SCCM Resource Library-Hepatorenal Syndrome: Can the Kidneys Be Saved From the Wrath of the Liver?

Video Transcription

Good afternoon, dear colleagues. Today I would like to talk with you about the effects of liver disease on renal function, in particular, Hepatitis A syndrome.  But first, I would like to start by thanking the organizers for inviting me to this wonderful session.  Before diving into the actual topic, please allow me to declare that I have no conflicts of interest.  When discussing the effects of liver disease on renal function, we will take a look at the definition and diagnosis of Hepatitis A syndrome, the clinical management of Hepatitis  A syndrome, and the choice and use of vasopressors in Hepatitis A syndromes. Generally speaking, Hepatitis A syndrome represents a continuous spectrum of kidney  injury in patients with liver disease, ranging from functional injury all the way to parenchymal damage.  Different concepts of Hepatitis A syndrome consider three main contributors to the evolution of Hepatitis A syndrome.  We have circulatory dysfunction with subsequent splenic arterial vasodilation and renal hypoperfusion,  microvascular dysfunction, and inflammation with the release of danger signaling molecules. It is in particular inflammation that is being thought to be promoted by bacterial  translocation from the gut in the setting of portal hypertension. Historically, we have differentiated between two forms of hepatorenal syndrome.  Type 1 represents the rapid form with a more than 50% decrease in renal function within less than two weeks, frequently caused by sepsis or hemorrhage.  Type 2 hepatorenal syndrome represents the slow progressive form of renal dysfunction in the setting of refractory ascites.  Interestingly, the traditional approach requires us to exclude underlying parenchymal kidney disease before being able to make the diagnosis of hepatorenal syndrome.  Emerging concepts of renal injury in patients with chronic liver disease are trying to incorporate  established criteria such as the K-DIGO criteria that are based on changes in serum creatinine and urine output to diagnose and stage AKI.  There's further great interest in assessing the duration of kidney injury in these patients to differentiate between acute, subacute, and chronic disease processes.  The International Club of Ascites has made a first step in that direction by revising the traditional hepatorenal syndrome criteria.  In their 2015 revision, they state the following, cirrhosis and ascites have to be present while excluding other underlying etiologies.  They now consider hepatorenal syndrome type 1 a form of acute kidney injury but diagnosed only by serum creatinine criteria.  They purposefully exclude urine output criteria mostly for conceptual reasons. Interestingly, the revised criteria still require the exclusion of underlying structural  kidney damage to make the diagnosis of hepatorenal syndrome. This leaves us with interesting questions.  For example, what do we do in the setting of acute on chronic kidney injury like in a patient who has diabetic nephropathy but then develops nephrosis and subsequently shows  worsening renal function? These type of patients are clearly not included in those revised criteria.  Also not included in these revised criteria for hepatorenal syndromes are patients with acute liver failure or acute on chronic liver failure, two entities that are frequently  characterized by rapidly worsening renal function. Before moving on, I would quickly like to go back to the role of urine output for diagnosing  acute kidney injury in hepatorenal syndrome. As you can see from this figure here, urine output criteria play an important role in  the prognosis of AKI in patients with chronic liver disease. Patients diagnosed with AKI either by serum creatinine criteria or urine output criteria  have roughly the same risk to die. When we combine these two criteria, the mortality risk drastically increase for these patients,  showing us that urine output criteria add substantially to the mortality risk of patients with hepatorenal syndromes who develop AKI.  Let's now take a look at the treatment of hepatorenal syndrome. This stage-based approach as published by the International Club of Ascites can serve  as an excellent framework to discuss our management, although in my opinion, adherence to the various stages does not seem necessary.  Whenever we diagnose someone with hepatorenal syndrome AKI, we need to continue with close monitoring of these patients for changes in their renal function.  We also need to make sure that we correct any underlying hypovolemia and avoid nephrotoxic drugs or diuretics as much as possible.  If AKI continues to worsen, our next steps are the application of albumin together with vasopressors.  Neither one by itself is effective. Albumin is usually administered in doses of 20 to 40 grams per day while closely monitoring the patients for signs of circulatory overload.  Vasopressors – and I'll talk about the different ones in just a few minutes – are usually titrated to either an increase in MAP by 10 millimeters of mercury or simply  trying to bring the MAP above 70 millimeters of mercury. While the necessity to use vasopressors in the setting of hepatorenal syndrome is not  controversial at all, the choice of vasopressors remains intensely debated. As you can see from this network geometry of clinical randomized trials, you will notice  that it's been mostly telepressin and norepinephrine that have been studied, while there are some  studies looking at either midodrine plus octreotide or dopamine plus furosemide for management of these patients.  Based on the available data, we can state right now that telepressin plus albumin decreases  short-term mortality when compared to placebo, but also shows some serious adverse effects, as I'm going to outline in a few minutes.  We can also state that telepressin plus albumin and norepinephrine plus albumin are superior to midodrine plus octreotide plus albumin for the reversal of hepatorenal syndrome.  As telepressin appears to be close to FDA approval, I would like to spend the next few slides discussing its effects and side effects a little bit more closely.  In addition to the data that I've shown you before, we have some very recent data looking  at the efficacy and side effects of telepressin in a prospective randomized controlled trial.  The confirmed trial included 300 patients with cirrhosis and ascites, who also demonstrated a rapid increase in serum creatinine, while showing no improvement after withdrawal of  diuretics and volume expansion with albumin. These patients were then randomized to either 1 milligram of telepressin or placebo IV every six hours.  As you can see from the table in the lower left corner, telepressin was significantly superior to placebo when looking at the primary endpoint of verified reversal of hepatorenal  syndrome. However, we also have to note that while the reversal of hepatorenal syndrome is important,  this study did not show any significant differences with respect to 90-day mortality or number of liver transplantations performed.  The confirmed trial was not only remarkable for the results with respect to the efficacy of telepressin, but also for the results with respect of adverse respiratory events  in patients who had received telepressin. As you can see here, there was a considerably higher rate of death from respiratory failure  in patients that had received telepressin versus those that had received placebo.  Similarly, a recent meta-analysis showed that while telepressin was equally effective to norepinephrine with respect to reversal of hepatorenal syndrome, it had a significantly  higher odds ratio for adverse events than norepinephrine plus albumin. Also a recent open-label randomized controlled trials in patients with acute on chronic liver  failure revealed that the rate of adverse events was significantly higher for patients receiving telepressin versus those receiving norepinephrine.  These repeated reports of serious respiratory adverse effects with the administration of telepressin should prompt us to take a closer look at the pharmacology of telepressin and  compare it to that of norepinephrine. And I think it's fair to speculate based on our pharmacological knowledge.  We know that both telepressin and norepinephrine lead to vasoconstriction in the systemic circulation with a subsequent increase in left ventricular afterload.  Norepinephrine, however, leads to vasoconstriction in the precapillary pulmonary vasculature and also has a somewhat positive inotropic effect.  Telepressin on the other side lacks any inotropic effect. It, however, leads to pulmonary arterial vasodilation and pulmonary venoconstriction.  We can therefore speculate that when telepressin is administered together with albumin, we  could find increased pulmonary fluid extravasation, in particular when volume expansion with albumin is exaggerated.  And these two together then could potentially lead to increased pulmonary edema, which might  explain the observed rate of respiratory adverse events after telepressin administration. So where do we currently stand regarding the use of vasopressors in Hepatitis A syndrome?  Although very close, telepressin is still not FDA approved. We are therefore left with currently available substances for the treatment of Hepatitis  A syndrome, meaning norepinephrine plus albumin or vasopressin plus albumin. Although based on their similarity, one should have the same concerns for the use of vasopressin  as we have for the use of telepressin in the setting of volume expansion with albumin. This will require close monitoring of volume status and cardiorespiratory function, which  is also true for norepinephrine administration, and thus ultimately require admission to the ICU. Will our management change with the approval of telepressin?  I don't know. We will have to see. To summarize my talk, I've shown you that the diagnosis and definition of Hepaturinus syndrome continue to evolve.  We can state that Hepaturinus syndrome type 1 is now considered Hepaturinus syndrome AKI, similar to KDGO criteria.  The role of urine output in diagnosing and staging Hepaturinus syndrome AKI remains to be seen, but it appears that urine output should play a greater role than it currently is.  Also, the inclusion of underlying parenchymal disease in the definition of Hepaturinus syndrome  AKI, in particular with respect to acute on chronic processes, appears to be necessary but has not occurred yet.  And last but not least, we will also have to include the duration of renal dysfunction in our definition to better differentiate between acute, subacute, and chronic processes.  With respect of Hepaturinus syndrome treatment, we can state that vasopressors together with albumin remain the foundation in the management of our patients.  We can currently not make recommendations regarding the choice of vasopressors, however, we know that there's only very limited efficacy when vasopressors are used without albumin.  Last but not least, I want to highlight that we still cannot make any recommendation regarding the use of tips in the management of Hepaturinus syndrome.  And with this being said, I would like to conclude my talk and will be happy to answer any questions. Thank you very much for your attention.

