SCCM Resource Library-Maintaining Renal Function in Patients With Cirrhosis: New Guidelines and Evidence in Identification and Management of Hepatorenal Syndrome and Acute Kidney Injury

Video Transcription

My name is Dean Karvelas. I am from the University of Alberta in Edmonton, Alberta, Canada. And my two colleagues are Bill Pepper from the Medical College of Wisconsin,  and Dr. Jody Olson, who is from the University of Kansas. And we're going to be talking today about renal function and cirrhosis,  going over some of the new guidelines and some of the changes in the management of hepato-renal syndrome.  So this session is an interactive session. There'll be some audience participation. And you'll notice on your seats that you have a clicker. We're going to have some pre-questions.  There'll be three didactic lectures that you're going to get. And then after that, we're going to go through a case.  And there'll be a couple of questions that you'll be able to vote on in terms of your responses. Okay, so first question is just to get a kind of poll of our audience.  We're just wondering your background, and you can take a moment to answer this.  Excellent. So we've got a variety of different members of the multidisciplinary team.  What is your current serum creatinine benchmark for a confirmed diagnosis of acute kidney injury,  HRS, and cirrhotic patients following withdrawal of diuretic use and plasma expansion? Okay. And what is the most common pharmacotherapy used by your critical care team,  in addition to albumin, in the management of patients with hepato-renal syndrome? All right.  So the objectives for this first talk, and as mentioned, these three talks are going to be complementary,  is to describe the different etiologies of acute kidney injury and cirrhosis and understand its context within acute on chronic liver failure.  We're going to review updated clinical definitions of acute kidney injury and cirrhosis and examine the role of etiology of AKI in the natural history of cirrhotic patients  in both the absence and presence of liver transplant. We'll examine some of the utility of traditional blood tests and novel biomarkers  in accessing AKI and cirrhosis and review criteria for consideration for combined liver-kidney transplant.  So as you may be aware, acute on chronic liver failure is essentially a syndrome of chronic liver disease, decompensated cirrhosis, and evidence of organ dysfunction.  And probably the most widely used definition is the European CLIF definition, and I just highlight their definitions of organ failure.  And what's fairly accessible is there's a nomogram where you can calculate not only the ACLF grade, but the ACLF score out of 100, which also includes white count and age.  And we know that with ACLF and the increased severity of ACLF with multi-organ failure,  certainly in the absence of liver transplantation, this is associated very nicely with a worsening of prognosis.  Certainly with a CLIF-ACLF score of more than 70 is associated with almost 90% mortality at day 28.  But one of the other things that it's important and it comforts us as critical care providers is that ACLF can be dynamic  and that there are patients that actually improve by at least one organ failure after a course of therapy.  And from this recent study that we looked at of over 867 ACLF patients in the ICU,  of the 419 patients that had some serial data, we noticed that at least 40% of them improved by at least one organ failure.  So the differential diagnosis of AKI in ACLF and cirrhosis obviously is important because different etiologies have a different natural history.  And I just kind of highlight the different kind of standard differential diagnosis of AKI in cirrhosis that we see,  including prerenal azotemia, of which hepatorenal syndrome, as you can see, is only one subtype of AKI in cirrhosis.  You get glomerular nephritis that can be associated with hepatitis C. It can be due to nephrotoxic agents. You can get ATN. And it can also be obstructive.  So more recently, you're probably familiar with the different ATKI and KDGO definitions of acute kidney injury that we use in the critical care and the nephrology literature.  And there's been some harmonization with some of the liver organizations that have harmonized the definitions of AKI and cirrhosis to be fairly similar.  And now we identify that stage 1 AKI is actually an increase of creatinine of 0.3 milligrams per deciliter above baseline or an increase of 1.5 fold of baseline.  And there are further gradations that kind of grade you as having stage 1, 2, and 3 AKI, which you can see in currently the most commonly used biomarker is still creatinine.  And we also identify things like whether there's progression or improvement.  And as he has mentioned before, we can see that these definitions now of AKI and cirrhosis align fairly nicely  with some of the standard more commonly used critical care definitions of AKI.  And the reason why I mention all this is that having AKI in a cirrhotic patient in itself portends an incremental worse prognosis.  This was a nice study that was done by Florence Wong and her colleagues that showed in cirrhotic patients with infections  that having irreversible AKI or ATN portended a 10-fold increased mortality at day 30. So this is something serious, and this is a very high-risk population.  This was a nice retrospective study that came from Spain. And as you're probably aware, because of our concerns of bleeding risk in cirrhotic patients,  we don't tend to do a lot of kidney biopsies in patients with cirrhosis and chronic renal dysfunction.  So this was a retrospective audit of 562 patients where they delineated different causes of AKI.  And what you can see is that hepatorenal syndrome, which we'll be talking a lot about today, only made up about 13% of all cases of AKI in cirrhotic patients.  However, by far, it had the worst prognosis with a 90-day mortality of almost 85%. So this is very important, particularly in the setting of the absence of liver transplant.  We kind of mentioned before about these new stages or new stages of AKI and how well do they discriminate between different ACLF and cirrhotic patients in terms of prognosis.  And you can see by this study that was published in 2013, they actually work pretty well.  And you can see a stepwise drop once you go from stage 1 certainly to stage 2 and 3 AKI compared to baseline.  But I do want to mention that one of the challenges that we deal with in cirrhotic patients is that a lot of these patients tend to have a lot of muscle wasting and sarcopenia.  And as you know, this is one of the things that impacts the validity of kratin as a biomarker. So kratin is affected by age, by gender, muscle mass, different medications.  The assay can also be confounded by bilirubin. So if a patient has hyperbilirubinemia, this can impact the validity of this marker.  And the question is, do we have better biomarkers available? So there have been many different biomarkers that have been looking at the renal tubule  that have been evaluated in different populations of AKI. And really the importance of having a novel biomarker would be, could we differentiate different etiologies of AKI?  Could this marker itself give us any further prognostic information in the absence of liver transplant? And in the setting of a patient going for a liver transplant,  does it give us key information about whether the kidneys will recover and we can avoid doing a liver-kidney in a patient?  So one of the simplest markers that we have is urea or fractional excreted urea. And this was actually done in a very nice study just last year.  What I just kind of highlight here is we know that urea excretion is decreased with decreased renal perfusion and activation of the renal angiotensin system.  So this happens in pre-renal azotemia, and as we'll learn more in hepato-renal syndrome,  and you get increased excretion of urea in the setting of renal tubular injury in something like ATN.  And what they showed in kind of a matched population of patients of around 100 serotics, that they were able to delineate a cutoff of 33.4 in a patient with ATN  compared to less than 28 in a patient with HRS. So this is just an example of something that's cheap. People have also looked at things like NGAL,  which has been studied in a variety of different patient populations. And this was a study that was also published in Europe in 2012. This was urinary NGAL.  And what Fagundes and colleagues was able to demonstrate is that there was a statistically significant difference between urinary NGAL levels  in patients with ATN and all other etiologies, and that different levels of NGAL were able to stratify people between HRS and pre-renal azotemia.  But as you're aware, as severity of renal disease increases, patients can become oliguric, and you may not have a lot of urine to test for a urinary biomarker.  And unfortunately, if you look at the plasma levels of NGAL, they didn't really discriminate between any of these different etiologies. And this isn't something that we widely have.  This was another group, Belcher, where they put together a series of different biomarkers of which urinary NGAL was one of them. They also looked at the fraction excreted sodium.  They looked at albumin. They looked at IL-18. And really what they were trying to discriminate here  was between patients that had HRS that potentially could get better with a liver transplant versus ATN where this is something that will not get better with a liver transplant  and you might be looking potentially at a liver kidney. And what they found was that if you met the four cutoffs of these different biomarkers,  your odds of having ATN went up 13-fold. And I've kind of mentioned ATN a couple of times,  and the question is why not just transplant a patient and see how they do on dialysis for a while. Well, we do know that if you have ATN going into a liver transplant,  the odds of having chronic kidney disease go up significantly compared to patients with other causes of AKI. As you can see in this slide,  some very nice data that was published from Mitra Nadeem's group in California. But what some people don't realize is that having ATN pre-transplant  actually portends a worse outcome mortality-wise post-liver transplant. So those patients that got only a liver and had chronic kidney disease from ATN  actually had significantly decreased survival at only 50% at five years. So this really isn't an option, and this comes to the question of whether we list people for a liver alone  or a sequential liver kidney. So Josh Levitsky, this group in Chicago have looked at other plasma biomarkers,  as we've mentioned before, because a lot of these patients may be oliguric, looking at differentiating between reversible and irreversible AKI.  