutoff of serum creatinine 1.5 was considered as AKI, but this cutoff is no longer used, and HRS non-AKI is further subdivided into HRS acute kidney disease, where EGFR is less than 60 ml per minute for less than three months, and HRS CKD is if EGFR is less than 60 ml per minute for greater than three months. The pathophysiology of development of AKI in patients with decompensated cirrhosis and ascites is fascinating. The hallmark of portal hypertension is splanchnic vasodilation and central hypovolemia, which basically led to neurohormonal hyperactivation, stimulation of sympathetic nervous system, renin-angiotensin system, as well as ADH axis. This creates a balance between the intrarenal vasodilators, which are mainly prostaglandins and nitric oxide, as well as intrarenal vasoconstrictors. As a result of that, there is a postglomerular vasoconstriction, as well as slight limitation of decrease in renal blood flow, which causes slight decrease in glomerular capillary pressure and slight or no decrease in GFR. So mainly the kidneys are maximally auto-regulated. And whenever there is a second hit in terms of severe sepsis, intravascular volume depletion, type 1 HRS, radiocontrast agents, or other unknown factors, or alcohol-associated hepatitis, that tips the balance in the favor of those intrarenal vasoconstrictor, resulting in decrease in renal blood flow, further decrease in glomerular capillary pressure, leading to acute kidney injury. So the most important thing is whether the patient meets the criteria of acute kidney injury. If a patient has cirrhosis and does not have ascites and kidney injury, it is not hepatorenal syndrome. For somebody to have a hepatorenal syndrome, they have to have extreme portal hypertension in terms of like decompensated cirrhosis and ascites. So mainly rule out the inciting factors, rule out other nephritic and postrenal etiology, and then look at the urinary biomarkers. None of these urinary biomarkers are diagnostic. However, they can lead you to make a diagnosis of pre-renal AKI versus ATN. So again, if fena is less than 0.5%, if urea is less than 21%, no cast, no response to volume expansion, it favors HRS AKI. If fena is greater than 1%, if urea is greater than 33%, patient has muddy brown cast, it favors more ATN. But life is not that perfect. We always get into these middle intermediate type of AKI. So what do we do in these scenarios? So currently there is, at least at University of Michigan, we have urinary N-gal, which we can order. So urinary N-gal is one of the protein which goes up, you know, within one hour of the acute kidney injury. And if the N-gal is less than 100, it favors HRS AKI. If it is on day one greater than 110 or on day three greater than 220, it favors more ATN kind of physiology. However, you know, if you wait for day number three, patient already has a really, maybe progressed more to the AKI. So that's why I think it is important to send this urinary N-gal sooner than later. So what is N-gal? So it is a 25 kilodalton glycoprotein that's produced by neutrophils, epithelial cells, including tubular cells. It's filtered by the glomerulus and reabsorbed by proximal tubules and is released in the setting of acute kidney injury. So what happens is that it can be spuriously elevated in infections also because it is also produced by neutrophils. So the first and foremost thing in the management of acute kidney injury or HRS AKI in patients with cirrhosis is to look at the therapeutic targets. So liver transplantation is a therapeutic cure for patients with HRS AKI. Then again, intravenous splenic vasoconstrictor and volume expansion with albumin that Dr. Wong is going to talk about in her talk could serve as a bridge to transplant and have shown improvement in reversal of hepatorenal syndrome. Role of tips is controversial in these patients, and we're going to talk about these in subsequent slides. So the mainstay of treatment is to hold the diuretics, consider volume expansion with albumin one gram per kg body weight for 48 hours, and hold non-selective beta blockers in patients, especially if they have systemic inflammatory response. But albumin infusion, as we all know, is double-edged sword in the sense that from the entire trial, we learned that albumin infusion led to high respiratory failure in non-large volume paracentesis or SVP-related albumin infusion. Therefore, careful monitoring of patients for incident respiratory failure is very important so that they don't get into trouble. So this was the question which Dr. Jas Bajaj and NASCAL investigator tried to answer, and these slides are courtesy of Dr. Bajaj, who presented this paper at State of the Art DTW last year. So in this study, what they aimed to determine was what are the predisposing factors for incident respiratory failure. So NASCAL, as you all know, is a 12-site consortium of 511 hospitalized patients. The mean age was 57 of these patients. Fifty-eight percent were men. Thirty-eight percent had diabetes. The most common etiology was alcohol, and the median MEL score was 23 in these patients. Nineteen percent developed respiratory failure, and what they found was that any new onset of AKIs greater than or equal, stage two or higher, use of albumin, grade three and four, HE, and shock were independent predictors of respiratory failure. So look at the odds ratio. So use of albumin was associated with 2.7 percent higher fold of respiratory failure in these patients. However, we