Video Summary

The speaker discusses the effects of liver disease on renal function, specifically focusing on Hepatorenal Syndrome (HRS). HRS is a spectrum of kidney injury in patients with liver disease, ranging from functional to parenchymal damage. HRS is characterized by circulatory dysfunction, microvascular dysfunction, and inflammation. The traditional approach to diagnosing HRS requires excluding underlying kidney damage, but newer concepts suggest incorporating established criteria for acute kidney injury (AKI). There are two types of HRS: type 1, which is rapid and often caused by sepsis or hemorrhage, and type 2, which is slow and occurs in patients with refractory ascites. Treatment for HRS involves close monitoring of renal function, correcting hypovolemia, and avoiding nephrotoxic drugs. Albumin and vasopressors are used if AKI worsens, and although the choice of vasopressor is debated, telepressin appears to be effective but has serious adverse effects such as respiratory failure. The speaker emphasizes the need for further research and the inclusion of urine output criteria in diagnosing and staging HRS.

Asset Subtitle

Renal, GI and Nutrition, 2022

Asset Caption

SCCM's Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU were published in March 2020. This session will cover these recommendations and continued controversies surrounding managing these complex patients. The guidelines cover recommendations for cardiovascular, endocrine, hematologic, pulmonary, and renal considerations. This session will cover selected topics, including hemodynamics and resuscitation, coagulopathy, and renal complications.

Meta Tag

Content Type Presentation

Knowledge Area Renal

Knowledge Area GI and Nutrition

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Kidney

Tag Liver

Year 2022

Keywords

liver disease

renal function

Hepatorenal Syndrome

circulatory dysfunction

microvascular dysfunction

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