Good afternoon, and welcome back to Session 3 of the postgraduate course. On behalf of my co-moderator, Dr. Graciela Castanaro, President of ALE, as well as Chief of Hepatology in Mexico City, and I'm Sumit Asrani, Chief of Hepatology and Liver Transplantation in Baylor, Dallas. Thank you for attending Session 3. This session is tabled Crosstalk with Cardiopulmonary and Renal Systems. If I can please ask all the speakers to come join us up on the podium. Just once again, if we can just show the Slido slide. Reminder that through the app, I think, let me just check what color it is, for submitting questions. I think we are in orange. There should be questions that will pop up in a second. This is the venue to, one, submit your questions for Q&A, as well as for the poll for the question that I'll ask momentarily. And just a reminder that even if we don't get to all the Q&A, we will try to collate all the answers and then send it out after the meeting. And reminder that this course is also available on demand. Let's start with the case. So this is case 3, falling off the cliff. So you have a 66-year-old man with mast cell-related cirrhosis, transferred from the community hospital and recently put on the liver transplant wait list. This patient was hospitalized two days before with rising creatinine. Baseline creatinine was between 1.2 to 1.6. He had hematemesis times two in transit. Respiratory distress upon arrival was intubated. Past medical history, portal vein thrombosis after a gastric sleeve, which resolved with anticoagulation, type 2 diabetes. Social history, just stopped smoking. Current MEL 3.0 is 33. Chest X-ray shows cardiomegaly, enlarged pulmonary artery, and interstitial edema. Next slide. And the three questions, if you can please use your phone. One, does this patient have acute and chronic liver failure? Two, what is the likely cause of the respiratory distress? One is HPS, B is portal pulmonary hypertension, C, volume overload, D, diastolic heart failure, or E, aspiration pneumonia. And three, what should be done for kidney function? A, albumin challenge, B, turlepressin, C, dialysis, or D, proceed with liver transplant. Let's see the first slide. So case one, does this patient have acute and chronic liver failure? Audience suggesting this is a patient with acute and chronic liver failure. Let's go to case two, sorry, case three, question two. What is the likely cause of the patient's respiratory distress? 40% of the audience thinking this is because of volume overload, with about 20, 20, 20 thinking this is aspiration pneumonia, portal pulmonary hypertension, or HPS. And let's go to question three. What should be done for his kidney function? Albumin challenge, 55% suggesting that, dialysis, turlepressin, about 20%, and about 10% suggesting we should proceed with liver transplantation. Okay, so with that context, here are the four talks for this session. Is number one at two o'clock, it's the vascular system and cirrhosis, 220 cardiopulmonary complications, next followed by kidney in patients with cirrhosis beyond turlepressin, and finally critical care for acute and chronic liver failure. And I'll turn it over to my moderator. The first speaker is Professor Yasuko Iwakiri. The Professor Yasuko will talk to us about the vascular systems in cirrhosis, opportunities for translational research. Thank you. Thank you. Thank you for the kind invitation. I'd like to thank the organizers for this kind invitation. Today's talk, I'm going to talk about the role that vascular system plays in the pathophysiology of cirrhosis and portal hypertension. I'm a basic scientist, so I'm going to discuss the basic scientist's perspective on the vascular changes in the liver of cirrhosis and portal hypertension. The first part of my discussion, I will talk about the mechanism behind the increased intrahepatic resistance that leads to the portal hypertension. And the second, next, I will talk about the changes in the extrahepatic circulation when portal hypertension is developed. Lastly, I will talk about the translational research opportunity focusing on the lymphatic vascular system. This is the simplified diagram showing the intrahepatic sinusoidal microcirculation. The liver receives approximately 75% of the blood from the digestive organ through the portal vein and the rest coming from the hepatic arteries. Branches of hepatic vein, portal, branches of portal vein and the hepatic arteries merge into the sinusoidal microcirculation exits from the central vein. Sinusoidal microcirculation is covered by the specialized endothelial cell called liver sinusoidal endothelial cell or LSEC. LSEC has a specialized structure compared to the endothelial cell in other organ system. LSEC has the fenestra structure which is the small pore structure ranging from 50 to 200 nanometer. This allows relatively large molecule get into, filter into the liver parenchyma and feed into the liver. LSEC do not have the basement membrane and then it's not covered by smooth muscle cell so that is a difference from the other endothelial cell in other organs. On the top of the LSEC, this is a KUPA cell. This is a resident macrophage found in the liver. So this is a diagram, this is enlarged diagram of the sinusoidal microcirculation. Here is LSEC, underneath of the LSEC you find the hepatic stele cell. In normal situation, hepatic stele cell is in quiescent state and there's a space between the