don't have any way of measuring how we can determine whether these patients have reached euvolemic status, because most of these patients have edema as well as ascites. So it is very difficult to clinically assess whether they are fluid overloaded. Most of the time, they are fluid overloaded, but they are intravascularly depleted, so whether we should give more albumin or less albumin. So this question was answered by the study of 53 presumed AKI patients, where the investigators used inferior vena cava diameter as well as inferior vena cava collapsibility index to guide the fluid management. So patients who have IVC diameter less than 1.3 centimeter and IVC collapsibility index greater than 40 percent were fluid depleted. IVCD greater than 2 centimeter and IVC collapsibility index less than 40 percent were fluid expanded or fluid overloaded. And those patients who have IVC diameter less than 1.3 and the collapsibility index less than 40 percent were considered to have intestinal abdominal hypertension. So what they found was that they used this point of care echocardiography to assess these parameters within zero to 72 hours prior to enrollment to albumin or normal saline. And what they found was only 19 patients were eulemic. 15 patients were fluid depleted. In these patients, they gave them IV albumin, and the AKI improved in 40 percent of the patients. In 11 patients, they were fluid overloaded, so they recommended IV furosemide, and AKI improved in 30 percent of the patients. And then eight patients had intra-abdominal hypertension in whom they recommended paracentesis, which resulted in AKI improvement in 50 percent of the patients. So this is, again, something which is not routinely used, but it would be nice to have this so that we can guide the fluid management in our patients who are so difficult to assess their volume. So, again, as I said, the role of TIPS is controversial. As you all know, that MEL score was initially developed in patients to risk stratify the patients who were undergoing TIPS procedures. So what TIPS does is it creates a shunt between the branch of portal vein and the hepatic vein to decompress the portal pressure. So in this study of seven patients with type 1 HRS and child-recorded PEW score less than 12, the reversal of HRS was seen in four out of seven patients, but at the end of three months, only two patients were alive. And this was the study. The second study was by Dr. Wong in 2004, where they treated 14 of their type 1 HRS patients with mitodrine and octetide. Initially, of those 14 patients, 10 had reversal of HRS, and out of those 10 patients, five received TIPS, and all of them had favorable bilirubin and INR as well as child-recorded PEW score less than 12. And it resulted in normalization of GFR in all five patients. So basically, if somebody is having a floated HRS AKI, TIPS should not be used in those patients. However, if their HRS has improved and they have MEL score which is less than 18 or so, then TIPS can be attempted in those patients. And these patients mostly have also refractory ascites. Then what is the role of renal replacement therapy? Every day on rounds, we have been asked, like, patient has now creatinine of 5, not making any urine. Our nephrology colleagues say, well, is this patient a transplant candidate or not? So in those patients who have progression to stage 3 AKI despite best supportive care and pharmacological therapy, the question we have to ask ourselves is whether these patients are transplant candidate or if they have pathway to early liver transplant, especially in patients with alcohol-associated hepatitis. If the answer is yes, then the renal replacement therapy should be offered to these patients regardless of the etiology of AKI. If that answer is no, then you have to again go back to see whether this is an ATN versus HRS AKI. If it is an HRS AKI, then this is unlikely to improve, especially if the creatinine is that high and patient has progressive kidney disease. So in that scenario, we do not offer renal replacement therapy to these patients. However, if they have ATN, then a trial of RRT can be given to these patients in an attempt to see if kidneys will open up. So the other thing is that we should also consider the strategies to prevent acute kidney injury. So some of these strategies are to avoid nephrotoxic drug and IV contrast in these patients, consider albumin replacement with large volume paracentesis, consider albumin with the treatment of SPP, and close monitoring of electrolyte after dose changes in patients whose diuretic regimen were changed. Liver transplantation as a therapeutic option is curative for these patients. Majority of the patients improve their kidney function and they get renal recovery after liver transplant. So this was a study which we published a long time ago. We know that serum creatinine is a predictor of weightless mortality as well as post-transplant mortality. So the question we asked if there is a survival benefit of liver transplantation in patients who have high serum creatinine. And what we found, so what is survival benefit? Survival benefit is if the weightless mortality, if the post-transplant mortality is lower than weightless mortality. And you know, patients with MEL score greater than 24, up to 40, they have very high weightless mortality. And if there is, with the change in serum creatinine, these patients still get the survival benefit of liver