Good afternoon, everybody. So we'll switch gears and sort of focus in now on hepatorenal syndrome and specifically HRSA-KI. And I'll focus on the diagnostic criteria, if you will, and then Dr. Olson will follow up with the therapeutic strategies. This is my disclosure. So from an outline standpoint, we'll start with reviewing the different etiologies of AKI in decomposite cirrhosis slash ACLF and talk about the differing prognostic values of these different forms of AKI. And then an important point for the audience is to review how the diagnostic criteria for HRS have evolved over time, and luckily in the right direction. And then we'll move on to the current guidelines that help us with the diagnostic evaluation of AKI in cirrhosis and specifically lead us towards a diagnosis of HRSA-KI. And then I want to finish up with a couple of other points. The next issue would be just the evolving role of biomarkers in the diagnostic evaluation of AKI. And this is borrowed from the critical care literature. And then finally, finish up with the important issue that's becoming more of an issue, especially in our patients now with NASH, is how does the presence of CKD in patients affect the diagnostic evaluation of AKI in the cirrhotic patient? All right, so let's start with etiologies of AKI in the cirrhotic patient in the ICU. So when you look at this, again, as you can imagine, you have your usual differential diagnosis. So you'll start with the usual suspects of prenatal azothemia, hepatorenal syndrome, ATN, that you're all familiar with, and just a couple of other additional etiologies that may be pertinent to this patient population is intra-abdominal hypertension, which can cause AKI from 10 societies in particular. And then another unique thing on the differential is bile cast nephropathy, especially in a patient with severe jaundice. So the important point, as you imagine your cirrhotic in the ICU, and especially with AKI, is that AKI in ACLF can be multifactorial. So you can have two of these etiologies, such as septic ATN and HRS, coexist. And that, as you can imagine, makes the diagnostic and therapeutic approaches a bit challenging. So you may have to think sort of dually as you try to target multiple potential etiologies. So now let's talk about what has been studied as far as the causes of AKI in cirrhosis. And this is a list of studies over the years that has looked at potential etiologies as these patients present to the ICU. As you can see, they have bucketed into AKI prevalence and then the etiologies of hypovolemia, ATN, and HRS. And if you scan this table, what you can see is that there's a wide range of reported incidents of HRS in particular. And that, in part, is because the definition of HRS is now evolving over time. And we'll get into more in detail about that issue. But luckily, what has happened is that the definition of HRS has evolved where we are picking up diagnosing HRS with lower creatinine values. And so that is giving us an opportunity to make the diagnosis earlier than later in this patient population. And I'll expand on this a bit more, but what we've done basically in the hepatology community is borrowed the wisdom from the KDGO guidelines and critical care that is now enabling us to diagnose hepatorenal syndrome earlier, which I think will be very important, especially as you hear from Dr. Olson about therapeutic strategies. So now let's talk about prognostic indicators or the importance of the etiology of AKI in cirrhosis. Just to give you a couple of sort of data points here, so this is a study from many years ago, a prospective study, looking at different causes of AKI in the cirrhotic patient in the ICU and how it impacts survival. And when you look at all these different etiologies, including hypovolemia, infection, and parent common nephropathy, HRS was independently associated with a higher 90-day mortality with a significant odds ratio. Similar data in another study that looks, again, similar etiologies in a cirrhotic critically ill patient, and you can see that, again, HRS, and this is HRS was infection, was again associated with higher 90-day mortality. So I've given a couple of examples, but these studies highlight that there is a higher mortality associated with the HRS phenotype of AKI compared to other etiologies and further underlines the importance of early, accurate diagnosis and subsequent therapy in order to reverse this form of AKI and subsequently improve survival. All right, so now let's switch gears and talk about how the diagnostic criteria in HRS have evolved. Just to draw your attention to this slide, on the left is what I'm defining as the old name of HRS type 1, and on the right is the revised HRS AKI. So let me just draw your attention specifically to these two boxes, if you will. So in the Dark Ages, in the left side, we were defining or waiting for the creatinine to be greater than 2.5 before we decided to invoke a diagnosis of HRS and then think about therapy. As you can imagine, in a typical cirrhotic patient with a low muscle mass, you are waiting too long before you make a timely diagnosis of Hepatorenal Syndrome. The rest of the bullet points on that is, we'll talk about that more, but it's basically you have to withdraw diuretics, you've got to give an adequate volume challenge to tease it out from prenatal azotemia, and avoid the usual nephrotoxins, so I'll skip the rest of those bullet points. But on the right is the newer definition of HRS AKI, which has changed the paradigm for this disease process and given us an opportunity to think about timely diagnosis and therapy. We've basically borrowed from the KDGO guidelines, and you're looking at an increase in serum creatinine greater than 0.3 within 48 hours, or an increase in serum creatinine greater than 1.5 times the baseline. So that is the important take-home message from a diagnostic standpoint, as to how the change in the diagnostic criteria is really making a difference with respect to improving the prognosis in this disease process. All right, now let's talk about staging of HRS AKI. So we have, in the liver world, have now again borrowed from the critical care AKI staging criteria with some limitations, if you will. So let me just go through this. So stage one is increase in serum creatinine greater than 0.3, or increase in serum creatinine greater than 1.52, less than two-fold from baseline. In the European guidelines, they have further subdivided stage one into stage 1A, where creatinine is less than 1.5, and in stage 1B, it was creatinine greater than 1.5. This, by the way, has not been incorporated into the U.S. guidelines, but I think it has. I'll show you the importance of this sort of sub-definition. Stage two is increase