hepatocyte and then the LSEC is known as the space of disse. In normal situation, various molecules plays important role for the maintenance of the blood pressure and hepatic resistance. Nitric oxide is one of the key molecules that plays important role in the maintenance of the vascular tone within the sinusoidal microcirculation. The nitric oxide particularly generated by the endothelial cell, endothelial isoform of nitric oxide synthase called ENOS is quite important. ENOS derived nitric oxide maintain the vascular tone, NO as a vasodilator and NO also maintain the hepatic stele cell in quiescent state, therefore NO work as anti-fibrosis because when the hepatic stele cell is activated, that become fibrotic. NO is also important for the maintenance of fenestral structure of LSEC. Then ENOS derived nitric oxide inhibit the KUPA cell activation, therefore anti-inflammatory and also NO inhibit the platelet adhesion to endothelial cell, thereby anti-thrombotic because the platelet adhesion to the endothelial cell, the initial event that promote the thrombosis. In cirrhotic liver, LSEC dysfunction contribute to increased intra-hepatic resistance. Fibrosis contributes significantly in the increased intra-hepatic resistance, accounting approximately 70%, but however today I will focus on more toward the dynamic element which contribute to the increased intra-hepatic resistance, decreased nitric oxide production contribute the vasoconstriction within the liver sinusoidal microcirculation and decreased nitric oxide also contribute to the capillarization of LSEC, which is characterized by the loss of basement membrane, loss of fenestra and basement membrane. Decreased nitric oxide also contribute to the activation of hepatic stellar cell. So this activated hepatic stellar cell become myofibroblastic contractile phenotype that wrap around the LSEC that also increase the contractile contraction within the microcirculation increasing, contribute to increased intra-hepatic resistance. When portal hypertension is developed, it impacts significantly in the extra-hepatic circulation. Key features of early changes in the extra-hepatic circulation are the development of portosystemic collaterals and excessive arterial vasodilation in the systemic and particularly the splanchnic circulation. These key features together exacerbate the portal hypertension and ultimately leads to the development of the hyperdynamic circulatory syndrome characterized by decreased mean arterial pressure, decreased systemic vascular resistance and increased cardiac input, cardiac index, I'm sorry. Ultimately result in the multi-organ dysfunction and complication. The development of portosystemic collateral formation occurs through the opening of the pre-existing vessels and the angiogenesis or angiogenesis. Excessive arterial vasodilation in the systemic circulation but particularly in the splanchnic circulation plays key role in the development of the hyperdynamic circulatory syndrome. This simple diagram shows the splanchnic circulation. The arterial supplies such as mesenteric arteries feed into the blood into the splanchnic organs or digestive organs and then flow into the portal vein. In cirrhosis, there is increased vasodilator molecules particularly the endothelial cell, nitric synthase or e-nose derived nitric oxide overproduction leads to the mesenteric artery or splanchnic arterial vasodilation. This increased vasodilation in the splanchnic circulation stimulate the heart or increased cardiac output to fill the dilated arteries and more blood coming into the splanchnic circulation and more blood also going to the portal venous circulation thereby exacerbate or worsen portal hypertension. Concurrently, the blood escaping through the portal systemic collaterals also prompts the increased cardiac output and more blood supply to the splanchnic organs and then more blood to the portal vein and further worsen the portal hypertension and ultimately leads to the development of hyperdynamic circulatory syndrome. I would like to share the important quote from the Dr. Robert Grossman who is the prominent physician scientist and who pioneered the concept of hyperdynamic circulatory syndrome. He was my mentor and then inspiration of all my research behind all my research. He said the hyperdynamic circulatory syndrome observed in chronic liver disease is a great example of research that originated from the clinical observation by astute bedside investigators and progressed to the experimental laboratory. He also said that the hyperdynamic circulatory syndrome should be better called progressive vasodilatory syndrome because vasodilatation is the factors that brings about all the vascular changes and finally leads to the multi-organ involvement observed as a consequent of this hyperdynamic change. These are some of the examples of extra-hepatic complications in cirrhosis where splanchnic arterial vasodilation plays key roles. These include cirrhotic cardiomyopathy, hepatopulmonary syndrome and hepatorenal syndrome and other complications of liver cirrhosis with portal hypertension including ascites, esophageal valysis and hepatic encephalopathy. Hepatopulmonary syndrome in great detail will be discussed by our next speaker, Dr. Mike Fallon and hepatorenal syndrome will be discussed by Dr. Dean Corvallis. Acute on chronic liver failure, ACLF, is defined by the multi-organ dysfunction and complication. This will