And this was only done in a small patient population, but it just kind of shows you down the road that we're hoping potentially  that we'll have better blood tests that will help us differentiate between ATN or irreversible AKI versus something like hepatorenal syndrome,  which should get better with transplant. So if you look at the current management, and there's going to be a little bit of repetition between the talks,  and you'll see this algorithm that was published by Paolo Angeli in the International Club of Ascites, generally for somebody with stage 1 or early AKI,  you want to remove offending agents such as nephrotoxic drugs, et cetera, rule out infection, hold diuretics, consider a fluid challenge. And then really at this point, for example,  if you end up with progression to stage 2 or 3 AKI, and despite fluid expansion, and they meet criteria for HRS, then you're really considering vasopressor therapy,  which we'll hear a lot more today in the coming talks. So one of the controversies in ACLF is when to start renal replacement therapy.  And as you're probably familiar, there are a variety of different studies that have looked at timing of renal replacement therapy in the general critical care population,  and we continue to have equipoise with regard to this. This is just one study that was published in JAMA in 2016 that looks at starting renal replacement therapy at stage 2 or 3 AKI  that showed potentially an associated benefit, although we're still waiting for the results of the START-AKI trial, which will be coming out soon.  With regards to modality, it is generally easier to run. If you are going to run a cirrhotic patient on CRRT, continuous veno-venous hemofiltration is a little bit easier  because it's a simpler circuit, and most of the time you don't necessarily need to give anticoagulation. Circuit anticoagulation is challenging  because we know that there's a delicate balance of coagulation in a patient with liver disease, and heparin can be a challenge.  And also patients with liver disease do not metabolize citrate well to bicarbonate, so there's a risk of citrate toxicity with prolonged exposure,  although we're probably learning more and more that short-term exposure to citrate regional anticoagulation in liver patients is probably okay.  And a couple of controversies that we probably won't talk about today because it can be challenging. The role of RRT in patients that aren't transplant candidates,  this is a very challenging question that needs further discussion. So one thing to mention as well, and this is from the nephrology literature,  that also if a patient with liver cirrhosis and ACLF ends up on renal replacement therapy, not surprisingly your survival is poor, and this is likely a subset of sicker patients.  And really this comes to the question of the bridge to transplant. So one thing I want to mention as well is one of the hardest things  to differentiate is this functional HRS that often with liver transplant will improve when we improve the physiology of the patient versus something like ATN, which is irreversible.  And right now our data is primarily based on expert opinion and some anecdotal information that we were saying that, you know,  often you'd wait six weeks to two months on renal replacement therapy or a GFR of less than 30 when you would then refer them for a combined liver kidney.  However, more recently it was really nice to see this publication in 2016 in the American Journal of Transplant where now this UNOS accepted criteria  of saying renal replacement therapy for at least six weeks or a combination of renal replacement therapy and a GFR of less than 25,  you would call this what they called a renal failure group and you'd list this patient for a combined liver kidney.  And what they found when they retrospectively went through the UNOS database that if you met this criteria of either of renal failure,  you did statistically significantly better with a combined liver kidney transplant than you did with a liver transplant alone, and that's shown here.  But what is interesting is that for people that jumped the gun, meaning that you didn't have, it was less than six weeks  that either you had a GFR of less than 30 or you're on renal replacement therapy, you actually did worse if you got a combined liver kidney transplant, which is interesting.  Just to kind of give you some further information, we're not going to talk in great detail about artificial liver support today, but currently this is a care gap.  The trial of albumin dialysis of MARS, or the molecular absorbent recirculating system, the biggest study was the Bonares trial which was published in 2013  that didn't show mortality benefit. So we can't really advocate for this at this point in patients with HRS. One thing I do want to mention that we're seeing in a lot of centers  is actually intraoperative continuous renal replacement therapy, and one of the rationale for this is that we get a lot of patients  with cirrhosis and ACLF and AKI that are in the ICU waiting liver transplant. Particularly with complications such as hyponatremia,  these can be very difficult patients to manage from a hemodynamic and a fluid point of view, but also in terms of shifts of sodium and potassium.  And there have been a lot of retrospective studies that suggest potentially there may be a benefit to intraoperative CRRT.  There was one pilot study that our center completed recently that was just published that looked in patients with at least stage 1 AKI and a MELD of greater than 25,  whether there was a benefit of intraoperative CRRT. And just so you know, our standard protocol was using CVVH in the operating theater.  Just to kind of mention, the challenge with a study like this is that there was a large amount of crossovers. So if you're in a center that is very keen on something like this,  there are a lot of anesthetists that will strongly advocate for putting the patient on intraoperative CRRT. And we noticed that there was seven patients that crossed over  to the intraoperative CRRT group. And just to really summarize, that this study essentially was a negative study.  There was no significant differences in either renal or overall outcomes. And one of the things to also mention that was beneficial, at least,  is that there weren't a lot of significant complications. So this continues to be an area of equipoise where we, while there are some people that use this,  we can't certainly advocate for this on a routine basis at this point. Finally, I just want to mention, in terms where there's a more defined role  of CRRT as actually an acute liver failure, where this study from 2018, I just want to emphasize that clearly there have been multiple studies that have demonstrated  that you can get a reduction in arterial ammonia, which certainly in acute liver failure correlates with the development of intracranial hypertension.  And this was one of the first studies that showed that after adjusting for severity of illness, that CRRT was independently associated  with an improvement in mortality in acute liver failure patients. So simply, just to remember that CRRT is not just a renal support device, it's actually an extracorporeal circuit.  So just to kind of summarize, AKI and cirrhosis, etiology significantly impacts mortality. ATN is associated with increasing rates of CKD  and decreased survival rates post-transplant. Studies differentiating different etiologies lack a gold standard because, unfortunately, we don't do a lot of renal biopsies.  Serum creatinine, which is the most commonly used biomarker, is confounded by a variety of different factors in cirrhotic patients.  Novel urinary and plasma biomarkers that may assist us in the future need further work. And currently, most centers are using this guideline of six weeks  of either a GFR of less than 25 or are on renal replacement therapy when considering a combined liver-kidney transplant. Thank you very much.  I will move the focus of the talk now to speak a little bit more about the pathology and the development of hepato-renal syndrome and acute kidney injury in patients with cirrhosis  and early considerations in treatment. As most people recognize, in patients with advanced cirrhosis, there are a multitude of physiologic changes that result in significant  hemodynamic and circulatory changes that have pronounced impact on a multitude of organ systems within the patient. As patients develop advanced cirrhosis, they begin to develop  portal hypertension, which results in secretion of vasodilatory mediators such as nitrous oxide, carbon monoxide, and other endocannabinoids.  And this results in a situation where you have splanchnic vasodilation. These same inflammatory mediators can result in the development  of what we call cirrhotic cardiomyopathy, which results in decreased cardiac output. Combined with splanchnic arterial vasodilation, low cardiac output,  and effective arterial hypovolemia, patients then have activation of other compensatory mechanisms, which include vasoconstrictor responses  such as the renin-angiotensin system, and the development of very pronounced and very profound renal vasoconstriction.  Also contributing to the hemodynamic and alterations in inflammation that occur in patients with cirrhosis are the features  of bacterial translocation that result from changes in the intestinal flora as well as changes in tight junctions allowing more readily bacterial translocation.  Damage-associated molecular patterns can result in a pretty very marked inflammatory response. Again, all of these feedbacks result in the development  of significant acute kidney injury. And this can be seen in many patients with advanced liver disease. Reviewing the circulatory abnormalities that develop  in patients with cirrhosis. Again, recognizing portal hypertension, we see portosystemic shunting. Most people recognize that patients with cirrhosis have what appears  to be a cirrhotic type of physiology with increased cardiac output, increased heart rate, and low systemic vascular resistance. Again, the complication of cirrhotic cardiomyopathy,  which is actual cardiac dysfunction that occurs in patients with cirrhosis, further contributes to the cardiac abnormalities. As noted in the previous slide,  splanchnic and systemic vasodilation occur. This results in activation of renin-angiotensin system in the sympathetic nervous system.  