Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 141 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is what you need to know about hepatorenal syndrome, new definitions, treatments and clinical pearls. So clearly, we're talking about hepatorenal syndrome today, Dr. Khyati Patel 00:47 and the reason we're talking about it today is because there's sort of a new classification of its name. Is that right? Dr. Kane, yeah. Dr. Sean Kane 00:55 So we have kind of new definitions that came out about five years ago, but even newer clinical practice guidelines from the American Association for the Study of liver disease, or AAS LD, and those are 2021, guidelines that are referenced in our show notes at HelixTalk.com there's some new stuff in the area that we'll be talking about today. Dr. Khyati Patel 01:13 Okay, that's exciting. So perhaps to set the stage, let's maybe kick off with a case that we have. Ah, who's a 48 year old male, came to the hospital with altered mental status, worsening ascites and shortness of breath, and patient has past medical history of alcoholic cirrhosis, therefore the ascites and then several recent hospitalization because of the alcohol intoxication, withdrawal and then decompensation of his cirrhosis, the serum creatinine on presentation is 2.1 this is much elevated than what his baseline is. His baseline is around 1.1 and so the questions that kind of come up to your mind is, you know, does this patient, Mr. Ah, has hepaterenal syndrome, and you know, is this just a new renal impairment, or is it somehow tied to the history of the cirrhosis, or is this kind of there is more to the diagnosis? Dr. Sean Kane 02:10 Then, of course, if he does have this thing called hepatorenal syndrome, do we do anything different for that compared to just run of the mill acute kidney injury that we see all of the time in the hospital? So kind of started with some background, hepatorenal syndrome itself is something we've known about for a really long time. We have a pretty good sense of the pathophysiology. Part of that is that it's not simply you have renal impairment and you have cirrhosis. There's actually an interplay between the cirrhosis and the renal impairment that occurs, Dr. Khyati Patel 02:39 technically, depending on the degree of renal impairment. You know, there's a couple different flavors or types of hrs that exist. And so we have hrs type one, which is redefined to be called hrs Aki, which has presentation of acute kidney injury to it when it presents acutely as well. Patient can come up with the, you know, poor serum creatinine kind of quickly. So that's type one, and Dr. Sean Kane 03:08 then type two. HRS. Type Two is now the new term is hrs Naki, n Aki for non acute kidney injury, or non Aki. This is where you have renal impairment that happens in the context of cirrhosis over a longer period of time, so we're talking like weeks to months, as opposed to this acute onset. So kind of kudos to the people that came up with the guidelines. I think hrs Aki tells you exactly what it is, versus remembering type one versus type two, which one is which and things like that. Yeah. Dr. Khyati Patel 03:36 And I think to understand this better, it is important that we talk about the underlying pathophysiology of how this is happening, right? So in short, the hrs, Aki, there is too much vasoconstrictions in the GI circulation, and then too much vasodilation everywhere else. So the kidneys are not getting perfused properly because of too much vasodilation, and that's where the acute injury, the kidney injury, is coming from, yeah. Dr. Sean Kane 04:05 So really, in essence, this is kind of a form of pre renal, acute kidney injury. Pre renal just means that you're not getting enough blood flow to the kidney. The difference between, you know, run of the mill, pre renal, Aki, which is caused by dehydration or vasodilation, or bleeding, or something like that. The difference here is that that vasodilation is being driven by the cirrhosis, as opposed to a medication that's causing vasodilation or dehydration or something like that. Dr. Khyati Patel 04:32 And if we can kind of dive further into what really happens, you know, going back to cirrhosis, because, as we said, that hrs AKI is sort of like the complication of cirrhosis. In cirrhosis, we have a process called portal hypertension, and what's happening is, because of the cirrhotic tissues, it's much harder to pass the blood through the liver, and so the portal vein pressure kind of goes up, and then to compensate for it. Body kind of releases these vasodilatory compounds. So yes, it ends up causing vasodilation of the GI or this blanket circulation. However, the vasodilatory compounds go everywhere else too and end up causing vasodilation peripherally as well. Dr. Sean Kane 05:18 Then, of course, the body knows that the systemic blood pressure is too low, so in response to that, it's going to release things like renin, angiotensin, aldosterone, epinephrine, norepinephrine, and all of those compounds are going to cause vasoconstriction to counteract that systemic hypotension that happens, and unfortunately, that means that the kidney, because of reduced blood flow, because of all this vasoconstriction, the kidney, is not going to get the