transplantation, although their magnitude, although the magnitude of survival benefit for somebody who has a MEL score between 24 to 26, and a serum creatinine of four is slightly lower than somebody who has serum creatinine less than one, but they still get the survival benefit of liver transplantation. So in conclusion, AKI is quite common among hospitalized patients with cirrhosis. HRS is one of the most ominous complication of patients with decompensated cirrhosis and ascites and carries a very poor prognosis. Characterization of AKI is very important for its management. TIPS is controversial in patients who are having florid HRS AKI, and the measures should be taken to prevent AKI. And above all, if somebody has decompensation of portal hypertension, they should be referred for liver transplantation. Thank you. Okay, Dr. Sharma, thank you very much. That was spectacular. So we're going to move over to Dr. Wong now. Before she takes over, I just wanted to correct the mistake. So we can't use chat for this. So if you have a question, put it in the Q and A, and we'll try to get to all those questions. So Lawrence, take it away. Okay, thank you. Let me get my slides on. Can you share? It's the green button at the bottom. Hang on. Let me get my slides on first. Can you now see it? Yeah, can you hit the slide show? Yep, the one down on the bottom. No, yep, there you go. Yep, no, yep, perfect. Slowly, it's coming. Coming. So good afternoon, everyone. First of all, I would like to thank the Portal Hypertension SIG for giving me the opportunity to share with you all on the use of terlipresin in patients with HRS AKI. And it is indeed an honor for me to be sharing the platform today with Dr. Sharma. So here are my disclosures. So you have already heard from Dr. Sharma how to evaluate a patient with cirrhosis and AKI. And AKI is something that frequently does not occur alone, but rather it can occur together with other organ failures. So when you have multi-organ failures in a patient with decompensated cirrhosis, it is called acute on chronic liver failure. And not only do you need to deal with the AKI, you also need to treat individual organ failure. So let's now just concentrate on the patient with AKI and you have already heard, you need to determine the phenotype of the AKI, whether it's related to structural renal disease, which you have to treat according to the AKI etiology, or if it is related to functional changes in the systemic and the renal circulation. And if you decide that it is a functional type of AKI, that means it's related to changes in hemodynamics. Frequently you have a second hit or a precipitating factor and such as infection. Therefore you need to treat the precipitating factors and then volume expand the patient with albumin at the dose of one gram per kilogram of body weight to a maximum of 100 grams of albumin per day for 48 hours. If the patient responds, then the patient likely has renal asthma. If not, then the patient is likely to have HRS AKI. And so if the patient meets the criteria for HRS AKI, you've heard that the patient needs to be assessed for liver transplantation, but at the same time you need to treat the AKI. You ask yourself, is the patient a candidate for basal constrictor therapy? And there are several things that we need to consider. How sick is the patient? How many organ failures there are? How bad is the AKI? You've heard about albumin potentially giving patient respiratory failure. Therefore you need to assess the respiratory status of these patients. And if the patient does not have multi-organ failure, creatinine level is not too high, or the patient does not have respiratory failure, then the patient should be assessed for treatment with terlipresin and albumin. And at the same time, don't forget to assess the patient for liver transplantation. So I'm just going to spend the next 20 minutes talking about terlipresin. And you can see here that there are many agents that have been tried to treat patients with HRS, AKI, and worldwide, terlipresin is the most widely used basal constrictor to treat these patients. What actually is terlipresin? It's actually similar to lysopressin, which is an analog of arginine vasopressin. So it is actually a prodrug of lysine vasopressin, and it has three more glycine molecules attached to the lysine vasopressin. And there are various vasopressin receptors. We have the V1 receptors, which are mostly situated on blood vessels. And by attaching to the V1 receptor, the terlipresin causes basal constriction. There are also V2 receptors, which are mostly on renal tubules. And by attaching to a V2 receptor, it initiates free water retention in the kidneys. And there are also the V1B or the V3 receptors, which are actually in the brain. It actually causes ACTH release, and therefore stimulating cortisol release from the adrenal gland. So now we're going to concentrate on the V1 receptors. And as you can see, terlipresin has got an affinity for V1 receptors significantly better than AVP or lysine vasopressin. And therefore terlipresin is the preferred drug than vasopressin in the management of patients with HRS-AKI. And you can see that all three compounds also have affinity for the V2 receptors. Once again, terlipresin attachment to the V2 receptor is significantly stronger than lysine vasopressin or arginine vasopressin. So once you have terlipresin attached onto the V1 receptors, here are the physiological effects. First of