So, as we did previously, it would be great if you have questions as well. You can come up to the first mic. It seems to be working the best, but we'll get started with the case. I have no disclosures. So, this is Miss KD, and she's a 52-year-old female with decompensated cirrhosis, secondary to NASH, and active alcohol use. She's coming into your emergency room with abdominal pain, fever, and new onset of confusion. With regards to liver complications, she's had moderate ascites despite diuretics, hasn't yet needed a tap. Variceal bleed she had three months prior. She's got type 2 diabetes for the last 10 years, and she's on several medications including diuretics, Natalol at 80 milligrams a day, some insulin, and some Ceptra that was started for urinary tract infection. On examination, her blood pressure is 95 over 45, so that yields a MAP of 62. Her temperature, she's febrile at 38.5. She's got a BMI of 21. She's generally tender in the abdomen. She's got moderate ascites and bilateral pedal edema with some chronic stigmata, and she's muscle-wasted. So, you notice that she's got a cane by her bedside. So, her labs, if we look at her labs on that first day of presentation, and we compare from a month ago to today, and particularly for the creatinine, but her white blood cells have increased up to 14. Her creatinine has gone, and I put the units for our Canadians as well, 95 micromoles per liter now, or 1.1, and previously that was 45 and 0.5 respectively. Belly rubin, you can see, is up, and her ascites fluid polymorphs are consistent with a diagnosis of spontaneous bacterial peritonitis. So, first question, just to reinforce the point, is this acute kidney injury? I mean, her creatinine's only 95 or 1.1. Hands down, yes. Okay. How do we use, how do you use sarcopenia, or this, she's muscle-wasted, she's using a cane. We've heard that females may be underrepresented by the, not served well by our current estimations of creatinine and GFR. So, how do you use that information, or how do you see that being used in the future, potentially? Sarcopenia may explain the low baseline value of serum creatinine in this patient, of course, and we should take care about this in the evaluation of the lab investigation. Yeah. Is there anything upcoming? Josh, you had sort of touched on it a little bit. I mean, I think there's lots of ways to measure GFR. You wouldn't do it in acute kidney injury setting. Certainly, I would imagine that that 0.5 serum creatinine in this patient is, it probably should be like 0.1. And so, I mean, we never measure it at this stage, though, but the 1.1 is actually pretty advanced, significant AKI. And so, you know, that's a doubling, and I think, as hepatologists, over time, we're really glad that criteria have changed to take away cutoffs, because this is significant. I think stage two, like AKI, or three, I mean, it's almost, it's more than, it's a doubling of the creatinine, and you don't have to be going above 1.5 or 2.5. But the sarcopenia aspect of it, I think if you calculate her estimated GFR, like I said, I think I've been just kind of knocking down about 10 points in sarcopenic patients, 10 to 15 points off their GFR to really get an idea of what their true GFR in my mind, and use that as sort of their measure. Puneeta, can you tell us what was her map at the time of the diagnosis of her SVP, because she's on a very high dose of beta blocker? Yeah, it was 62. Before? No, Florence asked at the time of her SVP, so currently she's 62. Yeah. Okay. So, I've put in a little bit of stuff as far as differential diagnosis for the AKI, just giving an idea of how you guys might approach that, and that's a practical point. She's got a few things on history that obviously might confound the diagnosis. Anyone want to just take that quickly to walk us through? Okay. This patient has a stage 2 AKI, so I will immediately withdraw the beta blocker. I will immediately change the antibiotic treatment, because she was on trimetoprimsulfomatosazole, and now we have an SVP episode, and I will stop the diuretics, and I will give albumin, 1.5 gram per kilo the first day, and 1 gram per kilo after two days, the third day from the diagnosis of SVP, and then I will see what happened about serum creatinine beta. Okay. Would you ask for any additional tests at this time? I would love Lupe's urinalysis, and MSU, because this woman just had a UTI. I mean, I know we're hepatologists, but the urine is very useful. So, not only that, I mean, Pablo didn't mention this, but of the non-urinary injury markers, which we do not have in the US, the other thing that we have looked at in addition to the epiurea is fena and albumin in the urine as surrogates. I mean, not having anything, you know, impairs our diagnostic capabilities, but you want to get a fena, and we found that the fena is the lowest in the patient, and notice that in the internal medicine books, less than 1%, you say it's pre-renal. In patients with psoriasis, everybody has less than 1%, so you don't start by that cutoff. In our paper with Veltcher, what we found is that if you have 0.1 or less, that only patients with HRS have this. Again, this is a limited number of patients, but the lower the fena, the more you may be inclined to diagnose HRS, because the patients are intensely renally basal, because they are retaining sodium very avidly. On the other hand, albumin, albuminuria, seems to be, it's sort of like a surrogate of tubular damage, so if you get a positive albumin level, it would direct you more towards ATN, because like Paulo said, at the end of the day, you're going to expand her with volume. If that doesn't