amount of blood that it needs. That it needs. And because of things like renin, angiotensin, aldosterone, the body's going to start holding on to more sodium and therefore more fluid, and that's going to drive more of the ascites that will happen as the patient's cirrhosis decompensate. So we see, basically because of that portal hypertension, the net effect is that you get too high of a blood pressure in the GI circulation, and then too low of a blood pressure in the systemic circulation. And again, we want to fix that right? Dr. Khyati Patel 06:11 And so at this point, Dr. Kane, even though this is kind of like the progress of cirrhosis, we have two organs involved, right, the liver as well as the kidney. And so something tells me that the prognosis is not very Dr. Sean Kane 06:23 good, yeah, and that's Dr. Patel. A really key thing, especially in the ICU literature, is the more organs that you have that are failing, the higher your mortality rate. And this is no exception. So as you mentioned, we at least have two organs failing, the liver and the kidney. These patients as a median stay in the hospital for 30 days, three zero days. It's a really long time. About a quarter of them are going to need hemodialysis. They have acute kidney injury, though, that kidney failure will progress and they'll need to be on dialysis. And then the in hospital mortality rate is 37% that's a huge mortality rate. And in addition to those that die in the hospital, almost 10% will go into hospice, which typically means that they'll be dying in days to weeks. And of those that survive their hospitalization, about a third of them will come back to the hospital within 30 days, so readmission. So this has a really high morbidity and mortality rate, Dr. Khyati Patel 07:19 and then kind of going back, let's kind of talk about how we define hrs, right? So again, this is more than just having renal impairment with cirrhosis, as we kind of talked about how these two organ have a very strong interplay. And the older definition was there was an acute kidney injury in cirrhosis. But now with the hrs one, there is specific serum creatinine thresholds that are required. Yeah. Dr. Sean Kane 07:47 So historically, to have acute kidney injury and you are cirrhotic, you had to have a SIM credit and of one and a half or higher, and you had to be doubled from your baseline. So if your baseline is one, that means that you'd have to have a SIM cretin of two, and that number would also have to be above one and a half. And then for hrs, one, you'd have to have a serum creatinine of at least two and a half, and again, it would have to be doubled from baseline. And there are some other criteria and factors that we won't get into right now. The problem with that is that both of these definitions relied on a very specific serum creatinine threshold, so you had to be above one and a half for acute kidney injury, and above two and a half for hrs. And the problem with that is that, especially in cirrhotic patients, they're more likely to have muscle wasting, so they don't make a lot of Creatinine to begin with. And then the liver is responsible for converting creatine from the muscle into creatinine. And if the liver is not working very well, that means that means that the serum creatinine levels are going to be falsely low. And again, it's harder for these patients to mount a really high serum creatinine level. Dr. Khyati Patel 08:48 And so I like when the organizations come together and kind of agree on guidelines and standards, how we are looking at this, some creatinine, right? So in 2015 these definitions were updated, and you know, some of these definitions were kind of barred from the standardized the AKI definition. Can you? Can you shed some light on that? Dr. Sean Kane 09:06 Dr. Kane, yeah. So, you know, historically, we had something called acute renal failure that no one agreed on the definition. So then a group got together and they came up with the rifle criteria. And the rifle criteria was what they called acute kidney injury. So we now standardized it. But then two other standardized definitions came out, Ken and now kidigo. And kidigo is kind of the third set of definitions for acute kidney injury, and those are the ones that were kind of adopted in 2015 for this definition of hepatorenal syndrome. Dr. Khyati Patel 09:36 And so the hrs one is now being called hrs Aki, and that's where they're looking at, you know, not a particular number of serum creatinine, but more of looking at serum creatinine increase. So you're looking at absolute increase in serum creatinine by point three milligram per deciliter, and that it's like 50% higher than the baseline. So both look. Net absolute number, or the percentage increase from baseline. Dr. Sean Kane 10:03 And you know, again, this is developed from the kidigo criteria for Aki, and that criteria has different stages. So there's stage one, two and three, and then the hrs Aki definition kind of borrowed from that. So there are different stages based on, effectively, how high your cretin is compared to your baseline. Dr. Khyati Patel 10:21 So we have hrs two, which is now being called hrs noci and Aki, where patients are not meeting the hrs Aki criteria, but their eGFR is low, below 60. So this is any