And this results in very dramatic and very pronounced sodium and water retention. So you have patients that are clearly very volume overloaded  with large volume ascites, tissue edema, yet they do not have fluid where you want it, which is in the effect of circulating volume.  All of these systems, again, result in renal vasoconstriction, which can ultimately progress to the development of the hepatorenal syndrome.  With regard to cardiac physiology, some of the potential mechanisms that result in decreased cardiac output in the cirrhotic cardiomyopathy  are the downregulation of beta-adrenergic receptors, upregulation of cannabinoid 1 receptors, and increased effects of hemoxygenase, carbon monoxide, nitric oxide synthase-induced  nitric oxide production, and release of other inflammatory mediators such as TNF-alpha. Back to the point that Dean made in his first talk,  we don't want to transplant people too early. And this slide demonstrates very dramatically what happens with pronounced vasoconstriction in patients with hepatorenal syndrome.  So this is, on the left, you see a selective angiogram of a patient with confirmed hepatorenal syndrome. And you can see very, very poor arterial blood flow in this patient.  Now, this is a post-mortem angiogram in the same patient demonstrating that you have return of normal arterial blood flow  in a patient after you remove the chemical mediators of vasoconstriction. And this is a very pronounced impact on patients with chronic kidney disease.  This is why you can perform a liver transplant in somebody who's been on dialysis for three or four weeks, and their kidneys wake up almost immediately,  and they have returned to oftentimes completely normal renal function when the case was hepatorenal syndrome as the reason for acute kidney injury.  When thinking about the development of the pathologies that occur in patients with advanced cirrhosis, refractory ascites, hyponatremia, hepatorenal syndrome,  all of these result from progressive alteration in the pathogenic mechanisms which lead to the development of ascites. Again, thinking about cirrhosis,  we know that intrapatic resistance is not simply a feature of architectural disruption of the liver, but it's also mediated by chemical mediators as well.  We see the development of portal or sinusoidal hypertension. This, again, as I've referred to previously, results in splanchnic and systemic vasodilation.  Effective arterial blood volume continues to decrease, and you have activation of the neurohormonal compensatory systems. Again, this results in profound sodium retention,  the development of eventual refractory ascites, which heralds a poor prognosis. You see the development of water retention resulting in hyponatremia, renal vasoconstriction,  with the development of hepatorenal syndrome. Bacterial infections are... The importance of bacterial infection cannot be overstated in patients with cirrhosis.  Bacterial infections are probably the most common precipitant of the development of hepatorenal syndrome and probably the most common precipitant  to the development of the syndrome known as acute on chronic liver failure where a patient with previously compensated cirrhosis suddenly decompensates.  Dean talked about the use of creatinine as a marker for the assessment of renal function in patients with cirrhosis.  There are obviously significant pros and cons to using creatinine as a biomarker for assessment of kidney function in patients with advanced liver disease.  The pros, this is very easily obtainable a test. It's part of most chemistry profiles. It's relatively inexpensive. Repeated measurements are generally reliable.  And it's included in the MELD score, which we obviously use for risk stratification in patients with chronic liver disease as well as for organ allocation in the United States.  But there are also several cons to using creatinine in this patient population. It overestimates the GFR. There's decreased creatine production.  Low muscle mass contributes to the impact of interpretation of creatinine. Patients oftentimes have very poor protein dietary intake, high urine secretion.  It has a poor sensitivity for the assessment of kidney dysfunction. And there is some interlaboratory variability.  In the liver world, there's actually a fair amount of controversy about using urine output as a marker for the criteria for the development of acute kidney injury.  But this is a nice study that was performed at the University of Pittsburgh. And it demonstrated that in patients who have poor urine output  is also a significant marker for the development of kidney injury. So patients who had urine output and urea for greater than 12 hours  or output greater than 0.3 milliliters per kilogram per minute for greater than 24 hours had significant decrease in overall survival.  How do we treat hepatorenal syndrome when we believe that's the diagnosis? So non-pharmacologic strategies include, obviously, treatment of infection.  You always want to avoid NSAIDs. For patients with decompensated liver disease, those who've had GI bleeding or the development of ascites,  ACE inhibitors, and ARBs are contraindicated at that point in time. And then we use several pharmacologic strategies. This includes volume expansion.  Depending on the fluid situation for the patient, you may consider crystalloid. But in patients that are already volume overloaded,  consideration of volume expansion with concentrated albumin, not 5% albumin, either 20% or 25% concentration. And the addition of vasoconstrictor agents,  such as mitadrine plus octreotide, norepinephrine. And in any country outside of North America, terlopressin is a consideration as well.  One of the things that's very, very important in patients with suspected hepatorenal syndrome is maintaining and improving the mean arterial blood pressure.  This study published in American Journal of Kidney Disease in 2011 demonstrated a strong correlation between increases in mean arterial blood pressure  with improvement and decrease in the serum creatinine. A mean arterial blood pressure increase is needed for an increase in renal function to be predicted.  And so looking at this slide, we can see that depending on what the serum creatinine was at baseline, the percentage in serum creatinine improvement  in order to reverse or to attain the serum creatinine goal is significantly higher. So for example, if you have a much higher creatinine,  you need a higher percent change in creatinine. Again, this slide on the right demonstrates that with increasing mean arterial blood pressure,  the higher you push up the mean arterial blood pressure, the more impressive your improvement in serum creatinine is over a seven-day time period.  That slide contained only randomized controlled trials. The role of albumin in the ICU has always been a very controversial topic because of certain studies that have assessed  fluid resuscitation strategies and all comers to the ICU. But when we're talking about a liver disease predominant population, we have to remember that albumin  is a very pharmacologically active and biologically active molecule. Albumin has numerous impacts on overall physiological changes in the patient.  It obviously increases oncotic pressure because it has high concentration and an excellent intravascular distribution. It improves stabilization and transport of certain molecules.  This has to do because it's a negatively charged molecule. It has several binding sites that can also bind metal binding as well as bilirubin. It has immunomodulating properties.  It can stabilize the endothelium. It has an important hemostatic effect. And it also alters capillary permeability due to its extracellular distribution.  Volume expansion with albumin in patients with spontaneous bacterial peritonitis has also been shown to be extremely beneficial. In a meta-analysis of patients with SBP,  demonstrated that albumin infusion prevents the development of renal impairment, and it also reduces mortality. Another study, well, actually, it's  still looking at 19 studies with different vasopressors revealed that adding albumin to different vasoconstrictor agents had a significant impact on both reversal  of hepatorenal syndrome as well as overall survival. You can see that in patients with higher albumin dosage, they had significantly greater overall survival  at all different time points. In the United States, especially where we do not have turlopressin and we're trying to treat patients on the floor,  we're often relegated to using mitogen octreotide because norepinephrine frequently necessitates transfer to the intensive care unit.  When comparing the efficacy of mitogen plus octreotide versus norepinephrine in the treatment of hepatorenal syndrome and as well as its impact  on mortality, we can see that compared to mitogen plus octreotide, noradrenaline has a significant impact on both reversal of hepatorenal syndrome as well as short-term mortality.  This is probably where we underserve our cirrhotic  patients in the United States because oftentimes we're trying to treat them with mitogen octreotide on the floor and don't often move them to the ICU.  And there's clearly a benefit to using norepinephrine in this patient population. I'm looking at a randomized perspective double-blind placebo-controlled trial of turlopressin  for type 1 hepatorenal syndrome. Remember, type 1 hepatorenal syndrome is a nomenclature that we don't use anymore, but this is a more acute form of hepatorenal syndrome.  We see that, again, compared to placebo, turlopressin has a significant impact in reversal of hepatorenal syndrome. There was no significant mortality benefit  in this patient population. When comparing norepinephrine versus turlopressin in the reversal of hepatorenal syndrome, we can see, again, that there's not  a significant difference in mortality rates or in rates of hepatorenal syndrome reversal between norepinephrine or turlopressin. What appears to be much more important  was that you reverse the hepatorenal syndrome than what agent you're using.  A couple studies examined the use of bolus dosing of turlopressin versus turlopressin for continuous infusion. We see that in the case where turlopressin was used  in infusion, even with lower doses of turlopressin, there was no significant change in the overall outcomes in patients who received higher doses versus lower dose turlopressin.  