be discussed by Dr. Scott Biggins later in the session. Lastly, I would like to talk about translational research opportunities. At the moment, only medical therapy for the treatment of portal hypertension is non-selective, non-invasive data blocker which is quite effective but developed many years ago, like 50 years ago. So one of our research, one of our interest is to develop new therapy for the patient with portal hypertension who suffers from the serious complication of liver cirrhosis with portal hypertension like ascites and hepatic encephalopathy and so on. So one of our research avenues for the development of the new therapy is the modulation of lymphatic vascular system. There are two vascular systems in the liver. One is the blood vascular system, the other is the lymphatic vascular system. Compared to the blood vascular system, lymphatic vascular system is not much known. This black arrow shows the direction of blood flow. This red arrow shows the direction of lymph flow. Hydrostatic pressure applied during the blood flow filters plasma component into the space of DCEP between the LCEP and the hepatocyte, mixed with cellular waste materials, metabolites and antigen and so on, and then drained into the lymphatic vessels located mostly located around the portal tract area. Approximately 80% of the lymph produced within the livers are accommodated by lymphatic vessels in the portal tract area. So the lymphatic vessels are important for the removal of waste materials from the liver. Therefore, the coordination between the blood vascular system and the lymphatic vascular system plays an important role in the maintenance of liver homeostasis. So this is immunohistochemistry showing the lymphatic vessel around the portal tract area. We use the D240 or portal planning as a marker of the lymphatic endothelial cell. You can see there are many lymphatic vessels around the portal tract area. There are some lymphatic vessels found in the capsular area and also the central venous area. In this case, you can see red are the capsular lymphatic vessels. Most known function of the hepatic lymphatic system would be the fluid homeostasis. This diagram shows the thoracic ducts which collect the lymph produced by the peripheral tissue and organs including the liver. Approximately 25 to 50% of lymph passing through the thoracic ducts originate in the liver. Therefore, the liver is the highest lymph producing organ among the other organs. In cirrhotic patients, the lymph production from the liver increased up to six fold. So lymphatic dysfunction then leads to the situs formation. Other function of a lymphatic system include immune cell traffic in regulation because lymphatic vessel can collect those infiltrated immune cells. Lymphatic system is important for the removal of cellular by-products and metabolites produced from the hepatic cells, thereby important for reducing the inflammation within the liver. Lymphatic vessel dysfunction is also important function leads to a situs formation. Here is the intra-hepatic events that leads to increased lymph production. As I mentioned, in cirrhosis, there's an increased intra-hepatic resistance and that leads to the increased hydrostatic pressure. This also then increase in lymph production and finally leads to the fluid leakage from the capsular lymphatic system when the lymphatic vessel is dysfunctional. So it's known as weeping liver. Once portal hypertension is developed, as I mentioned, there are extra-hepatic events taking place. The arterial vessel dilation in the splanchnic circulation leads to the hypovolumia state. This kicks in the sodium and water retention in the kidney and along with the hypoalbuminemia and fluid leakage into the peritoneal cavity leads to the ascites formation. So there are multiple lymphatic vascular system outside of the liver like mesenteric lymphatic vessels and gut lymphatics, they also play an important role for the ascites formation. There are several preclinical studies recently published showing that enhanced lymphatic function alleviate portal hypertension, ascites, and hepatic encephalopathy. Vascular endothelial growth factor C is the most potent lymphangiogenic factors. Lymphangiogenesis is the new lymphatic vessel formation. VEGF-A form, for example, on the other hand, increase angiogenesis. So VEGF-C and A's forms has a distinct function. So this paper published by Dr. Kawa and Siv Sarin's group shows that the administration of recombinant VEGF-C improved mesenteric lymphatic drainage and decreased portal hypertension and ascites in the cirrhotic rats. Manipulation of lymphatic system also can be effective for the treatment of the complication of portal hypertension such as hepatic encephalopathy. Our group recently shows that the injection or overexpression of VEGF-C in central nerve system increased the lymphatic vessel numbers in meningio-lymphatic system, increased the meningio-lymph drainage, leading to decreased neuroinflammation and increased motor function of the cirrhotic rats with portal hypertension, cirrhotic rats with hepatic encephalopathy. Thereby, so the manipulation of lymphatic system also effective for the treatment of complication of reverse cirrhosis. I want to summarize what I talk during my lecture. Increased hepatic vascular resistance due to fibrosis or dynamic components such as decreased nitric oxide, endothelial cell dysfunction, thrombosis and contractile