respond, you're left with, is it ATN or is it HRS, and that's the main differential. I just want to ask Paulo, why are we skipping day two? My practice is just to give albumin every day. This is totally empirical, you know, but we have a controlled clinical trial showing that it is working, so before to state that you can change this behavior, you should have a strong evidence. So these are our guidelines for the management of patient with SBP, and I want to ask Tupere, do you think that urinary engulfing presence of a sepsis like this one, and probably urinary tract infection, will be helpful in the differential diagnosis in between ATN-AKI and HRS-AKI or not? I think that, you know, in our study that we just published, we found that the best day for the assessment of the difference between ATN and hepatorenal syndrome is day three after the administration of albumin, and in this particular case, you know, there are many patients who have this acute kidney injury when they have the acute phase of spontaneous bacterial peritonitis, and after three or four days, acute kidney injury is resolved. So I would not check, I would check standard urine analysis, but not any biomarker, wait what happened until at day three, and then decide. Okay, how many people have the renal biomarkers available to them in their hospitals in the audience? Anybody? Yeah, so not, less than one percent, Lupe is calculating. Okay, so not that common. So urine output is 20 cc's an hour, which falls below that 0.5 cut off. The urinary sodium is less than 10, FINA of 0.2, your analysis is bland, and the renal ultrasound is normal. How many people actually calculate the FINA? How many are doing urinary sodium? Yeah, so a lot more, but Lupe, reinforcing the point that the urinary sodium and the FINA are, obviously one is dependent on the other, but. So if the urinary sodium is more, is 50 or something like that, it's unlikely to be hepatoneural syndrome, for example, just like that, but so we always get urinary sodium and FINA, but again, we wait to see if, we wait to see when we're really faced with ATN versus HRF. The only obvious issue that comes up, the patient's on diuretics, and so sometimes the urine sodium can be high. It doesn't matter, because in a way, well, I don't know, I would like to hear their opinion. If it's low, yeah. I'm sorry? In the way, you know, they have refractory, they're already excreting almost always less than 10 these patients that come in. If they're excreting a lot, I don't think diuretics are making a difference in these patients anymore, but this patient did not have refractory ascites. She hadn't had a paracentesis yet, but she has ascites. Yeah, not refractory though. So you think that, um, you think that, developing AKI, so by definition, this patient has refractory ascites, because you cannot treat it with diuretics. So I guess my question is, if your urine sodium is 50, they're on diuretics and they come in like this, you don't think, you think you would exclude HRS? I would pretty much, I would veer against it, yeah. I mean, you never have the, never. You can use all these, and for the audience, it's not about looking at tests, it's looking at the patient as a whole, right? So this helps you in making the differential by no means, you know, if you think that there may be a diuretic effect, you know, God bless, and maybe it is, but you have to take it in the context. Sometimes you say, you know, there's no way this is a peritoneal syndrome, there's clearly APN, the patient was taking NSAIDs, blah, blah, blah. It doesn't matter what the urinary biomarkers show. So there has to be a clinical context in how the patient appear with the AKF. That makes sense. Okay, so as for Dr. Angeli, she started on antibiotics for her SVP, her diuretics are held. Now this point about holding the beta blocker is clear. I just wanted to raise the issue of nadolol versus propranolol on the safety with renal insufficiency in general. Any comments on that? I think Paolo has been rather taxative saying that he would withdraw beta blockers. Another option would be... Sorry. I think, sorry. Dr. Angeli has suggested quite taxatively to withdraw beta blockers in these patients with previous varicial bleeding. I think that the dose of beta blockers was rather high, but another option could be to reduce the dose of beta blockers. I also would have changed nadolol, at least in Spain is rather difficult to get it, but I would have changed it by propranolol, which is easier to titrate. So I do have a comment about this and it has to do with the map, right? So there's a recent study from Michael Mann's group that is probably like a month ago in CGH that looked at the effect of beta blockers in different scenarios in patients with ascites, in patients with SVP like this patient, and in patients with acute onchronic liver failure. And they found that beta blockers are overall beneficial. They are associated with a better survival in these scenarios, refractor-sized AKI and SVP and acute onchronic liver failure. But the subgroup that benefited the most were those that had a MAP of more than 65. So in MAP, in patients with a mean arterial pressure of less than 65, they were equal. So in a way, so you don't want to, I mean, this MAP is down to 60. I would definitely discontinue the beta blockers at this point. I understand that the patient is on a high dose, but I'm a little scared. What you have to know is that if, for those of you that are in the U.S., if you look at up-to-date, it says discontinued forever. No, that is wrong. Once the MAP comes back to normal, and I don't know if it's going to come back