Studies comparing turlopressin to norepinephrine in management of acute kidney injury in patients with the acute on chronic liver failure syndrome.  This was an open-label, randomized, controlled trial of consecutive ACLF patients admitted with hepatorenal syndrome greater than stage 2.  Turlopressin infusion was used at 2 to 12 milligrams per day plus albumin at 1 gram per kilogram per day concentrated albumin versus norepinephrine  at 0.5 to 3 micrograms an hour plus albumin. You can see that, again, there was a significant improvement in outcomes in patients who were in the turlopressin group.  This included an important statistically improvement in survival. With that, we'll move on to the next section of this talk.  Okay, good afternoon, everybody. So we're going to review the basic pharmacologic principles for the prevention and treatment of hepatorenal syndrome.  We're going to compare and contrast some of the contemporary therapies to get a better feel for where the data lie, and we'd like to help you establish  an evidence-based treatment plan for patients with hepatorenal syndrome. So as mentioned before, hepatorenal syndrome is a rapidly progressing,  potentially fatal condition if left untreated, and it occurs quite commonly in patients with decompensated liver failure, and at present, there are no approved pharmacologic.  Hello? There are no approved pharmacologic agents available in North America for the treatment of hepatorenal syndrome. So as a pharmacist, these are the four roles that I play  in the management to help my providers manage hepatorenal syndrome. First, do no harm prevention. Determine a hierarchy of drug therapy, right,  considering that each drug has certain abilities and strengths. Optimize drug dosing and renal replacement therapy and optimize drug management post-transplantation.  So as Jodi mentioned earlier, the prevention, avoid NSAIDs, avoid inhibitors, avoid ARBs as well. Decrease or withdraw diuretics when the patient is acutely decompensated.  Make sure you manage volume. Determine a threshold at which to discontinue beta blockers. There's a little bit of controversy out there, but by the time you're hypotensive  and underperfusing the kidney, that's time to withdraw drugs that potentially affect perfusion. And maintain main arterial pressure.  So that's what we're going to talk about a little bit today, and Jodi presented that Velez paper from over a decade ago that correlates reductions  in serum creatinine as it's related to increases in main arterial pressure. If you were actually to take a look at all the clinical trials that have been published since then,  you would find the same phenomenon as well. So the idea is you want to try to find a drug therapy that affects your main arterial pressure,  and all drugs have different abilities to do that. So placebos have very little effect to do that, okay? Generally speaking, the volume expansion  that you get from a little bit of crystalloid in the form of placebo is not going to bump up your main arterial pressure very much.  Midodrine and octreotide, at the survey at the beginning of this presentation, that seems to be among the most common therapies that's implemented by this audience.  There's a role for it, but when you look at the delta map from baseline and the ability that it has to reduce serum creatinine from baseline,  it's not the most powerful agent that's out there. The agents that do optimize that outcome are vasopressors. Now the decision becomes, what vasopressor do you want to pick?  Catecholamines or vasopressin-vasopressin analogs. So terlopressin is a synthetic vasopressin analog. Selectively has greater affinity for the V1 receptor,  and it's localized in smooth muscle, and it helps with splanchnic vasoconstriction, reduces splanchnic blood inflow, and therefore portal pressure, redistributes part  of the intravascular volume to central circulation, and published literature provides evidence that terlopressin improves renal function in patients with hepatorenal syndrome.  And when available, it's considered the standard of care. So first we're going to review a trial that was published a few years ago, the REVERSE trial by Boyer and colleagues.  And there's two different primary outcomes, the complete hepato-renal syndrome reversal and hepato-renal syndrome reversal.  And when you look at the reduction, you see that the terlopresin plus placebo achieves that outcome more commonly, though it fails to achieve statistical significance.  When you look at the reduction in serum creatinine, it did actually achieve statistical significance. When you look at the survival curves, this is interesting.  So when you compare the responders to non-responders of the placebo group, there's not a difference in survival.  When you compare the responders to non-responders in the terlopresin group, there is an improvement in survival. So that's something to consider.  You need to establish which patients are responding and which patients will not. The most recent data that are out there, the CONFIRM study, this has yet to be published.  It was presented just a couple months ago at the LIVER meeting. If you look at clinicaltrials.gov, you can find a little bit of information on there  about the inclusion-exclusion criteria. And it looks like it wrapped up just this past summer in 2019.  They compared terlopresin, one milligram IV every six hours, or placebo, both groups received albumin as a standard of care, as Jodi had previously communicated.  That's the standard of care. The study drug at day four could be increased based on the clinical response that was observed in the patient.  So if there wasn't an adequate reduction in serum creatinine, the dose could be increased.  And when you look at the clinical trials that have been published to date, generally you're looking at doses in the neighborhood of two to 12 milligrams per day.  And then the recommended albumin doses were per standard of care, treatment guidelines. So prior to this, the Boyer paper with about 200 patients had been the largest clinical  trial to date. Now this is the largest clinical trial to date with 300 patients. Patients were randomized in a two-to-one ratio.  Two patients for terlopresin for every one patient of placebo. And the 90-day follow-up, you can see that very few patients were lost to follow-up.  Only one group, one patient in the terlopresin group, none in the placebo. Survival was just about 50% in the terlopresin group.  And it was a little, excuse me, yeah, and a little bit lower than that in, excuse me. Mortality was about 50% in the terlopresin group, and it was a little bit lower than  that in the placebo group. So the primary endpoint of the confirmed trial was an instance that verified HRS reversal  defined as the percent of subjects with two consecutive serum creatinine values less than or equal to 1.5, at least two hours apart from one another, and alive without renal  replacement therapy for at least 10 days after achieving verified HRS reversal. There are a multitude of secondary outcomes that they looked at.  The incidence of HRS reversal, which has a slightly different definition, serum creatinine values less than or equal to 1.5 while in treatment until day 14 or discharge.  Durability of hepatorenal syndrome reversal defined as the percent of subjects with hepatorenal syndrome reversal without renal replacement therapy to day 30.  And the incidence of hepatorenal syndrome reversal in SIRS patients and the incidence of verified HRS reversal without HRS recurrence by day 30.  So when you look at the demographics, they're fairly similar. The typical patient was about 54 years old, more likely male than female. Common etiology was alcoholic hepatitis.  The serum creatinine was pretty similar at about 3.5. That's above the inclusion criteria, which was 2.25. A high percentage of patients had SIRS. The MELD was 32.  Child's pew would put them in a severity category of severe. We'll see. And when we look at the primary outcome, and this is the verified hepatorenal syndrome  reversal, and the definition is at the bottom, we see that the turlopressin group was more effective than the placebo group, 29.1% versus 15.8% achieving that outcome.  When we look at the HRS reversal, we see, again, that statistical significance was achieved, 36.2% versus 16.8%.  And taking it a step further, we can stratify the data by baseline serum creatinine. And what you see is that in the patients that had a lower serum creatinine, less than 3,  there was a very good response to turlopressin compared to placebo. And the effect of the placebo became considerably less as the baseline serum creatinine increased.  The same can be said for turlopressin, but there was still a sizable amount of patients that we would consider responders with creatinine of 3 to 5, and even up to 5.  Patients with baseline serum creatinines of greater than 7 were excluded from this trial. Primary outcomes, we achieved statistical significance in several of the outcomes.  The durability of HRS reversal, right, so it's a sustained effect, 31 versus 15%. The SERS subgroup, and this is consistent with what the post hoc analysis of Boyer and  colleagues found in the reverse trial. And then, actually, the statistical significance was not achieved for days alive by day 90.  So if you want a little bit more detail on the day-by-day reduction in serum creatinine,  you can see that there is, in fact, a separation between the two groups, a little bit of overlap, day 1 and day 2.  And then the confidence intervals on day 14 do overlap, but otherwise, there's a fairly clear separation between the two groups.  In the cumulative percentage of renal replacement therapy through day 90, the most benefit was  observed in the first 14 days of therapy, where terlopressin had more, the most benefit was observed in the 14 days, however, this benefit was lost by day 30 and day 90.  And then, the percent of renal replacement therapy post liver transplantation benefit the terlopressin group again.  So the length of hospital and ICU stay, the entire hospital stay was very similar between the two groups, but the length of ICU stay was much shorter in the terlopressin group.  Of note, terlopressin can theoretically be given peripherally and does not necessarily warrant an ICU admission.  And then, the survival in ICU admit subjects alive and without renal replacement therapy or transplant at day 14 was higher in the terlopressin group, 29% versus 7%.  