hepatic stele cell leads to the increase in portal pressure, so thereby, portal hypertension. Once portal hypertension is developed, there are significant changes taking place in the interhepatic circulation. Splanchnic arterial vessel dilation due to nitric oxide overexpression can lead to the development of hyperdynamic circulation and the increased portal inflow further worsen the portal pressure, portal hypertension. Ultimately, leads to decompensated cirrhosis. Thank you. The lymphatic vascular system is another vital component within the liver vasculature. BGFC plays a pivotal role as a lymphangiogenic factors promoting increased lymphatic drainage. Finally, modulating the lymphatic system and increased lymphatic drainage could be a new research opportunity for the development of developing effective therapies for liver cirrhosis and its associated complications. Thank you very much for your attention. Thank you. Thank you, Professor Iwakiri. To continue, the Professor Michael Fallon will take to us about cardiopulmonary complication, current diagnosis and management. The Dr. Fallon is a Professor and Chair of Internal Medicine at the University of Arizona. Thank you. Thank you very much. Let's go over cardiopulmonary complications of cirrhosis. So our task today will be to recognize clinical presentation, significance diagnosis and current therapy of cirrhotic cardiomyopathy, hepatopulmonary syndrome and portopulmonary hypertension. Let's turn first to cirrhotic cardiomyopathy. The spectrum of cardiac complications in cirrhosis has complexity. We know that certain liver diseases, including iron overload, copper overload and alcohol induced liver injury can affect cardiomyocyte function. We also know that metabolic associated liver disease where hepatic inflammation and fibrosis drive coronary risks as well as metabolic risks independent of liver disease and metabolic diseases can drive left ventricular hypertrophy and diastolic dysfunction. In addition, there are structural changes that may occur and then rare genetic causes. And within this framework is the concept of cirrhotic cardiomyopathy, first fully defined by the so-called Montreal Criteria in 2005. Cirrhotic cardiomyopathy was recognized to be latent. There were really no specific routine screening and it often presents under stress. So it is possible that cirrhotic cardiomyopathy with pre-existing diastolic dysfunction may have been a contributor in our case. According to the 2005 criteria using systolic and diastolic echo changes and a number of supportive criteria, more than 50 to 70% of all cirrhotics have cirrhotic cardiomyopathy. The problem is with that number, there's a very inconsistent impact on outcomes. So the implications of the diagnosis were not very well defined. So in 2020, the criteria were revised based on enhanced echocardiographic technology, particularly strain imaging to look at systolic dysfunction and so-called tissue Doppler imaging to look at diastolic dysfunction. These improve accuracy, particularly in the setting of volume overload, high cardiac output and low SVR cirrhosis. The supportive criteria were thought to be important, but needed further investigation. So if using these new diastolic criteria, which I've outlined here, any three of the four following criteria, approximately 20 to 25% of patients with cirrhosis have diastolic dysfunction. If you have an interest in learning more about these specific criteria, I point you to one, a beautiful review in hepatology by the Mayo Group and also the description of the revised criteria in 2020 by Manhol, Izzy and colleagues. In addition to diastolic dysfunction, a subset of patients also have systolic dysfunction possibly resulting from diastolic dysfunction where the EF is lower and the so-called global longitudinal strain absolute value is low, about five to 10% of patients. So rather than more than 50 to 70% of patients, it appears that maybe 25 to 35% of patients have cirrhotic cardiomyopathy. So the question for us is, can we really enhance the detection of these disorders using these technologies and does it influence outcomes? And if we take a further step back, the question is, well, why are we studying this at all? And I would say there's two reasons. One is there's classic work that shows that cardiac dysfunction drives the risk of hepatorenal syndrome and refractory ascites and there's disturbing studies published by Lisa Van Wagner and all that show that almost 3% of every patient that gets a liver transplant dies within 30 days. And more than 40% of those people die from a cardiovascular cause despite the fact that we do extensive cardiovascular testing before transplant. So we're missing something. And cardiovascular dysfunction influences outcomes. So what about these new criteria, particularly the diastolic dysfunction criteria? Are they useful? Do we have data for that? Well, this is one study, a prospective single center study of predictors of outcomes after tips done by the Toulouse group. They had 100 patients, very well characterized, and they found that 13% of those patients developed new congestive heart failure after tips. None of them had systolic dysfunction beforehand, but two of the three diastolic dysfunction new criteria were associated with decompensation. No difference in MELD, etiology, or even HVPG lowering amongst the groups. They also went on to describe the Toulouse algorithm, including