patient who has cirrhosis, but like that, baseline renal impairment. Dr. Sean Kane 10:40 And you know, the treatment for hrs noche or type two is a lot different than type one, so we won't get into it into today's podcast, but it is kind of a different animal in terms of how we manage those patients. Dr. Khyati Patel 10:52 But more so than just looking at the serum creatinine changes. Dr. Kane, I think there are some other components or criterias that have to be met to look at that diagnosis of hrs Aki, right? So we're looking to have patient with cirrhosis plus ascites in this picture, and Dr. Sean Kane 11:09 obviously they have to have acute kidney injury for hrs Aki, so just like we talked about specific staging from the kid ego criteria, and also we want to make sure that we've tried to rule out other causes of acute kidney injury. So remember, HRS-AKI is effectively a pre renal type of acute kidney injury. If someone has acute kidney injury for other reasons, like hypotension, causing acute tubular necrosis, or they got a nephrotoxin, or they're on NSAIDs, or whatever, they have a huge kidney stone, we want to make sure that we address those things first, instead of just calling everyone with cirrhosis and renal impairment this thing called HRSA ki because it's a very specific pathophysiology and treatment, right? Dr. Khyati Patel 11:51 And not to complicate things more, but I know patients with cirrhosis are typically on medications such as Spironolactone or furosemide, and those drugs are also known to cause renal impairment. So you're right, like, kind of looking at make making sure this is not due to any other external factor, but the disease process in itself, the next item as part of the criteria, it's pretty interesting. You need to kind of do something to the patient to confirm this. Can you shed some light on that? Dr. Sean Kane 12:17 Yeah, so this is interesting, because a lot of times when you have a diagnostic criteria, usually you don't have to give a medicine to kind of prove it, but in this case, that's actually what you have to do. So when patients with cirrhosis meet the criteria for acute kidney injury, you have to give them albumin for two days. So basically, you give them two days worth of albumin and demonstrate that their renal function doesn't recover. So if it recovers, then they just had acute kidney injury. You're done. But if you give them albumin and their sim credit and does not improve, then we now call those patients hrs Aki, and we do other things for them, okay? Dr. Khyati Patel 12:52 And we're going to talk about those other things in a little bit. And you know, just the pathophysiology is complicated, and we kind of laid the picture that the prognosis is not very good, because now you have couple different organs being involved. Is there anything we can do to prevent this? Dr. Sean Kane 13:09 Hrs, absolutely. So you know, there are certain conditions or disease states that happen in patients with cirrhosis, and many of those disease states actually can predispose someone to getting hrs, Aki. So for example, GI bleeding. Patients with cirrhosis are prone to having, especially variceal hemorrhage in their esophagus, and so if we can prevent them from bleeding, that can help them not have this acute kidney injury that we're talking about. So for example, we could give things like non selective beta blockers. Propranolol is a common one, where that can decrease splanchnic hypertension, that portal hypertension, and it makes those varices less likely to bleed. So if they don't bleed, then they are less likely to go into hepatorenal syndrome. Dr. Khyati Patel 13:53 Other thing that's very common in patient who have ascites is bacterial peritonitis, right? So preventing the spontaneous bacterial peritonitis. We call it the SBP, can also be helpful. We could look at doing either primary or secondary antibiotic prophylaxis, and some patients are even on maintenance antibiotic therapy with Ciprofloxacin or norfloxacin to prevent the SPP recurrence. Dr. Sean Kane 14:19 Then finally, albumin actually has a really interesting role here, and for any inpatient clinicians listening, you've probably heard about different institutions locking down the use of albumin in terms of you have to meet certain criteria, and it's a cost savings measure, but this is one of the circumstances where we actually should be using albumin. It's definitely indicated. So examples could be in someone who has SBP, they need to get albumin. This is a clear mortality benefiting therapy if you have documented infection in your ascitic fluid. And then two, in someone who gets large volume paracentesis, which means putting a needle into their belly there with a lot of ascites in there, if you. Pull out more than five liters. So think about that for a second. That's more than a gallon of fluid that you're pulling out. If you're pulling out more than five liters, you should be giving these patients albumin. And there's kind of an equation of how much albumin to give them. And the reason you do that is that if you don't give them albumin, they're more likely to get hypotensive they're more likely to get hyponatremia, and they're more likely to get hepatorenal syndrome. So albumin has a role for both of those