to normal or not, you have to restart the beta blockers. They have a survival benefit in patients even with the most advanced cirrhosis. All right. Let me add, if this will not be the case, in the sense that mean arterial pressure does not recover, you should offer immediately another option for the prevention of arrestial bleeding, that is, pump ligation, you know? I think obviously you've got competing risks. One of the big issues here is competing risks, and also there's the question of is it hepatorenal physiology or is it the physiology of sepsis? I think you can also take it a step back, and what is the intravascular volume? And in a situation like this, I think the patient would benefit from a higher mean arterial pressure than, if you are concerned about variceal hemorrhage, then terlopressin will kind of give you, if it's available, and hopefully we'll have it here sooner. Yeah. And the point that I had wanted to make is that Natalol is renally excreted, so in patients who, this patient clearly has an indication to stop it, but in your other group of patients, then Natalol in patients who have even a degree of renal insufficiency is not the choice that you should make. So how should we volume resuscitate this patient? Because residents on the ward are always like, oh, we can't give any saline, we can't give any ringers, we just need to give albumin. Dean, do you want to take that one? So, you know, I know there is a lot of good data for albumin, but I think we also have to emphasize that, you know, crystalloid or balanced crystalloids, things like plasmolyte, ringers lactate, and Hartmans, if you're in the UK, are part of your resuscitation protocol, and they're, you know, at the end of the day, if you're giving 25% albumin, you're giving a fairly large sodium load anyway. So, and we know that albumin is quite expensive. So I think it's kind of hand-in-hand that we don't exclusively resuscitate AKI or ACLF patients with just albumin. We do use crystalline. I would like to mention that this particular patient has SVP, so there are randomized control trials suggesting that we should give SVP. Yes, so albumin. A different thing is for a patient with AKI with a different course. Yes. And I also want to highlight that in the albio study, the only advantage for the use of albumin is in patients with sepsis shock. And this is in general population. Now we are dealing with a patient with cirrhosis, SVP, and almost severe sepsis. So I will prefer to use albumin. I'm not saying not to use albumin, but often if you're looking, for example, with echocardiography, looking at volume studies, to kind of adequately address intravascular volume, often you're going to have to use more than just albumin. So somebody like this, you could use albumin, but you could also give them two liters of crystallite, just like in the surviving sepsis guidelines. And do you have a preference between saline or ringers? So we don't use normal saline just because of the concern that it's got a pH of four and you can get a hyperchloric acidosis. So that's the idea behind the balanced crystallites. And the problem is if you look at a lot of these studies in cirrhotics that are comparing albumin to crystallite, often they're comparing it to saline. And we're not using, apart from the neural population, we very rarely use normal saline. So ringers. Yeah, ringers or plasmid. One thing that comes up is whether to use the small bottles or the big bottles of albumin. I tend to usually use the small ones just because there's less volume and less leakage and volume administration. Some of these patients have cardiac, cirrhotic cardiomyopathy and can actually flip into pulmonary edema if you go too far with it. The only time I've used the larger ones if I think if somebody is really dehydrated and needs extra volume. But it's pretty on the 5%, the 500 milliliters. Okay. So she gets albumin and crystallite therapy. And despite that, her creatinine rises. So it's 1.9 from the 1.1. And her blood pressure is still around the same. We check her ascites fluid count again and it's coming down appropriately so she's responding to therapy. So we don't have turlopressin yet in North America but hopefully it'll come. So at what point should we be thinking about starting vasoconstrictors on her? And when would you call our friends in the ICU? Well, the patient does not respond to the plasma volume expansion. So probably this is the time to look to renal ultrasound examination to the proteinuria. But the patient has type 2 diabetes so proteinuria may be present. And if the patient has a normal renal ultrasonography I will start with turlopressin plus albumin immediately. Okay. How early is too early, Paolo, for the starting with turlopressin? Would you start it at a certain creatinine threshold or? No. I would start, the patient is a six... She's 52. Yeah, and the weight is... She's, yeah, she's not that heavy. So I will start with two milligrams in continuous infusion per day. Right, but what if her creatinine was, what, do you have a threshold for when it's too early to start? Do you wait for the 1.5? No, no, no. No? No. What about here? This woman really now has stage three AKI and I wouldn't mess around with mitodrionucleotide. I'll call my friend in ICU. So, you know, the threshold is for stage one, not for stage two. Yeah. Kate. Everyone else? Well, as I say, we don't have turlopressin, right? So what we would do at this point is when I would get the urinary things and I would have a nephrology look at the sediment and make sure that there are no casts. Because if there's a bunch of casts in there, this woman came