BNP and some other factors to help predict outcomes before tips. But the bottom line is the diastolic dysfunction criteria predicted systolic dysfunction and heart failure afterwards. And finally, this study done from VanderWaal, which compared the original and the revised cirrhotic cardiomyopathy definitions and looked at cardiovascular outcomes after transplant. Retrospective study, 210 patients had all the information they needed. And when they compared the older, original cirrhotic cardiomyopathy definition, where 77% of their patients would have been characterized as having cirrhotic cardiomyopathy, more common in obese and metabolic disease, there was no correlation with major adverse cardiovascular events. Whereas using the revised definition, 30% of patients had cirrhotic cardiomyopathy, no correlation with obesity or metabolic disease, and there was an increased risk of major adverse cardiovascular events. So the new criteria may help us to predict outcome. So what's the pathogenesis? Well, we've heard a lot about the drivers of the hyperdynamic circulation, and I sort of see this as a interaction between inflammation, hemodynamic alterations, and metabolic alterations, that based on the individual organ, cellular, and disease susceptibility, with a different set of agents and mediators that affect different organs, drives these changes that we see. What about screening for cirrhotic cardiomyopathy? We screen everybody before, or we should screen everybody before tips, transplant, other major procedures, and I think we should really be using the revised criteria. There's no guidance otherwise, and there's really a significant need for further data. There are no specific therapies for cirrhotic cardiomyopathy, but you might wonder whether we're already treating it, or whether we could treat it by targeting the hyperdynamic circulation. Really not much data in this area. There's one study by Shiv Saran's group, by Prem Kumar, that looked at a subset of patients that had left ventricular diastolic dysfunction, cirrhotics. They treated either with standard of care, which was no specific therapy, Carvedilol alone at a portal pressure lowering dose, or Carvedilol and Evabredine, which is a sinoatrial node blocker, to decrease heart rate. And what they found was, in the control group, left ventricular diastolic dysfunction progressed. In the Carvedilol group, there was a trend toward a decrease and in the dual treated group, left ventricular diastolic dysfunction actually decreased. Whether that really correlates with an outcome difference is not yet known, but it's important data around whether we can modulate diastolic dysfunction when we see it. So in summary, cirrhotic cardiomyopathy is latent, multifactorial, and impacts outcomes. There are revised criteria, they have increased accuracy, but they need validation. We should be screening with strain and tissue Doppler imaging before tips, transplant, other procedures, and we need to think about broadly, prospectively studying this. There's no specific therapy, but we may be already, and we may have the opportunity in certain groups to affect diastolic dysfunction. Let's move on to the spectrum of pulmonary complications in cirrhosis, because there's also complexity there. We know that certain liver diseases can result in pulmonary abnormalities, alpha-1 atripsin, PBC, cystic fibrosis. We also know that ascites and hepatothorax can cause restrictive pulmonary function changes and hypoxemia, and we know that sarcopenia and frailty can drive exertional shortness of breath and exertional hypoxemia. We also know that these individuals are not immune from COPD, asthma, and CHF, and that in this framework, we also have specific pulmonary vascular complications of liver disease, hepatopulmonary syndrome, and porta-pulmonary hypertension. What's a little bit surprising, that if you look at people that are evaluated for transplant, the pulmonary vascular complications are actually most common. They're subtle, there's, again, no routine screening, they have overlapping contributors, and they don't typically present acutely. They influence survival and liver transplant candidacy. So what are we specifically talking about with these agents? The first is hepatopulmonary syndrome, which is vasodilatation and angiogenesis, an extension of what Yusuko was talking about in the systemic circulation, in the alveolar microcirculation, affects gastric change, exsidious onset of shortness of breath, and hypoxemia. The other is porta-pulmonary hypertension, which results from vasoconstriction in remodeling and resistance vessels. More of a plumbing problem, less hypoxemia, and less late can create back pressure, peripheral edema, and even worse than porta-hypertension. When unrecognized, it can present acutely, and our patient did have dilated pulmonary arteries, but volume overload can create the same events. So how common are these disorders? Well, really about half of people have normal pulmonary vascular tone, three to 8% of porta-pulmonary hypertension, and almost 50% of people have this intrapulmonary microvascular dilation. If you look for it, half of those people appear to have abnormal blood gases with no other good cause, and we call that hepatopulmonary syndrome. So the definition of hepatopulmonary syndrome is cirrhosis and porta-hypertension, the presence of these intrapulmonary microvascular dilations, and abnormal arterial oxygenation due to the dilations. 