The survival really didn't differ between the two groups. You can't really tease out any meaningful statistical significance there.  And adverse effects is something that we always want to talk about. So adverse events in this population was quite common, 88%, and that's not particularly surprising  in this critically ill cohort that we're looking at. When you break down the types of side effects, you see the most common is abdominal pain  and terlopressin, perhaps related to splenic vasoconstriction, nausea, diarrhea, and dyspnea.  You should note that the permanent withdrawal due to adverse effects was higher in the terlopressin group, about double that, 12% versus 5.1%.  And the serious adverse events overall was similar between the two groups, 65% versus just about 61%.  So how do we put this most recent clinical trial in context of what's already out there? So 13 RCTs with 739 patients included in a network analysis, and all trials were two  arms, which makes analysis a little bit simpler. Six compared terlopressin with placebo, four compared with terlopressin with norepi, terlopressin  versus mitadrine and actreotide, or terlopressin with dopamine plus Lasix, and one compared norepi with mitadrine and actreotide.  And all the patients in this meta-analysis received albumin at baseline. And when you take a look at where the evidence lies and what the comparisons are, you can  see that the most evidence has been performed with terlopressin. So we're going to go through a meta-analysis now.  I want to draw your attention to the fact that, well, I'll get to that to the next slide, but intervention one versus intervention two, all right?  And if the group is to the right, it's favoring intervention one. So when you look at terlopressin versus placebo, and this is the reversal of hepatorenal syndrome,  you see that there's a benefit towards terlopressin. When you compare the terlopressin to the norepinephrine, there doesn't seem to be a significant difference  between the two groups. Terlopressin versus mitadrine and actreotide, again, you see a significant benefit towards  terlopressin, which you would expect based on most drugs' ability to have an effect on menotorial pressure.  And norepinephrine versus actreotide and mitadrine, probably unpowered to tell us much of anything.  Now, when you look at which group is favored here, notice that the axis is flipped, and this is the way that the study was published, and I didn't want to manipulate the way it  was reported. But this is focused on mortality and not reversal of hepatorenal syndrome. So terlopressin versus placebo, there's a benefit towards the terlopressin group.  Again, when you look at terlopressin versus norepinephrine, there doesn't seem to be a significant difference.  Terlopressin versus dopamine, there really isn't any additional differences between groups. So in summary, terlopressin and albumin are significantly better than albumin alone in  achieving hepatorenal syndrome reversal. Terlopressin is effective in improving renal function.  And this is especially true in patients with inflammation, as suggested by the evidence with SIRS.  And the response was durable and associated with lower incidence of renal replacement  therapy, both pre- and post-liver transplantation, and shorter lengths of ICU stays were observed.  So the take-home messages, if faced with AKI and cirrhosis, you want to optimize volume resuscitation. Colloid, replace blood, the best evidence is with albumin.  Again, not pre-renal, choose a vasoactive agent, and just recognize what the abilities of the drugs are.  The most evidence that's out there supports terlopressin, and you can use that if available. Norepinephrine seems to be a reasonable alternative.  Midadrenal actreotype, they do have a small marginal impact on increasing mean arterial pressure. But in general, it's a much weaker option.  And liver transplant results are best if AKI is reversed and renal replacement therapy is avoided, or at least minimized. And with that...  All right, thank you, Bill. So this is the fun part, I guess, after you've had your lunch. We'll have a little bit of audience participation.  We're going to present cases of two twin women, and I'll present the first one, and then Dr. Olson is going to present the second one.  So we have a 52-year-old woman with decompensated cirrhosis secondary to non-alcoholic steatohepatitis,  fatty liver, active alcohol use, unfortunately, so she has ongoing issues with alcohol, presents with abdominal pain, fever, and new onset confusion.  In terms of previous complications of liver disease, she's had a previous variceal bleed about three months ago, and has moderate ascites and has been on diuretics.  She's also a type 2 diabetic for 10 years, which is probably one of the reasons why she got NASH. Her current medications include her diuretics, Lasix and aldactone.  She's on Natalol for prevention of variceal bleeding, a non-selective beta blocker. And she's also on insulin and Ceptra for a recent UTI.  When you look at her on exam, her blood pressure is a bit low. It's 95 over 45, her pulse is 100. That gives you a map of 62. She's febrile with a temperature of 38.  She's a bit muscle wasted. Her BMI is 21, and this is probably also confounded by a couple of liters of fluid in the belly.  She's got pedal edema, has chronic stigmata of liver disease, and has a cane at her bedside, so she's got some functional muscle decline.  So we kind of mentioned all that, and just keep all of those in mind. So if we look at her lab work from a month ago, her white count was 8.6. In the emergency room today, it's 14.  Her creatinine was 0.5 milligrams per deciliter a month ago, and today it's 1.1. You're able to get a paracentesis done in the emergency room fairly quickly.  So she's now got a polymorph count of 800, which suggests spontaneous bacterial peritonitis. So first thing to think about is how does sarcopenia impact your assessment of renal  dysfunction? Because we've mentioned that this lady is quite muscle wasted. Just keep that in mind.  So question one, so she now has a creatinine that's gone up from 0.5 to 1.1 in a severely muscle wasted patient. Question one for your response is, is this AKI?  And the answer can be yes, this is HRS, yes, she's pre-renal, yes, she's got ATN, most likely, but etiology is unclear, no, this is CKD, or no, this is another diagnosis.  Interesting. So we agree it's AKI, but we want a little bit more information. So we'll give you a little bit more information.  So as we mentioned before, part of the reason why it's a little bit confusing is that she's  on diuretics, and we know that this can confound something like a urine sodium, determining how sodium avid somebody is.  She's also a diabetic, so there's always a question of whether she's got some proteinuria and diabetic nephropathy.  And when you have somebody with abdominal tenderness and ascites, we're wondering if this can also be septic AKI related to her SBP.  So with this information, sorry, just one other thing just to go back, and the information that you have based on all of this, if you had to put your finger on it, as we mentioned  before, it's difficult because we don't do kidney biopsies in patients like this. Do you think this lady's pre-renal?  Do you think this lady's got hepatorenal syndrome with the borderline blood pressure, or do you think she has ATN, or do you think this is polyfactorial? You can go ahead and vote.  So we want more information, and this is really kind of what we're... Which is actually the right answer. This is what we're...  Not a lot of these have one answer, but this one, this is kind of clear that we need more information.  So what additional tests would you order to help you determine the diagnosis for this lady, which is a kind of a rhetorical question, and is there a role for novel renal biomarkers  in routine practice? So these are things to think about, and obviously we all work in different places and have access to different diagnostic labs.  So what we could have, and we talked in the first lecture, that you can get a urine sodium and a phena. This is relatively cheap.  So you find that the urine sodium is less than 10, and she's oliguric. So she is sodium avid. You learn that the urinalysis is bland, so there's no active urine sediments.  It doesn't look like a raging GN, and she has a normal renal ultrasound, which is essentially  telling us she doesn't have any renal obstruction, and also it doesn't look like she has evidence  of a shrunken scarred kidney, so there's no obvious evidence of chronic kidney disease. One other take-home point that's not in this case is remember that one of the most important  things that we use as a biomarker to reflect HRS is actually blood pressure.  So if you're not hypotensive, it's unlikely going to be hepato-renal syndrome. So as we kind of mentioned in the previous talk, so in somebody like this that's got  AKI, hypotensive, who's sodium avid, you're suspicious now that this could potentially be HRS, so you initiate volume resuscitation with albumin.  This is still kind of in the ward setting. We'll assess the response to albumin. If you get deterioration, then you might consider vasoconstricting therapies, and one of the  important things that Bill mentioned in his talk is that if you have the availability of turlopress, and this is actually something that can be administered in a ward setting,  that the patient doesn't have to be in an ICU monitored setting. So despite albumin and crystalloid therapy, the next day her creatinine has now risen to 1.9 from 1.1.  Blood pressure is she's still sitting there with a MAP of 60. Patient has been started on ceftriaxone for SBP, and the fluid cell count was rechecked  with a repeat tap, and it's coming down nicely. So now as an intensivist, you're consulted to see this patient, and the question kind  of at this point is would you be using something like mitadrinone and octreotide on the ward because it's a busy day and you've got a busy unit, or would you bring the patient over  to the unit and put them on norepinephrine? So here are kind of those put in therapy. Would you leave the patient and just start them on mitadrinone, octreotide, and albumin?  Would you take the patient to ICU for norepinephrine for a challenge of intravenous vasoconstricting therapy or something else?  And just keep in mind that this was the naughty twin that was continuing to drink alcohol, so she's not a candidate for liver transplant.  