So my talk this afternoon is to review some key information from the AdKey International Club of Societies Consensus meeting on AKI and cirrhosis. For those of you who are not familiar with AdKey, this is the Acute Disease Quality Initiative. This was conference number 29. And this was really the brainchild of some very key thought leaders in the world of kidney injury and liver disease, Dr. Mitra Nadeem, Dr. John Kellum, and Dr. Ravinder Mitra. And they brought together a multidisciplinary and multinational group of experts representing hepatology, nephrology, critical care, surgery, and pharmacology. And there were four main goals, to refine the diagnostic criteria for acute kidney injury and cirrhosis and the hepatorenal syndrome, explore roles for biomarkers for diagnosis and prognosis, examine current and novel therapies for prevention and treatment of acute kidney injury and cirrhosis, and create a paradigm for post-discharge care patients who experience AKI-type hepatorenal syndrome in patients with acute kidney injury and cirrhosis. And I'm really going to focus on some key concepts that came out of this meeting, specifically points one and three, that challenge some of the traditional ways we thought about approaching the management and diagnosis of hepatorenal syndrome in patients with cirrhosis. Quick reminder, all kidney injury and liver disease is not hepatorenal syndrome. In fact, it's not even the majority. When you look at the types and prevalence of etiologies of acute kidney injury and cirrhosis, we still see that pre-renal azotemia is one of the number one causes of acute kidney injury. And it actually has a fairly good prognosis, with an overall survival at 90 days of 22%. But then we see hepatorenal syndrome type acute kidney injury and acute tubal necrosis, representing a significant proportion of kidney injury in patients with cirrhosis. And you see that the prognosis for both hepatorenal syndrome and ATN is quite different than pre-renal azotemia, with mortality rates of just at 50% at 90 days. I think most people in this audience recognize that the etiology of kidney injury and cirrhosis is really multifactorial. In patients with advanced liver disease, we see numerous mediators that drive the development of the potent renal vasoconstriction that occurs in hepatorenal syndrome. And in pure HRS, really we're dealing with structurally normal kidneys that due to significant changes in both systemic mediators, as well as splanchnic vasodilation and perfusion of the kidneys, we see significant decreases in renal function. But with restoration of normal liver function, these kidneys actually oftentimes return to normal. Now, you have to understand that HRS type acute kidney injury is on a spectrum. And many of these patients, if the liver injury is not reversed, if these patients don't go on to get transplanted, and their physiologic comorbidities are not managed, this often transitions later to acute tubular necrosis. Now, some of the important points from the meeting of the Adkey group, number one is to really revisit how we define hepatorenal syndrome type acute kidney injury and cirrhosis. So the traditional definition was an increase in serum creatinine of greater than 0.3 milligrams per deciliter within 48 hours, or an increase in creatinine of greater than 50% from baseline to have presumably occurred within the last seven days. But an important change from the Adkey meeting was to add urine output. And for an intensive care unit audience, I think this is an incredibly important point. This was not something that was traditionally considered a diagnostic tool for hepatorenal syndrome in patients with cirrhosis, and is currently not in the current guidelines for diagnosing cirrhosis from the European or the American liver societies. So this added to this urine output of less than 0.5 milliliters per kilogram for greater than six hours, with absence of improvement in serum creatinine and or urine output within 24 hours after you've adequately volume resuscitated these patients, and absence of a strong evidence of an alternative explanation fits into the diagnosis of hepatorenal syndrome type acute kidney injury. I show this slide every time I give a talk about diagnosis of hepatorenal syndrome type acute kidney diagnosing HRS in patients with cirrhosis. Remember that the traditional European and American guidelines don't use urine output. But this was an important study from the University of Pittsburgh demonstrating the value of measuring urine output as a tool to identify patients with kidney injury and cirrhosis. This was a large study of cirrhotic patients in the intensive care unit. And you can see that whenever you use either a serum creatinine definition for kidney injury or urine output definition, that the prognosis is relatively the same. So these first two lines are representing patients that have either serum creatinine criteria for acute kidney injury stage three, or urine output criteria for kidney injury stage three. And the prognosis remains the same. If you add in patients that have both serum creatinine criteria and urine output criteria, they have considerably worse prognosis. The study also demonstrated that when you use serum creatinine only to identify kidney injury and cirrhosis, you fail to identify a significant proportion of patients that have documented acute kidney injury. Another important point from the ADCA meeting was that we recommend against systematic administration of albumin for 48 hours as a requisite for the diagnosis of hepatorenal syndrome type acute kidney injury. So if you remember from the current guidelines, we say the liver guidelines would tell you that you need to adequately volume resuscitate patients. They tell you to monitor these patients and administer albumin for 48 hours. But if you remember the data from the confirmed trial that we presented at this conference several other times, we recognize that there was a large increase in respiratory events in patients with hepatorenal syndrome receiving turlopressin. And this was driven in large part by the large amounts of albumin that these patients were receiving prior to being enrolled in the