30% of transplant patients have it, about five to 8% will have a PO2 less than 60 and be considered severe. Insidious onset, if I really think about exam, if they're not blue, clubbing is probably the most useful predictor. And what about the clinical significance? Well, here's a comparison of some Kaplan-Meier survival estimates of HPS compared to control or non-HPS cirrhotics. If you look at our two multicenter PVCLD studies, outcomes in non-HPS patients over four years are really pretty good. If you look at a study done by Peter Schenk in Austria, HPS patients had poor outcome. Karen Swanson data from Mayo, HPS had worse outcome. The HPS group from our initial study and then our subsequent study, also worse outcomes than the controls. The presence of HPS doubles mortality and adversely influences quality of life. The surprising thing is it's not really related to the severity of hypoxemia. It's related to the tendency to develop intrapulmonary vasodilatation, which must affect other organs. The diagnosis we talked about is detecting the presence of vasodilatation and then in the appropriate setting doing arterial blood gases to assess oxygenation. How do we detect intrapulmonary vasodilatation? Two methods. One is so-called contrast transthoracic echocardiography where you inject contrast material intravenously. It goes to the right side of the heart and then in a delayed fashion through the dilated vessels in the lung gets to the left heart. Three to six cardiac cycles later, so-called delayed shunting. It's sensitive, it's specific. You can screen for cirrhotic cardiomyopathy. You can screen for porta-pulmonary hypertension. You can look for structural abnormalities. It's by far the best screening test. You can also use the MAA scan, which is the so-called macro-aggregated albumin scan, which is really just the perfusion component of a VQ scan. Normally, all the labeled albumin gets stuck in the lung as an A and doesn't go to the brain. If you have a hepato-pulmonary syndrome, it goes to the brain in B. You can actually quantify how much is going to the brain. The problem is this is not standardized across centers anywhere, and we don't really know what shunt value is actually bad or really bad or not so bad. So the pathogenesis I put in the same framework. The mediators come from the disease state. It's the individual cellular and genetic susceptibility of the host. Different mediators drive changes in the pulmonary microvasculature. What about therapy? Oxygen's important in people that are hypoxemic. Remember that HPS patients desaturate with exercise and also at sleep, so you have to be careful about when to use oxygen. Garlic has been used. There's one randomized controlled trial. Garlic is a mess of so many different things. I'll be more than happy to talk to anybody who wants to talk about garlic. Liver transplantation, more than 90% of people resolve, and there's mild exception now for those with a severe HPS, PO2 less than 60. The criteria are cirrhosis, portal hypertension, shunting by one of the methods we talked about, and low PO2. So what is the outcome for transplant? This is a nice update of the UNOS mild exception data, which really shows that long-term post-transplant survival is excellent in HPS, even in those with severe hypoxemia. However, you notice the curves diverge after two years, and those with very significant pre-transplant hypoxemia have worse outcomes, and a significant number of these outcomes are cardiovascular so prolonged pre-transplant hypoxemia seems to affect long-term cardiovascular outcome. So we need to think about very severe patients treating them quickly. So in summary, hepatopulmonary syndrome is a common cause of hypoxemia. If no transplant, increased mortality, 2.4-fold relative to non-HPS patients, there are no proven medical therapies, and liver transplantation reverses hepatopulmonary syndrome. So hepatopulmonary syndrome is an unlikely contributor to our case. So let's finish up with portal pulmonary hypertension. So portal pulmonary hypertension is pulmonary arterial hypertension in the setting of portal hypertension and or cirrhosis. To make the diagnosis, you have to do a right heart cath. The current WHO criteria are a mean pulmonary pressure of greater than 20, an increased PVR that reflects the remodeling and vasoconstriction and resistance vessels of greater than three wood units, presence of portal hypertension, and the exclusion of other types of pulmonary hypertension. You have to do a right heart cath because the hyperdynamic circulation, volume overload, as well as portal pulmonary hypertension can increase the mean pulmonary pressure and the estimated pulmonary artesystolic pressure on an echo. So the only way to distinguish these is to look at the pulmonary vascular resistance, and in portal pulmonary hypertension, it's elevated reflecting the vasoconstriction and remodeling. So what about the clinical significance of portal pulmonary hypertension? Well, we know that from a number of studies, including this study, which is the REVEAL study, retrospective study published by Mike Croca and colleagues that portal pulmonary hypertension has worse outcomes than idiopathic or familial pulmonary arterial hypertension. This has been seen in a number of different studies. So the presence of portal pulmonary hypertension increases mortality. What about clinical features? The