in serum creatinine at least two-fold, or greater than two-fold from baseline. And this will be an important marker for the audience, as this is where we start thinking about vasoconstrictor therapy, including turleopressin. And then stage three is, as you all know, this is just extrapolating from general critical care, AKI, is at least three-fold from baseline, or serum creatinine greater than four, or the initiation of renal replacement therapy. So I think you're all familiar with this staging process, because it looks very similar to what we do in general critical care. Interestingly, for unexplained reasons, the hepatology community did not decide to incorporate urine output as we normally do in general critical care, which I think needs to be revisited. And so currently, we are looking purely at increase in creatinine in order to stage AKI in the context of HRS. However, having said that, there's more and more debate regarding incorporating urine output into the staging criteria, and just one example of a study from Pittsburgh that actually incorporated urine output and demonstrated that there was a higher incidence and severity of HRS-AKI if you couple, if you complement urine output measurements along with increase in serum creatinine. So this is, hopefully we will revisit this issue soon. So moving on to prognostic utility of HRS staging, so how does it affect mortality, if you will, and again, this is a couple of examples here, but this is one study from, it's been almost 10 years ago, that documents that as your AKI worsens from stage one to stage three, you have worsening mortality. And again, when you think about the subdivision of stage one, A versus 1B, you can see a dramatic drop in survival when you go from 1A to 1B. Similar data from another study that again, re-highlights the importance of the staging of AKI with respect to prognosis, and again, highlights the difference between 1A and 1B in this, similar to what we saw in the first study. So again, this is all European data, and the European guidelines that we'll talk about with respect to therapy do make this distinction between stage 1A and 1B, however the US guidance, which I think most of you will be using, does not make this distinction, just for the record. So moving on to current guidelines for the diagnostic evaluation. So just to draw your attention to this diagram, you're starting with staging the AKI on the top, and then stage 1A on the left, which is just observation, removing your nephrotoxic agents, close monitoring, volume expansion, and then on the right side is stage 1B, 2, or 3, and that's where you start thinking about the same strategies, but also volume expansion with albumin for one gram per kilogram for two days, so 48 hours, and then you just basically walk down this algorithm, and Dr. Olson will elaborate on this more, but after you've ruled out all the other suspects, if you will, you've looked at a urine, make sure there's no ATN, you've done an adequate volume challenge, you've excluded prerenalisotemia, then you go down and think about a therapeutic intervention with a vasoconstrictor, such as trolipressin, which is now standard of care, if you will, for HRS AKI. Just to make the point again that the recent US liver guidelines, that's the ASLD guidelines, do not distinguish between stage 1A and 1B, and so what we are doing practically, if you will, is if your baseline creatinine doubles, which takes you to stage 2 AKI, that's a trigger for therapy with trolipressin, so just maybe a more practical approach to it, if you will, with respect to thinking about therapy. Now let me switch gears again, just share with you briefly some data regarding biomarker studies, a few studies out there, and just I'll give you one example here, very similar to what we've seen in general critical care, but there is some emerging data regarding especially the efficacy, or the utility, if you will, of Engel as a potential biomarker of interest in the context of HRS AKI, and again, similar to what we see in general critical care, you're ruling in ATN rather than ruling out HRS, so there's more data that is being emanated in this domain with respect to looking at the utility, the potential utility of biomarkers as we are trying to differentiate between HRS and ATN in the setting of cirrhotic AKI. And then finally, let me conclude with the, I think an important emerging concept as we take care of more and more cirrhotic patients with underlying CKD, and the classic patient would be the NASH cirrhotic with diabetes who may have diabetic nephropathy, so again, just to walk down this differential diagnosis, diabetic nephropathy in NASH, which is something we're seeing more and more often, there is a, for the sake of time we won't go into this, but there is an HRS which is non-AKI, which is CKD, which is sort of a more indolent course, which can also exist in the patient with cirrhosis, which is not an acute renal injury, and then other examples that may be unique to this population is IgA nephropathy in the setting of alcoholic liver disease, which is again, as you know, is an epidemic currently in the U.S., and then another example that's unique to this patient population is viral hepatitis-induced MPGN, and so when you think about these potential ideologies and the changing phenotype of our patients, especially with NASH, the presence of underlying CKD can further complicate your management of AKI in the acute setting, and have implications regarding renal replacement therapy and the consideration for combined liver-kidney transplantation. So just to summarize this part of the session, AKI and cirrhosis and ACLF can have multiple ideologies that can contribute simultaneous renal dysfunction and complicate our diagnostic and therapeutic algorithms. I've emphasized the importance of recognizing that HRS-AKI definitions have evolved, luckily, favorably, in order to incorporate AKI concepts from what we've learned from general critical care, and that'll facilitate early diagnosis and importantly, as you'll hear in the next talk, timely therapy, which makes all the difference. There are recently revised guidelines, especially from the AASLD, the U.S. liver community, that is now setting the sort of standard, if you will, to define firm guidelines for when to initiate totally present in particular. And then the emerging role of potentially biomarkers in further helping us with this diagnostic process. And then finally, please be aware the increase, the prevalence of CKD in this patient population that can further complicate the management of HRS-AKI in our ICs. Thank you for your attention.

hepatorenal syndrome

diagnostic criteria

therapeutic strategies

acute kidney injury

cirrhosis