all, in the cardiovascular circulation, there is an increase in the systemic vascular resistance, and therefore increase in the mean arterial pressure. And that is desirable because that will allow more blood to be pushed into the renal circulation. So an increase in the mean arterial pressure will increase the renal perfusion pressure, leading to a decrease in the renal arterial resistance. And at the same time, it will also reduce the portal vascular resistance to venous blood flow by reducing the, it causes vasoconstriction in the portal venous arterio and therefore allowing less portal venous blood to go into the splenic circulation and thereby reducing the portal blood flow and the portal pressure. And that has the effect of reducing vasodilator production, such as nitric oxide, and that will also help to increase the arterial pressure. And inside the liver, it will also decrease the hepatic arterial resistance and therefore reducing the obstruction to portal flow. So the overall effect of using telepresin in these patients is to increase the systemic mean arterial pressure, increasing renal perfusion pressure, and also reducing the portal hypertension. And telepresin therefore acts on the portal vein to reduce the portal inflow. And it has been used commonly in Europe as a treatment for variceal bleeding because it has been shown by reducing the portal inflow, you can actually reduce the variceal pressure by 20 to 30%. And so this is just to show you the pharmacokinetics of telepresin on splenic hemodynamics. By giving telepresin, you can see that there is a reduction in the hepatic venous pressure gradient, as well as a reduction in the portal venous blood flow by approximately 30%. However, its effect is not long lasting. It only lasts for approximately four hours and thereafter, the portal pressure goes back to the baseline level. And you can see that the effect of two milligrams of telepresin is significantly better than the effect of one milligram per telepresin. And that's the reason why telepresin has to be given as a bolus approximately every four to six hours. And so once you have diagnosed the patient with HRS-AKR, you need to act quickly because otherwise, if you have renal ischemia, then eventually, even if the patient starts off without tubular damage, you will eventually develop tubular damage. So even if you improve the hemodynamics, you're not going to reverse the AKI. And so this is a study that was conducted by the Naxos Consortium, which shows that if you wait for longer, then the serum creatinine tends to rise and these patients are more likely to be at risk for developing AKI. This is because when you have renal ischemia, there is hypoxia, which will recruit a lot of inflammatory cells. They produce a lot of reactive oxygen species, which can lead to tubular injury as well as endothelial injury, causing vasoconstriction and eventually more epithelial cell apoptosis and necrosis, as well as vascular damage, causing adhesion molecules and blockage of these glomerulus. And therefore, it is important that once you've diagnosed AKI, you need to act early. In addition, if you delay it, the patient may have more organ failure. And here, this is a study from a European-Italian study showing you that for the same degree of serum creatinine, if you have more organ failure, your response to treatment is reduced. So this is one organ failure, two organ failures and three organ failures. And for a patient with a baseline serum creatinine of three, if you have got three organ failure, you've only got about 35% chance of recovery. Whereas if you've only got one organ failure, you have close to 70% of renal recovery. So the message is get on with treatment for these patients. So what do you do? You've decided the patient does not have too many organ failure. The patient does not have respiratory failure. Terlepresin is the right drug for them. Terlepresin per ampoule contains one milligram. And because the effect only lasts for approximately four to six hours, you have to give it every six hours as bolus injections. And it's recommended that you should give patients albumin 20 to 40 grams per day. And you need to monitor the patient for volume overload from the albumin and terlepresin for ischemic side effects and also respiratory failure. You monitor the serum creatinine every day. And by day four, you look at the serum creatinine and compare it to the baseline level. If the serum creatinine decreases more than 30% from baseline, you just continue terlepresin and albumin at the initial dose until the serum creatinine is less than 1.5 milligram per deciliter for two consecutive days or for a maximum of 14 days. If the serum creatinine reduction is less than 30% from baseline, you can increase the terlepresin to two milligram every six hours. This is because two milligrams will reduce the portal pressure higher than one milligram every six hours. And the albumin dose remains the same. If the patient serum creatinine on day four is higher than what it is at baseline, then you need to permanently stop the terlepresin because the patient is not responding to pharmacotherapy and you need to discuss with the nephrology unit about starting RRT and get the transplant team onto giving the patient a liver transplant if appropriate, as soon as possible. So to date, there are four large randomized control trials comparing the use of terlepresin versus placebo, three from North America and one