So we've got a very proactive, aggressive group. A lot of us want to take this person for a norepinephrine challenge, and I think that's totally reasonable.  But the hospital that you're working in, your administrator calls you and tells you the ICU is full, so you go back with your outreach team the next day, the patient's  been put on mitadrinone and octreotide, creatinine continues to climb, it's now 2.2, blood pressure  still is a map of 60, so hasn't really had any improvement on mitadrinone and octreotide,  and as mentioned before from Bill's talk that there isn't really, you can get marginal benefits  with MOA therapy, but not as pronounced with some of the other vasoconstricting agents.  So at this point, would you consider a short-term trial of support with norepinephrine at this point?  And for the record, your administrator now says you've got beds and you'll be fine, because that's really what it's all about at the end of the day.  So just look at this question again. Now that Mrs. Katie's infection has been treated, do you think you're out and clear that the  AKI pathology will begin to reverse, or that the AKI pathology will not worsen because you've treated the infection, nor will it receive it without additional treatment?  Or will the AKI pathology continue to worsen despite successful treatment of the UTI and also the SBP? Interesting.  So usually when you get equal representation with each answer, it means it's a poorly worded question, so that's my fault.  So as we mentioned before, kind of in the first talk, that evaluation of the cause of etiology of AKI is important, because it has implications on prognosis and the absence  and presence of transplant. One thing to mention is that sepsis or SBP can trigger hepatorenal syndrome.  And just because you treat the infection, you can end up with a cascade with deteriorating kidney function.  So just because you clear the infection or the cell count in the ascites is improving, that doesn't mean that you're home and clear and that the renal function will actually  improve. So I'm going to hand over to Dr. Olson to talk about this lady's twin sister. So oftentimes, for the point of clarity, when we're having a controversial discussion, we  use an example exactly like this. So the same patient, but at this time, she is not a drinker.  So that opens up some more opportunities for consideration of alternative therapies, including transplants. So she is actively listed for liver transplantation.  She remains in the intensive care unit on vasopressors. Her creatinine remains elevated currently at 3.6 milligrams per deciliter in spite of aggressive support.  Her urine output has been 50 milliliters in the last 12 hours. She's 3 liters positive. Her pH is 7.3. Her K is 4.5. At what time would you consider renal replacement therapy?  And these are sort of questions for thought. There's a whole lot of variability that's going to go into how you're going to make these decisions at your specific facility.  It's going to depend on what your transplant wait times are, et cetera. How would you decide between continuous renal replacement therapy and intermittent hemodialysis?  Again, this may be expertise dependent. And what length of trial of renal replacement therapy would you consider? Same patient.  She's now been in the intensive care unit for seven weeks. She remains listed for liver transplantation in the ICU on vasosuppressor support.  The transplant team and the ICU team feel she is still reasonable to push forward with liver transplantation.  What tools can we use to predict her chances of renal recovery post liver transplantation? So now we have time on our side. We've watched her.  We've been aggressive with her therapy. We can start to use that to help influence decisions.  When should we start thinking about combined liver kidney transplant versus liver transplant alone?  Remember the things that Dr. Carvell has talked about in the slide that I showed you with the very pronounced vasoactive-mediated vasoconstriction.  Is this patient somebody who's likely to recover? And what factors go into deciding between liver kidney transplant that occur one after the other?  So liver transplant today, kidney transplant down the road, or doing a liver kidney transplant at the same exact time? And I'll make a couple of comments about some of these things.  So when do you start thinking about liver kidney transplant versus liver transplant alone? In the past in this country, it was sort of wide open and up to the transplant center.  You could make a decision about listing a patient for SLK honestly whenever you wanted. There were not hard and fast rules.  More recently, the United Network for Organ Sharing has given us some criteria that we should use for consideration for simultaneous liver kidney listing versus doing a liver  transplant alone. And among these are evidence of chronic kidney disease, and we use some very specific markers.  So if you have a patient with established chronic kidney disease, you're looking at a GFR of being less than 60 for greater than 90 days, plus a GFR that's lower at time of  transplant. You can look at sustained acute kidney injury. So that would be the situation in hepato-renal syndrome.  So a patient's GFR stays low or they're on dialysis for greater than six weeks. And if you don't meet those criteria, then it's absolutely reasonable to consider moving  forward with liver transplant alone. But there's some distinct advantages to considering a combined liver kidney transplant if it's otherwise appropriate for this patient.  Number one, kidney, when you transplant the liver with any other organ, you get a very impressive immunological protection.  So you can sort of treat these patients like a liver transplant alone, and the liver provides immunoprotection and prevents against rejection of other organs.  This has been shown both in heart transplantation as well as kidney transplants. Kidney transplant alone requires more aggressive immunosuppression than does a liver transplant.  So the suggested algorithm for decision-making regarding combined liver kidney transplants for hepato-renal syndrome.  Patients with normal renal function or chronic kidney disease that is in its early stages, you can move forward with liver transplant alone.  And if they don't recover down the road, then there are mechanisms for considering kidney transplant at an earlier date later.  But remember, patients that undergo liver transplantation and have sustained kidney injury afterwards have worse outcomes than those who don't.  For patients with acute kidney injury and a GFR of less than 35 milliliters per minute or a GFR of less than 25 milliliters per minute using creatinine clearance techniques or that  are needing dialysis, if it's been less than four to six weeks in duration, so it's acute kidney injury, less than four to six weeks duration, liver transplant alone, again, is  a reasonable consideration. And now we sort of have rules to enforce this. If it's greater than six weeks, then consideration of combined liver kidney transplant is important.  For patients with chronic kidney disease, prolonged depression in the GFR, then it is appropriate to move forward with consideration of liver transplant at that time.  And patients that have been transplanted with liver alone and they have ongoing dialysis needs, patients who had a kidney transplant in conjunction with a liver transplant deferred  due to high risk for kidney transplant at the time of the liver transplant, you can then consider doing a kidney transplant alone at a later date.  And so with this, we'll open it up for questions from the audience. We'd be happy to take any questions you have. Thank you.  Just use the microphones if you're going to ask a question. I think there's two of them.  Hi there. So just the far microphone. Hi there. My name is David Silberstein. I'm a pulmonary critical care physician in Los Angeles.  And we have a pretty robust, at least a pre-transplant liver service that sends their patients to the ICU.  And it's very disconcerting that certain drugs can be obtained all over the world except the US. Has anybody tried bolus dosing of vasopressin in a similar matter?  So that's a very good question. I can probably start, but then maybe you can... So what I can tell you, first of all, the good news is that we're hoping most likely  that turlopressin will probably be hopefully approved by the FDA in the next three to six months.  The big challenge still that we run into with vasopressin is that you have to run it in an ICU setting. So you can't run it on the floor.  And my honest opinion is that's really the biggest care gap is you have these patients that sit on the floor on mitotrin and octreotide for several days.  And in some cases, as Bill showed very nicely, that once the creatinine gets, you're certainly in the three to five range.  It gets very harder to kind of turn this around with vasoconstricting therapies alone if you wait too long.  And really one of the biggest goals then for us also is that at the time of transplant, if the patient's not on renal replacement therapy, you can use standard immunosuppressant  therapies with calcineurin inhibitors. So that's one of the biggest challenges. I haven't seen a trial with bolus vasopressin. I don't know if you've seen anything.  Hi. My name is Divya. I'm a critical care fellow at Mount Sinai Hospital in New York. I was going to ask that question, but I have another question.  Is there any utility, given the fact that a big part of the HRS pathology is vascular distribution, is there any utility in getting a vascular renal ultrasound as part of the  workup? Or I don't, is there any kind of information that that would give us to kind of point more  toward HRS in addition to the other tests that we do? HRS still remains a diagnosis of exclusion.  So and I think vascular ultrasounds, for the reasons that we showed you earlier, are not particularly helpful in this case.  So HRS still doesn't have a, you know, it still remains a diagnosis of exclusion. You have to treat the underlying causes. Urine studies can absolutely be helpful.  Urine electrolyte studies can help, but I don't think that there's a role for ultrasonography or for vascular studies at this point in time.  Again, you can see very pronounced vasoconstriction in these patients. Okay, thank you. Okay, we'll go to the other microphone. Hi, John Carr, Ann Arbor, Michigan.  