circumstances. It's very clearly documented and well supported by the guidelines, right? Dr. Khyati Patel 15:27 And I think that's why I was a little bit surprised when you said that we do a little confirmatory test with two days of albumin, because all I have heard is like this. I can picture albumin being locked up in the hospital, you know, being expensive, but here clearly there is, you know, benefit proven, and it should be used in the right manner, but that's preventative strategies. Let's say an acute kidney injury ends up happening. What are, what are kind of like the overarching steps we take to provide treatment? Dr. Sean Kane 15:56 Well, the first one is kind of obvious, and it's basically supportive care, right? So if they're getting a nephrotoxin like vancomycin or an aminoglycoside, you should try to not do that for them. Obviously, if they need it, they need it, but it's a risk and benefit thing. Two, remember, this is kind of a form of pre renal, acute kidney injury. So we don't want to diurese these patients. We don't want to make them hypotensive. So if they're on a diuretic, we're going to withdraw the diuretic. And again, it's really common that these patients are on spironolactone and furosemide for their ascites. So we're going to stop all of those. We're going to be thinking about, are they infected, and if they are treating the infection, sometimes we'll even empirically give antibiotics, because we presume that they have an infection, because it's fairly common in this patient population. Then finally, going along the route of diuretics, maybe they've been over-diuresis and now they're dehydrated, or maybe they've had diarrhea or some condition where they haven't been able to keep up with oral intake. We may need to rehydrate these patients. And again, this is typically not something we do commonly, because these patients often have too much fluid, but if they're dehydrated, we should be giving them IV Dr. Khyati Patel 16:57 fluid, and then the last thing was to kind of give them albumin, right? So this is going to depend on their staging of the Aki, and this is going to be a weight based dosing for albumin. Yeah. Dr. Sean Kane 17:09 So albumin in the US comes as either not so concentrated 5% and a typical dose might be like half a liter, or a concentrated 25% and that's the one that we're going to use in these patients, a 25% concentrated albumin. The dose is one gram of albumin per kilogram of body weight per day, and the max dose is 100 grams. Typically these come in 100 ml vials. So that means that you're working in units of about 25 grams. So for an 80 kilo patient, you might give them 75 grams, again, rounding to the nearest 25 so that would be 300 milliliters of albumin you give on day one and then on day two, again, this is kind of either going to improve their renal function or it doesn't. And if it doesn't, then we move down the hepatorenal syndrome pathway for treatment. Dr. Khyati Patel 17:53 And this is where the two day wait and trial period that you mentioned earlier was, let's say the renal function did not improve, and now we're going down the hrs Aki criteria route. What is the next approach for the treatment? More albumin? Dr. Sean Kane 18:09 Yeah, actually. So dosing here is different. For our albumin. We still use the 25% more concentrated product, but we're basically doing two things now. So once we've said yes, they have HRS‑AKI or just hepatorenal syndrome. We give them albumin every single day, and then we also give them a vasoconstrictor. And again, the rationale here is that one of the underlying problems here is that we have lots of vasodilation in the GI circulation, and that lots of vasodilation is setting this cascade of events that causes this hepatorenal syndrome. So if we give them a vasoconstrictor, we can prevent the underlying problem, which is too much of that vasodilation, and hopefully set everything right again. So it's albumin, although lower dose plus a vasoconstrictor. Dr. Khyati Patel 18:53 So we're kind of just attacking the problem from two different angles with two different mechanisms here, as you mentioned, Dr. Kane, the albumin dose is lower, but we still kind of go with using the concentrated the 25% albumin. Is there a particular dose, or we just kind of try to shoot in the middle? Is it a weight based dosing? Dr. Sean Kane 19:13 Again? Yeah. So we actually don't really know what the best dose is. The guidelines say somewhere between 20 and 50 grams. Almost all of the data uses 20 to 40 grams. But again, we have to work in units. In the US of 25 gram units, so we're either going to give 25 grams or 50 grams a day. Again, there's no data that says 50 grams is better than any other dose, but that's the dose that we use. And interestingly enough, we've never really studied this, except in one trial of 21 people, and that's literally the extent of our evidence that says that we should give albumin in this context of this hepatorenal syndrome. So for that reason, we're typically giving 25 or 50 grams. It's not a weight based dose for these patients. Dr. Khyati Patel 19:55 So Dr. Kane, you mentioned the strategy is give albumin and give vasoconstrictor. We just learned that, you know, we give a lower dose albumin. We're not really sure