from Spain. And you can see out of three of the four studies, three of them show significant increase proportion of patients reversing the hepatorenal syndrome compared to the use of placebo. And this is presenting the data a different way, showing that at baseline, all of the patient had renal failure at the end of treatment, significantly less number of patients had renal failure in the terlepresin arm, whereas in the placebo arm, the difference was not significant. However, the investigators also noticed that a significant number of patients who received terlepresin also developed respiratory failure, whereas that was not observed in patients who received placebo. And so when they wrote down the data further, it was noted that the bulk of the patients who developed respiratory failure had at least grade three acute on chronic liver failure. That is patients with three organ failure, including renal failure. So it could be respiratory failure, vascular failure, and renal failure. And whereas that was not observed in the placebo patients. And so when they were checking for predictive factors for the development of respiratory failure, they found that the patients who had a high INR, who actually had a high mean arterial pressure at baseline, and also patients who had a low oxygen saturation at baseline were the ones likely to develop respiratory failure. So a high baseline INR just represents that the patient's liver reserve is just not there. The mean arterial pressure being high, predisposing the patient to respiratory failure is related to the theory that when you use terlipresin to increase the afterload, and then you add a lot of albumin to increase the preload, and if there is any cardiac dysfunction, such as cirrhotic cardiomyopathy, then that will increase the pulmonary hydrostatic pressure significantly, leading to leakage of fluid from the pulmonary vasculature into the alveoli, causing respiratory failure. And so this is data that really hasn't been published, but I'm allowed to share it with you, showing that in patients with grade one or two acute on chronic liver failure, there was no difference in terms of survival between the turliprescent and placebo patients. However, in patients who have got at least three organ failure or grade three ACLF, those patients who received turliprescent actually had a significantly worse survival compared to the patient who received placebo. And so now it is recommended that in patients who have got three organ failure, not to use turliprescent. In addition, in those patients whose baseline serum creatinine was more than five milligram per deciliter, only 9% of patients had reversal of the hepatorenal syndrome with turliprescent. Whereas for patients whose baseline serum creatinine was less than three milligram per deciliter, half of those had reversal of their HRS with turliprescent. So it is now also recommended that patients who have a baseline serum creatinine of more than five milligram per deciliter not to receive turliprescent. It is likely that those patients have had their hepatorenal syndrome for quite some time and there is some structural damage to the renal tubules making an improvement in the hemodynamics, not able to correct the renal failure. So these are the recommendations that have been put in place. There are patients who have got alcoholic hepatitis, who's got sepsis or systemic inflammatory syndrome. They tend to have better response to turliprescent treatment. This is believed to be related to the fact that turliprescent, by reducing the portal pressure, it's able to reduce the extent of the bacterial translocation that occurs in these patients. Patients who have got ACLF greater than grade three or serum creatinine more than five, they're less likely to respond and more likely for adverse events. And patients who have got ongoing coronary, peripheral or mesenteric ischemia, they should not be given turliprescent because of the potential for ischemic side effects. Patients who are experiencing hypoxia or worsening respiratory symptoms, they should not be given turliprescent because of the risk for respiratory failure. And so I just want to talk briefly about response to treatment. If the patient responds to treatment, there should be reduction of the serum creatinine to less than 0.3 milligrams per deciliter from baseline. A partial response is defined as reduction of the AKI stage by one stage with a serum creatinine reduction to a value more than 0.3 milligram per deciliter above baseline. And this is just to show you in the appropriate patient, you should give them a trial of turliprescent. This is because if you can bring down the AKI stage by one, whether the patient started off with stage three AKI or stage two AKI, you can significantly improve their survival with or without a liver transplant. And this is a poster that was presented at AASLD last year. Showing that even patients who are a partial response, there was a reduction in the number of organ failure compared to the non-responders and also a reduction in the ACLF grade in the partial responders compared to the non-responders. Now, there has been a lot of controversy regarding not using turliprescent because that may reduce the patient's likelihood to receive a liver transplant. And these are data that were just presented at two recent meetings, one at ESO and one at DDW, showing you that in patients who receive turliprescent, yes, indeed, there was a reduction