history is really one of exertional dyspnea, chest pain, or no symptoms. And occasionally people can present with severe portal pulmonary hypertension without any pre-existing symptoms, so-called acute presentation. The risk factors include autoimmune liver disease and females, and from some really nice work that Hilary Dubroc has done, we know that females present with more severe portal pulmonary hypertension at a lower MELD and have worse survival, particularly in younger females. So this is a group we need to target quickly when we identify them. We also know that portal pulmonary hypertension patients have disparities with other forms of pulmonary hypertension, have lower socioeconomic status, increased healthcare utilization, and also another group we need to target to make sure we don't disadvantage this population in terms of how we might treat them. Finally, on exam, I really think edema out of proportion to ascites is a useful target. So we screen with transthoracic echocardiography. I think screening with a pulmonary systolic pressure of greater than or equal to 40 should trigger a right heart cath. Remember, systolic estimate versus a measured mean, pre-transplant, pre-tips, edema out of proportion to ascites, chest pain, shortness of breath, and no other cause. The pathogenesis, again, is the same scenario, different mediators. It's important to recognize that all of the therapies for pulmonary arterial hypertension focus on reconstituting endothelial dysfunction by increasing prostacyclin and anocyclic G production, and also inhibiting endothelin 1, which is increased. There are 12 FDA-approved drugs, and they use. So let's finish up talking about transplant for portopulmonary hypertension. If you look at the ITLS guidelines, POPH alone is not an indication for transplant. Only 50% resolve after transplant. Mortality is increased with severe liver disease. And we don't want to disadvantage other patients with decompensated cirrhosis. The current guidelines is you have to have clinically significant disease. That's a mean pulmonary pressure greater than 35 and elevated PVR. And they have to undergo, they have to otherwise be transplant candidates, undergo medical therapy, and improve. Mean pulmonary pressure less than 35, or a mean pulmonary pressure that can be higher than that as long as the PVR has normalized. So finally, what about transplantation? Well, here's an update. If you look at a multicenter French study published by Savallial or an update of the UNOS data from 2016 to 2019, patients who undergo transplant for portopulmonary hypertension do very well over four to five years. If you compare that to data that Mycroco published from the patients that did not undergo transplant at Mayo, it's very different, particularly after a year. And if you further divide those Mayo patients into those with low MELD, less than 15, versus high MELD, those with low MELD really did pretty well, almost the same over the first two years. Those with a high MELD did not so well. And if you look at the Savallia study as well, the patients that were not transplanted there, those that got no transplant with a low MELD, less than 15, their survival over four years was not any different than those who underwent transplant. And those with a greater than or equal to 15, really poor survival. So in summary, portopulmonary hypertension, 3% to 8% of candidates, increased mortality, can occasionally present acutely and could be a factor in our case, medical therapies effective in lowering pressures, outcome is influenced by liver disease severity, and liver transplant is effective in medical responders, reverses, only occurs in 50%, and we should be targeting people with a MELD greater than 15. Thank you. Thank you, Dr. Fallon. The next speaker is Professor Scott Begins, who will talk about the kidney inpatient with sciarrhosis beyond terlipresence. The doctor Begins, he served as the Washington Medicine Chief of Hepatology. He has currently taken a new role as Chief of Hepatology and Liver Transplant at University of Pittsburgh. Thank you. Thank you. I'd like to thank the organizers, and I'd also like to thank the AdKey workgroup that provided the basis for a lot of the material that I'll be showing here. So I have nothing to disclose. So over the course of this talk, we'll talk about patients with cirrhosis. And of those patients with cirrhosis who have acute kidney injury, we'll talk about the epidemiology, the definitions, the diagnostic criteria, some about the susceptibility and trajectory, how to prevent, what's evaluation, what kind of diagnostic tools are available, a little bit about management, and then some about post-acute kidney injury follow-up. So acute kidney injury in the setting of cirrhosis occurs in about 50% of patients and is clearly associated with increased morbidity and mortality. The incidence varies based on the heterogeneity and terminology. We'll get to a little bit about the changes in terminology. In this discussion here, the definitions and the etiology. About half of patients who have acute kidney injury with cirrhosis, it's because of hypovolemia. So don't go directly to HRS. Over a quarter will have acute tubular injury, and then the remainder will have paternal syndrome. Of those with acute tubular injury or HRS, there's a 50% mortality. So this is an important cause of mortality in the setting of cirrhosis. That risk is higher if