in hypotensive. This may be ATN, in which case I would be a little bit more reluctant. Sometimes, even if they have ATN, just because there may be some component of HRS, we may start, especially because we only have octreotide and mitodrion. It's a very weak, it's almost a placebo. So it's like a very weak basal constrictor combination. So we started the octreotide, we would have started the octreotide and mitodrion. We had an algorithm that actually, with Dr. Fortune, that we started at Yale where we would have buy-in from nephrologists and ICU and everybody else, that if in two days the patient would not respond to escalating the dose of octreotide and mitodrion to the maximum degree as per Dr. Angeli, they would go to the ICU and the ICU people would accept them and they would get norepinephrine. So yeah, we tried to analyze that data and the only conclusion is that people don't follow algorithms. So I can't even tell you what happened. We had patients that would go into the unit, they would start with norepinephrine and then we would go to sleep and the next day the patient was made comfort measure only. Yeah, we have the same issue. I kind of feel like they should be hit hard with norepinephrine earlier on, but the intensive care unit, well, you haven't tried octreotide and mitodrion. It usually doesn't work when it's really AKI HRS. I mean, it's maybe 15, 20% success rate based on the studies. But it's hard for us right now without turlopressin to convince the unit to take these patients until they're a little bit further along and then it's harder to reverse. So it's just. The way we talk to our ICU is the earlier you start, the shorter the patient stays in ICU. Really giving mitodrion and octreotide for two days, you're not going to see any response whatsoever. If the combination is going to work, it's going to work very slowly. And yeah, so you've sort of predicted what would happen. So we have MOA, as I mentioned. And so the patient was started on MOA as would be our typical mitodrion octreotide albumin. And during this, your resident asks if the serum albumin can be used to determine how to dose albumin or when to stop it. Like we see these patients who are on albumin for a long, long time on our wards. And the serum albumin level can sometimes get high. What do you guys think about that? Well, for many years, we went to the meetings saying that you should give albumin to improve the effective circulating volume, not to normalize the serum albumin concentration. Now we are moving back because we realized that probably the target, for example, in the treatment of responsive ascites, in the treatment of refractory ascites with long-term infusion of albumin is to normalize the serum albumin concentration. We need much more evidence before to confirm this target. But in the context of hepatorenal syndrome, this has never been checked before. So I will go on with albumin in spite of the value of serum albumin concentration. So we are limited because in our institution, they won't give us any more albumin once the serum albumin reaches 3.8. So that's where we are. Okay. So the next day, your creatinine is 190. And the intensivist you call, and they're just not keen, not a transplant candidate, and the intensivist doesn't see the long-term benefit of a short trial of support. So I heard Florence's explanation, which is get them in now, and you'll not have them in for very long. Dean, any thoughts as our intensivist on the panel? Yeah, because we're actually very nice people. I think there's a couple of issues here that also going into the ICU, and obviously it's challenging wherever you work, and I know that certain centers, the institutional practices are different. You know, one thing is that also coming into the unit, you're not obligated to do all escalation therapy. So you can try with pressers, and that will probably usually buy you some time. So if you do have, if really there are issues around goals of care or what the future holds, you do have to go to the ICU. You do have time with regards to, in terms of if you are initiating, I think in terms of what's a more challenging thing is initiating renal support. And as I kind of, we were talking about earlier, even talking about the whole issue of renal support in the patient that's not a transplant candidate is a very difficult topic, and it's not something you can kind of sum up in a case. But I certainly think in a case like this that bringing somebody in for a trial of isopressor support is reasonable, and furthermore, kind of like everybody said before, the problem that we run into sometimes is you're getting the phone call when the creatinine's four or 4.2, and at that point, it's very difficult to salvage somebody like that with vasoconstricting therapy. This is almost a daily discussion with intensivists. So what I want to say, if there is a perspective study showing that if we compare the ICU outcomes in patient with ACLF, in patient without liver disease and sepsis, in patient without liver disease, without sepsis, with another reason to stay in ICU, all the ICU outcomes are the same in terms of length of ICU stay, ICU survival, in-hospital survival, three-month survival. So I think there is no reason to refuse the admission to ICU for this type of patient that up to now has been treated with the octetide and midodrine that is effective in less than 20% of patient with HRS-AKI. And before to think about RNA-replaced therapy, we should give her norepinephrine and albumin in ICU. This is my opinion. I think the challenging thing is, and this is where your clinical judgment comes in, that there's really no