in the MEL score. However, these patients were not jeopardized in terms of their ability to receive a liver transplant. As you can see, those patients who received turliprescent had the same incidence of liver transplant all the way extending up to 90 days. So this was the latest American study on the use of turliprescent for HRS. And this is another study that was done after the confirmed study by the Philadelphia group, showing you that patients who receive turliprescent were able to receive a liver transplant and is mostly the patient who had a complete response to turliprescent rather than the patients who had no response. Of course, these patients also had a liver transplant, but receiving turliprescent and having a complete response did not jeopardize the chances of these patients receiving a liver transplant. And finally, the Italian study showing that in patients who responded to turliprescent, of course, there was a drop of their MEL score and they waited longer for their liver transplant. However, because they responded, you reduce the likelihood of them having long-term CKD after their liver transplant and also post-liver transplant, these responders had a significantly better survival compared to the non-respondents. So I think we're collecting sufficient data to show people that you should not hesitate about treating these patients with turliprescent and jeopardizing their ability to receive a liver transplant. So to summarize, renal failure is the most common organ failure in patients with decompensated cirrhosis. You need to recognize it early in order to initiate timely treatment. Turliprescent is the most commonly used vasoconstrictor worldwide. Careful patient selection is necessary as well as close monitoring during treatment as the use of turliprescent is associated with significant side effects. Remember, small improvement in serum creatinine with treatment even when you don't get complete HRS reversal is beneficial. And when the patient responds, the responders will have time to wait for the liver transplant. I'll stop here and welcome questions. Thank you. As well. So we have eight minutes till the end of the hour and we've got a whole bunch of questions. So let me go through the questions and then we'll ask our speakers to give us short answers so we can get through all these. So the first question is, how should clinicians use creatinine given that cirrhotic patients are often sarcopenic as an AKI marker? And that's a great question. And we all know that serum creatinine is usually lower in patients with cirrhosis. So by the time it, and that's the reason that the creatinine cutoff of 1.5 and 2.5 were removed because these patients are sarcopenic and even a little bit increase in their creatinine means that they had AKI and that's what rifle criteria are using. By the same time, I think cystatin C is one of the marker that we can use, but that's a great question because creatinine does not show the real renal function in patients with cirrhosis. So we really don't have anything great unless you can use cystatin C or something else. Also by Dr. Murad, Murad, what about AKI HRS prognosis in patients who've developed cirrhosis after they've had a transplant? Do they do worse than patients who haven't had a transplant already? That really hasn't been studied. So it is a different pathophysiology altogether. A lot of these patients get, first of all, unless the patient is cirrhotic again, the AKI has a totally different pathophysiology. So I don't believe you can use Turley-Preston unless we specifically look at that. Has it, has Turley, I mean, that's a great question. I think, you know, because a lot of them they're on calcineurin inhibitors, so they get, they probably have injury to their- They have tubular damage, yeah. Yeah, they have tubular damage. Has anybody ever tried Turley-Preston in a post-transplant patient? I don't believe so, but it also doesn't really make pathophysiological sense. Right, okay, good question. Next question, Dr. Kulkarni, when you transplant somebody, or when do you transplant somebody who's got HRS? You know, when is the point, this comes up all the time, when is the point of no return? And just throw it open, both of you all do a lot of transplants. So when do you, when do you, how long is too long to wait? So ideally they should be listed, and if they are not listed, they should be evaluated for transplant, and they're a good medical candidate. Based upon their MEL score, they should be transplanted, because HRS can be improved or reversed with Turley-Preston, but there are patients who will develop HRS again. So I feel that there should be a pathway for these patients to either get listed expeditiously, and once they are on dialysis, you cannot use Turley-Preston in those patients, so I think they should be transplanted. When do you decide on doing a kidney too? So will you, after, you know, a certain period of time, do you say, okay, the kidney, the native kidneys aren't gonna recover, and we need to do a liver kidney? That's an excellent question, and that is all dependent on like, how long these patients were on dialysis, how long is there, whether it is because of the, whether the patient already had a chronic kidney disease, because there is a medical eligibility criteria for these patients. Majority of the time, if they are HRS AKI, it was one of the study which showed that the non-recovery rate is 9%, but these patients have