about what dose that exactly is, but we probably have some more data on the type of vasoconstrictors we can use. The first one we're going to talk about that's probably a preferred vasoconstrictor. But the unfortunate part is that it's not available in United States. Can you shed some light on that? Dr. Sean Kane 20:21 Yeah, so that agent is called terlapressin, and I'm sure you know anyone practicing on the inpatient side that's read an article about hepatorenal syndrome, or looked at the guidelines, or read the up to date article, it said something about terlapressin. And then you try to get some terlapressin, and you realize it's not available in the US, and you're like, why the heck is it even mentioned in the guidelines? If it's a drug we don't have. This is literally the first line therapy. So it turns out that terlapressin is not available currently in the US, and we'll talk about why in a second, but this is basically a vasopressin analog. So we do have vasopressin, but vasopressin in the US has never been really studied for hepatorenal syndrome, and it's interesting how it's given. So this does not require a central line, even though it's a vasopressor. So you give it either as an IV push or continuous infusion. And if you give it as an IV push, it's every six hours, you can actually titrate the dose based on the patient's improvement or lack of improvement in renal function. The continuous infusion is a little bit better from a safety standpoint, but most trials have used IV push. Typical side effects are going to be gi oriented, so nausea, vomiting, diarrhea, and also some ischemic events. So again, this is a vasoconstrictor, so heart attacks, digital ischemia, on the fingers, things like that. Those are all things that we worry about. Dr. Khyati Patel 21:34 So Dr. Kane, I'm sure there is a reason why FDA hasn't, you know, approved early press then, but maybe we can talk about the efficacy for those countries that are using it. What studies do we have, and what kind of data do we have for that? Dr. Sean Kane 21:49 So by far, this is the best studied vasoconstrictor for hepatorenal syndrome, which is why it's the first line therapy. There were two trials that were done. One was called the reverse trial in 2016 and then really recent, the confirmed trial done in 2021, and basically, if we had to, like, condense these two trials down into the bare bones, basically, terlapressin definitely improves renal function, or in other words, it reverses hepatorenal syndrome, but it does not change mortality. It would be nice to do both, but still, there's benefit to improving renal function. Unfortunately, in that more recent trial to confirm study, they did have a signal of harm, and that signal of harm was increased risk of pulmonary edema and respiratory failure and respiratory death. And the hypothesis right now is that perhaps the combination of tertiary with albumin at the doses that they picked, maybe that was too much fluid for these patients that cause these respiratory issues, or maybe it's just a type one error in the we got unlucky in terms of more patients had these complications. So on the basis of that, the drug company did try to get it approved in the US recently based on the confirmed trial, but the FDA said, not yet. We need more data to really support the risk and benefit profile of the drug Dr. Khyati Patel 23:01 and so then, if this is not a go according to FDA, then we move on to other known vasoconstrictor or vasopressors, we can say. And the common one we have heard being used in ICU patients is norepinephrine. Am I right? Dr. Sean Kane 23:16 Yeah. So we use norepinephrine as our first line vasopressor for most shock states in the ICU. So many people are very familiar with the drug. It's an alpha one agonist, so vasoconstriction with a little bit of beta one support, so a little bit of inotropy with it, it's always given as a continuous infusion. Generally, you need a central line, especially for longer term use, and generally you have to be in the ICU. Most institutions don't allow this to be used outside of the ICU or in the ED, unlike with terlapressin, where we titrated it based on renal response in terms of the SIM credit and getting better, all of the studies that use norepinephrine basically try to get the patient's blood pressure 10 millimeters of mercury higher than it was at their baseline. So if they come in with a map of 80, you're going to give norepinephrine titrate it to a map of 9010 higher than their baseline. Dr. Khyati Patel 24:03 And that's kind of like a benchmark; unless terlipressin was dosed or titrated to look at the serum creatinine improvement, the norepinephrine is titrated to look at the MAP improvement. Dr. Sean Kane 24:16 And generally speaking, most data shows that norepinephrine is just as good as terlapressin. There's a little bit of data, and kind of a subset of hepatorenal patients that maybe terlapressin is better, but generally speaking, norepinephrine appears to be as efficacious, with the caveat that you have to have a central line, and you have to be in the ICU, which is annoying, because terlipressin, you don't need those things, right? Dr. Khyati Patel 24:36 And then the things that we are going to monitor, given it's a vasoconstrictor, would