I really enjoyed the talk. Thank you for putting that on. This question is for Dr. Olson. I was interested in that slide you showed where the serum creatinine went down as the  blood pressure went up. And so my question for you is, at Kansas, in the nursing parameters for titrating your  vasopressors, do you shoot for a mean arterial blood pressure of 80 or 90 or higher? And my second question is, do you have any experience using angiotensin II or Geopressa  to improve blood flow in these patients? Thank you. So the second part first, no, I haven't been using it.  Dr. Subramanian, who, I don't know if you know him, but he does some of these liver  talks as well. He is using angiotensin, and I don't know what his experience has been. For us, when we have a patient that we have in the intensive care unit and we are suspecting  hepatorenal syndrome or they have acute kidney injury, I have an amazing relationship with the nurses that I work with, and they sort of get it.  Really what we're doing is typically targeting a MAP increase depending on where you start out.  So for people that are hypotensive and you're otherwise treating for sepsis, we start with a MAP goal of 60 to 65.  But if they walked in to the unit with a MAP goal of 60 to 65, then we start to push it up, usually aiming for about a 10 millimeter mercury increase over the baseline, and that's  just sort of written as part of an order, but the nurses understand it, and they know that we're targeting a higher MAP in patients if we suspect hepatorenal syndrome.  And this isn't universally true, but our nurses love liver patients. They don't mind the lactulose, and they really thrive on this.  But we also, our medical ICU is actually the transplant ICU as well, a specific unit. So we have nurses that are really adapted at post-liver transplant care, and so they  sort of are in tune to pre-transplant care as well, and it just works out nicely. Okay, thank you for the talk.  I noticed that in the case you mentioned, the patient had acute kidney injury and was still on Nadelol, on furosemide, and on sulfamethoxazole trimethoprim.  I would stop these first before I give anything. So I think the item is that sometimes iatrogenic parts are important.  As you've seen in kind of three different talks, and that was meant to be a typo actually, but generally the first line that we do is you would stop those agents.  And I think the more important thing that it's more for educating our hepatology colleagues is as critical care docs, we tend to think more of the intravascular volume.  So if you think a patient is either vasoplegic or underfilled, the last thing you want to  do is leave them on diuretics or a beta blocker, and really the biggest threat to life at this point is AKI. So I agree with you.  Hello. I'm Sun Choi. I'm from Bronx, New York, and I'm anesthesia critical care. I have a question that since you told me that pterodepressin is going to be approved within  six months, so if that's going to happen and it comes into our practice, how is it going to affect us? Like is it going to replace vasopressin totally?  Or because, you know, in anesthesia we give like a vasopressin-continuous infusion intra-op or during the liver transplant.  So do you think they're completely replacing the vasopressin because pterodepressin is more selective V1A agonist? Do you see that happening? Or is it like used at the same time?  So one thing I can say, and this is just based on, I did part of my training in the UK where they've had pterodepressin for over 10 years. So there's going to be a variation.  So I think it's twofold. The first thing is really where it's probably going to change care.  It's actually the pre-ICU setting that we're now going to be getting phone calls from ward patients saying, Doc, we have this patient with AKI.  They've now been on pterodepressin for 48 hours and they're not getting better. And one of the things that we did mention is generally if you don't have response to  this in kind of 48 to 72 hours, it likely means it's not going to work. So the one thing is we're going to have now all these ACLF AKI patients that are probably  already have been given a trial of pterodepressin. The other thing that probably isn't necessarily as related is there's also data in variceal  bleeding that I know that in the, I'm from Canada, in the US, people are a little more  picky on the indication for a drug, but vasopressin or pterodepressin is used widely in variceal bleeding patients, even outside of the ICU in Europe. We may notice that as well.  I think interoperatively really where you have a variety of different vasoconstricting  agents at your disposal, certainly for a perioperatively for a transplant, you may not see as much of a difference.  So in centers even where they have pterodepressin, they still use norepinephrine and vasopressin during transplantation. I don't know if you guys have anything to add, but great.  Thank you very much. Yeah. Hi, I'm Akash T from King's College Hospital in London, and I'm a pediatric intensivist there.  My question is about the urine output criteria to diagnose AKI in serotic patients. So the chart which you shows, it shows like 0.2 milligram per deciliter, but does not  mention anywhere urine output because that was initially thought that that might not help.  And then when I listened to the second speaker, we see that if you add in oliguria, your probability of picking up an AKI is much better or it's equally important.  So where are we at this moment in diagnosis of AKI in cirrhosis? I mean, I'll say two things about that, and then come back to this.  It was actually controversial amongst some of the people that were helping write the criteria.  So that paper was written by John Kellum and his group. And if you know Mitra Nadeem, who we've worked, I mean, she's sort of made a push for urine  output criteria to be part of the diagnosis, but it's been met with some controversy amongst the group.  I think as intensivists, and that's where we're maybe a little bit different, I think we believe in it and utilize it, but it was just not part of the formal criteria.  And I don't know if you have anything. So the biggest thing, it's actually an epidemiological question. If you look at trials, people just don't document urine output very well.  So in a lot of the bigger studies, and this even goes in the general crit care population when we had the RIFLE criteria, they just found that a lot of the missing data was for  urine output. So I know that things have changed with electronic medical records and everything like that,  that we're a little bit better at quantifying fluid output, but it's just something that's poorly done. That's the reason why we don't have it in the criteria. Hi. My name is Megan.  I'm a pharmacist in Chattanooga. My question is about duration of therapy for either vasopressors or octreotide mitadrine.  I guess how long do these therapies continue, and then does your answer change if the patient ends up on CRRT?  Sorry, I'm having a little bit of trouble hearing today, worse than usual due to a head cold.  So, you know, I think it's reasonable to say that you should expect a response in the first few days.  If you're not going to see an acute response and mean arterial pressure in the first three to four days, I would say at the longest, then your therapy is probably not going to work.  Right? These are drugs that have pretty quick onsets of action, and if you're not seeing a physiologic  response, I think you need to think about adding on therapy or switching therapy. So from there, I think one thing I would add as well, and Jody can correct me as well,  most of the time, if we see people that don't respond to vasoconstricting patients and we transition them to CRRT, at that point, usually we'll just follow a map of 65.  So it's basically, it's kind of through our standard, you know, and this has been published in the surviving sepsis guidelines.  So we're not necessarily, if at that point, we think probably you've got established HRS  AKI, and really you're heading towards potentially a transplant, and this hasn't turned around,  turned the corner with vasoconstricting therapies, you may just back off to a lower, or basically accept a standard map that we do in ICU, and then wait things out. Okay? Thank you.  Thanks for great talks. My question is, IV diuretics as part of a HRS protocol when you're on norepi? I don't know if that's something that you guys do.  So I'll give my answer, and then, so generally we don't, and this kind of also goes back to the question of what is the etiology of AKI.  So if it's truly HRS and the patient is sodium avid and underfilled, you're actually filling the tank, and generally you wouldn't.  However, there are other cases of AKI in cirrhotic patients and ACLF patients that end up in  the ICU, and ATN is an example where we can actually fluid overload patients, and occasionally  we get overaggressive with albumin where patients are truly fluid overloaded, and then we will  diurese those patients, or even in the setting of renal replacement therapy, you'll alter or filter them. I don't know if you have anything to add. I completely agree. Yeah.  All right. Well, this will be our last question. Hi. My name is Sean. I'm a pharmacy resident at Cleveland Clinic, and still getting familiar with some of this  literature a little more.  I had a question. If a patient does, you start them on albumin on your presser agent, and they progress to CRRT, what is your practice for your albumin?  Are you continuing your typical albumin dose, maybe 50 grams or 40 grams for the duration of CRRT, or are you taking it off after a couple of days? What's your typical practice?  So it sort of depends on what the goals are. I remember that these patients can still have, what are you using the CRRT for? Is it for fluid removal? Is it for clearance?  Is it some combination of both? I don't think giving albumin forever is probably the answer. I think it's one of the questions we get most often, when do you stop?  For me personally, oftentimes, once you have a serum albumin that's in the normal range, then we start to back off on daily usage and start to target it more intermittently.  But if I think it may help me mobilize fluid, especially somebody who may be going to the operating room for transplant, or if we're trying to get rid of significant interstitial  edema, we may continue to use it. But personally, I'm still watching the serum creatinine, serum albumin.  If it's consistently above four or three and a half, then we're not giving additional albumin until it falls again. Okay, thank you very much for your participation.