very high mortality in the immediate post-transplant, because these are very sick patients. So with the new policy, you can always transplant them with liver transplant alone, and if their kidneys don't recover after transplant, you can enlist them within 60 to 365 day for a safety net kidney. So I think it is kind of nice, because instead of throwing a kidney and a liver in a very sick patient, and waiting to see if the kidneys are gonna work in these patients or not, definitely with the newer policy, it becomes easier to transplant them with liver transplant alone, and if they don't recover, then enlist them for safety net kidney. Fair enough. What's the longest duration you've ever had anybody on dialysis that you did a liver alone? So previously, I think it was 90 days usually, and most of the time, we are in Michigan, so our median male score that get transplanted is around 26 to 30. But most of the time, they have like acute dialysis less than six weeks or so. So we usually transplant them as liver transplant alone, unless and until there is a clear-cut CKD, which has gotten worse, and these are ESRD patients. Okay, great. The rules are about the same in Toronto, and if they have got ACLF grade three, we need to really think seriously about whether the patient is going to pull through. So we usually bring in the palliative care team and start talking to them about palliative care. It's not that we don't do ACLF grade three patient, but the patient has to be, otherwise, you know, before being ill, Wrigley was very robust and has a lot of family support. And our rules for kidney transplant, simultaneous kidney transplant is about the same as Michigan. Okay, great. There was also a question about continuous infusion of Terlepresin. What do you think about that? The Italians are very, very strong on continuous infusion. Terlepresin in North America does not have the indication to use continuous infusion. It is supposed to be better. You use starting two milligrams per day. Continuous infusion, you can have the same results and less side effects, but unless you want to use it off-label, these manufacturers not advocating that without proper data. Right, okay. Now, my favorite question here, and one that I like, I love this question. So somebody asked about central venous pressure monitoring in these patients. I like it actually to assess volume status. I like point of care ultrasound. So Pratima, I think that's great, but I think CVP monitoring helps. So what about, can you guys address that and infusion of albumin as well as Terlepresin? CVP monitoring, sorry. CVP monitoring is not practical in the ward unless the patient's actually in ICU. The ward staff will not do it for you. And Terlepresin is supposed to be given in the ward. So I guess I use my best clinical judgment. And so I like what Dr. Sharma is talking about, this IVC measurement, which we don't use, but we should actually try it more often. Now, the albumin dose that's been recommended for use with Terlepresin, no one has ever done a dose response study on albumin. So it was a number just plucked off the sky. So I recently did a review on albumin. And in fact, the incidence of respiratory failure with albumin use, not only just for Terlepresin patients, but for other indications, it is there. It's somewhere around 10 to 15%. And what I realized is that when you give a hundred mils of albumin, you actually pull in approximately 500 mils of fluid. And that's the reason why they get into trouble with volume overload. It just basically being hyper-oncotic, it sucks in fluids from the interstitial space, from the intercellular space. And so that's why these patients need to be monitored very carefully. So titrate albumin carefully then. Yes. And when you get above a hundred milligrams, watch out. Yes. Okay. All right. We're right on time. Dr. Sharma, did you have any other comments about CVP monitoring? No, I completely agree with Dr. Wong that, you know, the nurses, we cannot do it. It's not practical. And the AKI is, it's a very common diagnosis in patients with cirrhosis. So we cannot put everybody in the ICU to monitor like the CVP while we're giving them volume expansion. So I think the point of care echocardiography is the way to go, but we all have to learn it. And I think we should make it as a portal hypertension SIG deliverable, maybe, you know, consider as an educational opportunity or maybe, you know, doing a limited pilot. I'm happy to partake with Dr. Wong in this. Yeah. That's a great suggestion. I just argue with the ICU and try to get them in the ICU. Yeah, but you can't fit them all in. That's right. Our ICU is full of post-transplant patients. They tell me, go and deal with it the best way you can. Right. All right. Well, we're just on time. So again, I really want to thank Dr. Sharma and Dr. Wong, spectacular job, great presentations, excellent questions. This was a stupendous success. So stay tuned to everybody for the next portal hypertension SIG. And thanks everyone for coming and thank you again to our speakers. So we'll give you guys a virtual round of applause. I don't know where that is. No, I lost. I guess we don't have one. So anyway, well, thanks you guys. See everybody later. Thank you so much. All right. Bye-bye. Thank you, bye-bye.

acute kidney injury

AKI

decompensated cirrhosis

terlipressin

hepatorenal syndrome

HRS AKI

ascites

mean arterial pressure

renal perfusion pressure

serum creatinine