be side effects of arrhythmia, especially afib, or as you mentioned earlier. Dr. Kane, certain ischemic events could end up occurring and obviously tachycardia. So. Dr. Sean Kane 24:51 Dr. Patel, if you think about it, our first line therapy, we can't get in the US. Our second line therapy, you have to have a fairly invasive catheter and be in the ICU. Our third line. Therapy is kind of our compromise here. So if a patient either is not appropriate for the ICU or for whatever reason, it's not reasonable to give them norepinephrine or the risk and benefit, maybe they just had an MI, or they're tachycardic right now, our third line option is the combination of midodrine with octreotide. Dr. Khyati Patel 25:19 So midodrine is an oral therapy. It's an alpha one agonist, and the one thing that I remember from it being outpatient is that the only problem with this is that it has to be given multiple times a day. So we're looking at three times a day, and then it's titrated Again, very similar to the norepinephrine where we're looking at increasing the patient's MAP, or map, to about 10 more millimeter per Mercury octreotide, on the other side, is interesting. And I know octreotide is, you know, either given sub q or IV, that's a Somato statin analog, yeah. Dr. Sean Kane 25:56 So this is basically blocking some of that vasodilation in the GI circulation. So it is addressed in the underlying pathophys of the condition. It is either given as a continuous IV infusion or three times a day subcutaneous injection. Either one is fine. There's really no data saying that one version is better than the other, but this is considered a last line therapy because it has been compared to terlipressin and norepinephrine, and it's not as good, so it's less effective at improving renal function. And hepatient renal syndrome, from a side effect standpoint, it's kind of nice. So midodrine is associated with some bradycardia, but fairly rare and usually not super clinically relevant. Then octreotide. We can also see bradycardia. We can also see some of the diarrhea, nausea, vomiting type stuff, and it can either make your glucose go up or down. It kind of does both. So, you know, in my experience, I haven't seen a lot of this, but it is well described in the package insert for octreotide. Dr. Khyati Patel 26:51 So we got the first line therapy, which is not available in the US. We got the second line therapy, like you mentioned, Dr. Kane requires a little bit more invasive approach, in the third line therapy is not really as effective, but putting it all together, the combination of albumin and vasoconstrictor, let's talk about length of therapy. You said that these patients usually end up spending about 30 days in the hospital. How long do we continue these therapies for? Dr. Sean Kane 27:18 So best case scenario is that you initiate therapy for hepatorenal syndrome, and within days, the patient's renal function goes back to normal. You pat yourself on the back and then you stop your therapy. So once renal function goes back to normal, you're done. If at day number four, things are not improving, it's unlikely that things are going to magically improve on day five. So the recommendation is, by day four, if things aren't getting better, you stop therapy, both for efficacy and kind of futility reasons. And then if they do kind of improve, but they don't improve all the way back to baseline, the recommendation is 14 days of therapy. So if they continue to improve, but maybe not all the way to their baseline, you get 14 days. And then at day 14, you would stop your therapy. Dr. Khyati Patel 28:02 Besides these medications, are there any other therapies, including any surgeries or procedures that we conduct for these patients, and do they provide any mortality benefit? Yeah, the Dr. Sean Kane 28:13 treatment of choice here is actually liver transplant. This is the definitive therapy, because it fixes the underlying pathophysiology, which is portal hypertension. So even if you give a patient terlipressin With albumin and their renal function goes back to normal, their risk of dying in the next 30 days is really high still. So the way that you address that is by fixing the underlying problem with a liver transplant. Unfortunately, not everyone is eligible for liver transplant, and some people will die before they even get a liver transplant assigned to them. So you know, this is best case scenario, but not going to happen for everyone. The other therapy that is often considered is hemodialysis. So we mentioned earlier that about a quarter of patients will end up on dialysis who have hepatorenal syndrome, and it basically buys you time. So unfortunately, if a patient with hepatorenal syndrome is requiring dialysis, the longer they're on dialysis, the more likely it is that their kidney function will not return, even if you give them a transplant. And if someone is not a liver transplant candidate, meaning for whatever reason, they can't get a liver even if you give them dialysis, their mortality rate is about 90% nine 0% really indicating the futility of this, because you haven't fixed the underlying problem of their cirrhosis. So in those cases, if they can't get a liver and they need dialysis, palliative or hospice care is probably the