trial. So what we're really saying is that you need to adequately assess the volume status in these patients, but it is not a requisite to give albumin for 48 hours before making a diagnosis of hepatorenal syndrome and initiating these patients on appropriate vasoconstrictor therapy. Also remember that the presence of underlying kidney disease does not exclude a diagnosis of superimposed hepatorenal syndrome type acute kidney injury. Second, we recommend personalized strategies for the management of AKI based on the individual patient's kidney, liver health profile, and AKI phenotype. So again, this recognizes that patients may also have some underlying structural kidney disease, but can also have superimposed hepatorenal syndrome on top of this. I think for the ICU audience, this is critically important, the next point I'm about to make. Physical exam in combination with imaging, both static and dynamic measurements to guide fluid resuscitation throughout all phases of treatment to avoid volume overload is incredibly important. Again, we saw an important safety signal in the US confirmed trials for turlopressin in which there were significant increase in severe respiratory events associated with the initiation of turlopressin. And again, we really believe this is because the way the trial was organized, patients were receiving lots of albumin in advance of starting turlopressin or other vasoconstrictor therapies. Another important concept that came out of this meeting was that we recommend crystalloids preferentially balanced salt formulations as a first-line therapy for patients with AKI requiring fluid resuscitation in absence of a clear indication for other fluids. And I think this is starting to come in line more with other critical care guidelines for how we're using albumin. It was part of the driving force for what prompted the AdKey meeting was to look at how are we using albumin in these patients. And really, when you're meeting a patient for the first time that's undervolume resuscitated, we can probably get away with using crystalloids in the early phases of resuscitation. This is another slide from a previous AdKey meeting, and I think it's how all of us think about approaching fluid resuscitation in the ICU. You really need to determine where the patient is in the resuscitation spectrum. And for patients who have been adequately volume resuscitated before they show up in your unit and clearly are not volume depleted, you can move into a diagnosis of HRS and initiate vasoconstrictor therapy quite early without having to flood them with additional albumin and risk the development of pulmonary edema and other respiratory complications. I think another challenge for patients that are co-managing HRS with a hepatology service is that hepatologists are always very, very fearful of using diuretics in patients with a presumed diagnosis of hepatorenal syndrome. Remember that the previous guidelines from the liver societies always tell you to withhold diuretics before you can make the diagnosis. But remember, many of these patients are gonna show up into your unit very volume overloaded. So for patients that are clearly demonstrating evidence of volume overload, we recommend discontinuation of all fluids and initiation of diuretics or renal replacement therapy in patients with acute kidney injury who demonstrate signs or symptoms of volume overload. We recommend initiation of renal replacement therapy be an individualized decision with consideration of clinical context and anticipated or observed life-threatening acute kidney injury-related complications. I think this is always a very controversial topic in patients with ACLF and kidney injury. I'd point to one study that I don't show you a slide for, but I will talk about in a session tomorrow. When we looked at a small group of patients with severe alcohol-associated hepatitis required renal replacement therapy, 30% of these patients survived no longer needing dialysis at the end of the study. So it is not always futile to consider renal replacement therapy in patients who have ACLF grade three, even if they're not a liver transplant candidate. We recommend expedited evaluation for liver transplant in all patients with decompensated cirrhosis following an episode of AKI, because the only thing at the end of the day that's likely to give patients a durable response and a durable chance at long-term survival is liver transplant. Finally, additional management strategies. We recommend initiating vasoconstrictor therapy, preferentially Turlopressin as first line, in combination with concentrated albumin immediately upon the establishment of HRS-AKI. Again, think about where the patient is in the volume resuscitation spectrum. They may not need daily large doses of albumin. We always recommend close monitoring of volume status during treatment for HRS-type AKI with dose of albumin being adjusted daily based on patient's volume status, and with immediate discontinuation of anybody who's demonstrating signs of volume overload. Lastly, liver transplant, again, remains the only definitive treatment for patients who develop hepatorenal syndrome. Key take-home points from the ADK meeting. Again, urine output should be considered as an important tool in the assessment of acute kidney injury and cirrhosis. The systematic administration of albumin for 48 hours as a requisite for establishing the diagnosis of hepatorenal syndrome is no longer recommended. Do not delay initiation of vasoconstrictor therapy once a diagnosis of hepatorenal syndrome has been established. Remember from the confirmed trial, the earlier you start it, the more likely you are to have a durable response. Judicious monitoring for volume overload and consideration of diuretics for renal replacement therapy when volume overload is identified is an important tool for management, and all patients with hepatorenal syndrome must be evaluated for transplant candidacies. This is the only thing that's going to give them a lifetime chance of good response. Thank you very much for your attention, and I'll turn it over to Dr. Dong. Thank you.

AKI

cirrhosis

hepatorenal syndrome

vasoconstrictor therapy

liver transplant