Video Summary

The video transcript discusses the management of hepatorenal syndrome (HRS) in patients with liver disease. The speakers cover topics such as the etiologies of acute kidney injury (AKI) and cirrhosis, updated clinical definitions, and the role of biomarkers in assessing AKI. They also discuss the criteria for considering combined liver-kidney transplant and the use of renal replacement therapy in cirrhotic patients. The importance of differentiating between reversible and irreversible AKI and its impact on prognosis and survival post-transplant is emphasized. <br /><br />A specific study on terlipressin, a treatment for HRS, is also discussed. The study compared terlipressin to placebo in patients with decompensated cirrhosis and found that terlipressin was more effective in achieving HRS reversal and improving renal function. It was associated with a lower incidence of renal replacement therapy and shorter ICU stays. Adverse events were common but similar between the two groups. <br /><br />The study highlights the need for early diagnosis and treatment of HRS in improving outcomes for patients. Additionally, the importance of maintaining mean arterial blood pressure and optimizing drug therapy to prevent and treat HRS is underscored. Overall, the video provides an overview of the current understanding of renal function in cirrhosis and the importance of further research in this area.

Asset Subtitle

GI and Nutrition, Renal, 2020

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2020 Critical Care Congress held February 16-19, 2020, in Orlando, Florida, USA.

This program is supported by an educational grant from Mallinckrodt Pharmaceuticals.

Learning Objectives

Describe current guidelines and position statements for establishing diagnosis of hepatorenal syndrome (HRS) and acute kidney injury (AKI) compared with other AKI etiologies
Apply proactive evidence-based pharmacotherapy to patients who both meet criteria for HRS/AKI and show rapid serum creatinine elevation
Discuss current evidence in maintaining renal function and improving survival for different pharmacologic, interventional, and surgical treatments in the management of HRS/AKI

Hepatorenal Syndrome and Acute Kidney Injury: Current Knowledge and Unmet Needs

Constantine J. Karvellas

New Guidelines for Hepatorenal Syndrome and Acute Kidney Injury: Early Identification and Correct Diagnosis

Jody C. Olson

Evidence-Based Best Practices: Pharmacologic Options for Maintaining Renal Function in Hepatorenal Syndrome and Acute Kidney Injury

William Peppard

Applying Evidence-Based Strategies to the Management of Hepatorenal Syndrome and Acute Kidney Injury in the Critical Care Setting

Constantine J. Karvellas

Meta Tag

Content Type Presentation

Knowledge Area Renal

Knowledge Area GI and Nutrition

Knowledge Level Advanced

Membership Level Select

Membership Level Professional

Membership Level Associate

Tag Liver

Tag Kidney

Year 2020

Keywords

hepatorenal syndrome

HRS management

liver disease

acute kidney injury

cirrhosis

biomarkers

combined liver-kidney transplant

renal replacement therapy

terlipressin study

renal function improvement

early diagnosis

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