most appropriate step for those patients. Dr. Khyati Patel 29:35 So that rests the point, as you said earlier, that having this condition is, you know, bad prognosis in general, kind of going back to our patient, though, and then see where ah is, as we kind of laid the land. The patient has known cirrhosis and ascites, which is kind of like that. One of the criteria for hrs definition, the other thing we're looking at is the patient. Is renal function where it's at, rather, it's a baseline impairment, or is this more of an acute change? And we define this being an acute change, because patient's baseline was about 1.1 now it has increased to about 2.1 Dr. Sean Kane 30:14 Yeah, we didn't go over specific definitions, but the specific definition for this patient would be a stage 1b which would mean that we would be thinking about things like albumin for the patient. So at this point, we still can't say that they have hepatorenal syndrome, because remember, part of the definition is that you give two days worth of albumin to see if you can make the renal function go back to normal. So this is where we're going to stop diuretics for the patient, rehydrate, if appropriate, avoid all those nephrotoxins, and we're going to give him albumin. We're going to give a gram per kilogram per day, Max, 100 grams of albumin that concentrated 25% and if his serum creatinine improves, great. We pat ourselves on the back, and we don't say that he had hepatorenal syndrome. If, despite the albumin and despite the supportive care, the serum creatinine does not improve. Now we truly have hepatorenal syndrome. Dr. Khyati Patel 31:03 And let's just say, if we did confirm this patient having hrs diagnosis, then most likely, based on our care in us and the availability of medication in the US, patient would be in the ICU. And you know, we'll be doing that low dose albumin plus norepinephrine to improve the map by about 10 millimeter per mercury. And if Dr. Sean Kane 31:23 he's not in the ICU for whatever reason, or he's not eligible for norepinephrine, that's where we're going to reach for the same dose of albumin, plus we're going to give midodrin, plus we're going to give octreotide, and that, again, we're looking for a map increase of 10 and then we're going to do whatever we're doing for either four days if his renal function doesn't improve, 14 days if he doesn't quite improve to baseline, or if at any point he gets back to his baseline, we're going to stop our therapies. So you know, we have some show notes at HelixTalk.com specifically, we've got the AASLD guidelines from 2021 there's also some European guidelines, easl guidelines. Those are from 2018 and they're fairly concordant with each other. And for the listeners, if you want to know more, that's a great place to look. Dr. Khyati Patel 32:07 So to kind of summarize this amazing hepatorenal syndrome episode, Dr. Kane, I think the thing that I took away is, you know, at the basic level, the hrs AKI is kind of looking at pathophysiology caused by the portal hypertension that causes systemic vasodilation, which is kind of causing that pre renal Aki condition. Our treatment is too then focused on increasing that vascular volume and then causing the vasoconstriction, so the kidneys are perfused properly. Dr. Sean Kane 32:38 And as we said, there is kind of a newish definition of hrs Aki, as opposed to hrs type one. And basically they borrowed the standardized acute kidney injury definition from kidigo. And the definition of hepatorenal syndrome Aki, or HRS-AKI, requires that you have cirrhosis, you have ascites, and we've excluded other reasons for acute kidney injury, like intrinsic and post renal, acute kidney injury. Dr. Khyati Patel 33:03 So in case of Aki and hrs Aki, we're gonna start off with that concentrated 25% albumin, and that's gonna be given for that two days to kind of test it out. And if it's confirmed that patient has hrs Aki, then anywhere between 20 to 50 grams per day, albumin will be given along with the vasopressor therapy. Dr. Sean Kane 33:24 Then in terms of that, vasopressor, vasoconstrictor, terlapressin, is first line, but we don't have it currently in the US. Obviously, the manufacturer would really like that to happen, and they're doing studies to try to support its risk versus benefit profile, norepinephrine, if they're in the ICU is our next best option if they're not in the ICU. Our third line option is midodrine with octreotide, and we're going to continue until renal function is back to baseline. At day four, if nothing good is happening with renal function, we'll just stop for futility, or all the way out to 14 days if they are showing improvement but not quite back to their baseline. So I think that wraps up episode 141. Quite nicely, Dr. Patel. Again, we have some show notes at HelixTalk.com this is episode 141, we also release clinical pearls on Twitter, so you can follow us at HelixTalk. We love the five star reviews in iTunes, so keep those coming. So with that, I'm Dr. Kane and I'm Dr Unknown Speaker 34:16 Patel, and as always, study hard. Narrator - Dr. Abel 34:19 If you enjoyed the show. Please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there to suggest Narrator - ? 34:31 an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.