cookie cutter algorithm for this, that really there are many different phenotypes of ACLF. And as we kind of mentioned before, there's a certain proportion of patients with ACLF that have reversibility. And you may not necessarily know that at this stage in the game. I think it's different if you have, I mean, you have a patient who's 75 years old, who's not a candidate, who needs dialysis acutely to keep them alive versus a 35-year-old alcoholic hepatitis that may have, I mean, the data show it's not likely they're gonna survive if they need dialysis and they have severe alcoholic hepatitis. But I have some patients that have survived through that. And there is a potential for a liver recovery there where it's like a 75-year-old with NASH cirrhosis. And I mean, I just, I think that it's just a case by case. How long do you support them in the unit if they're not candidates? What's this short trial of support like? So I think that usually it's 72 to 96 hours, but I will be honest with you, it's easier to start somebody on something that's actually very difficult to, so often we end up dragging it out to seven, 10 days. That's the hard part. The stopping rules is the hard part. The stopping is the tough part, yeah. And I find on our wards, we've got lots of people staying on the medidernocteratide albumin forever. So I don't know what you guys would say about that. The guidelines clearly say two weeks, but is that what we're doing in practice? Is that what we should do? A lot of the times medidernocteratides actually started as a knee joint reaction by internal medicine residents. So they don't tell you about the patient until the creatinine is four. And at that stage, they would have had dragging it out for about three, four weeks. Okay, so let's flip. I didn't want to do a whole new case. So we've just got the twin of this lady now who actually is a candidate for transplant, and she's listed for a liver transplant. You do get her into the intensive care unit. Her creatinine really goes up quite high and stays around there. Her urine output is 50 per hour in the last 12 hours. She's getting positive. She's got a blood pH of 7.3 and a potassium of 4.5. So at this point, this is really bringing up Dr. Karvelis' topic around at which point would you consider renal replacement therapy? Like when is too early? When is too late? So I think at this point, it's very clearly you're stage three. The other thing to consider here as well is it's that question about going into transplant and are you optimizing the patient to get through a transplant? We tend to be, in our center, tend to be very aggressive with early renal support just because of the hemodynamic issues. And if you're on pressers already, we would go the CRRT route. Also because you don't necessarily get all the rapid osmotic shifts. And there are, most of the time with patients like this, you're gonna run into issues with sodium as well. So I think that's the other issue is that you can also mitigate hyponatremia as well. And it kind of goes back to the fact why it's so challenging to demonstrate benefit with interoperative use of renal support. If you can actually optimize somebody from a fluid balance point of view, and in general, often we're taking fluid off, we're bringing the potassium down. So if they go into a transplant setting where they may get a fair amount of volume with blood products and potentially get a potassium low, they can tolerate it reasonably well. Okay, so do you wait for them to get a bit fluid overloaded or is there a creatinine that you use to sort of say, oh yeah, we should start? Usually it'll depend on the creatinine but also the urine output. If they're oliguric, if they're not making urine, you know you're heading there anyway. One of the benefits of actually having a protocol for potentially using interoperative CRT is actually how we prep the patient. So even if you don't use it, it's the benefit of prepping them going into an operation where they're not fluid overloaded. And the surgeons like you a lot better after that. Okay. And then just the last point is that, pointing to what Josh was saying, you know, she's still in there, she's seven weeks in. And it sounds like we do have criteria for whether or not she would get a liver kidney transplant. So this all really comes together about how do we predict how she's gonna do and whether she needs a liver kidney transplant or a liver alone. And how do you decide that? Yeah, I think this patient meets criteria for AKI for an SLK. And the question is, you know, you kind of look at their real baseline creatinine and then you look at the patient who's muscle wasted and you just know that their GFR is worse than what you think it is, particularly from the beginning. So, I mean, this is somebody that we would do an SLK on. But like I said, I think there's an opportunity for biomarkers to help predict some of these patients can recover. It depends on their, if their native kidney function is, how old was the patient? 52. Was there any other morbidities, diabetes? So yeah, if it's not well controlled diabetes and, you know, you look at the renal ultrasound and I mean, in this, with the criteria, within her situation with her GFR and the muscle wasting, I would support her going through an SLK. Okay. Would you guys? So I gather that all the questions were answered, but if there's anything else that you, we have one minute maybe for one question, if there's anything. Thank you everyone for a wonderful session. All right. Thank you.

decompensated cirrhosis

NASH

alcohol use

ascites

variceal bleed

hepatorenal syndrome

acute tubular necrosis