there are pre-existing chronic kidney disease, sepsis, ascites, SBP, or encephalopathy. When defining cirrhosis, AKI, in the setting of cirrhosis, you can use the CADIGO criteria that are used outside of cirrhosis. So this has been standardized and looked at quite closely, as well as by the ADKI group and the International Ascites Group. The definition is that an increase in serum creatinine to greater than 0.3 milligrams per deciliter within 48 hours, or a 50% increase from baseline, or oliguria with less than a half a milliliter per kilogram over six hours or more. Important in that definition is the baseline serum creatinine. Ideally, that would be available within three months. If that's not available within three months, the first available within the last year. And in the rare circumstance, that's not available then to use your hospital admission value. So acute kidney injury is a syndrome that occurs within seven days. So if that acute kidney injury lasts longer than seven days, we're talking about acute kidney disease. So acute kidney injury is a subset of acute kidney disease. If that serum creatinine remains elevated, the impaired GFR remains elevated, the injury is still there, after 90 days, then it's chronic kidney disease. So this is really dependent on a definition of recovery also. So if the return to the serum creatinine within 0.3 milligrams per deciliter of baseline, that is considered recovery. So again, if that occurs within 90 days, acute kidney disease. Beyond 90 days, chronic kidney disease. So I spent a little time on this new nomenclature because the older terminology of HRS type 1 and type 2 are outdated and have been replaced by this AKI, AKD, and CKD definitions with an additional modifier of with or without HRS. And importantly, HRS can occur with acute tubular injury or pre-existing CKD. They are not mutually exclusive. HRS AKI occurs in the setting of cirrhosis with ascites. So that's an important designation. The Cadego criteria for the serum creatinine are listed there again as part of the definition for HRS AKI. And this happens in the absence of improvement within 24 hours of volume repletion. In the absence of another clear primary cause of AKI. But this may coincide with other kidney injuries or CKD. Now, speaking a little bit about susceptibility and their trajectory of AKI, this all begins, if you heard with the prior presentations, with the presence of portal hypertension. There's vasodilation, splenctin, and systemic vascular beds, activation of sodium and water conservation, and constriction of neurohumeral pathways leading to ascites. This is exacerbated by cardiac dysfunction, initially with hyperdynamic circulation, and then eventually cardiopressive substances, and as you heard earlier, cirrhotic cardiomyopathy. It's also exacerbated by systemic inflammation. This is a release of the PAMPs that you heard earlier in the course this morning, and upregulation of renal toll-like receptor 4. Their trajectory can be impacted by modifiable and non-modifiable factors. This is somewhat intuitive, where the modifiable factors are the severity of the injury and the milieu of pharmacology, including non-selective beta blockers. And non-modifiable factors being age, sex, and comorbidities, which certainly have an important impact on the trajectory. The trajectory of AKI is also determined by the adaptive and maladaptive responses in the underlying pathophysiology. So if you have tubular proliferation and repair, you'll have recovery. If you have fibrosis and tubular loross, you'll have non-recovery and likely move on to CKD. A few words about prevention, evaluation, and diagnostic tools. The prevention of AKI can be thought about in anticipated exposures and unanticipated exposures. The anticipated exposures, for example, fluoride and in contrast, paracentesis, nephrotoxins, and unanticipated exposures being volume depletion, perhaps diarrhea, variceal bleed, SBP, or emergent surgery. Regardless of the actual exposure, the fundamentals remain the same. Optimize the fluid status. Consider the administration of IV albumin, antibiotics where appropriate, and avoid NSAIDs. There are several diagnostic tools in our toolbox when we consider AKI in the setting of cirrhosis. But going back to the basics and assessing the intervascular fluid status is paramount. This is difficult, but critically important. The clinical exam is very critical here. There have been some studies looking at point of care ultrasound to augment the clinical exam. However, these are prone to inter-observer variability. And at least one study has shown to be a 20% underestimate and a 20% overestimate versus other gold standards. Utilization of the CK-EPI equation without the race variable can be helpful in assessing your GFR with the reminder that at low GFRs, the performance of this equation can be suboptimal. In that context, there's a move towards having complementary biomarkers, either functionally related or damage related. The function related biomarkers, such as Cystazine C, can be very helpful when available. And the damage related are a little bit more accessible, particularly albuminuria and increasingly urine and gout, which I'll speak a bit about in the next slides. Increasingly, it's noted that FINA, particularly if the cutoff of less than 1%, is less helpful, given that this is present very commonly in cirrhosis, even without AKI. Using lower thresholds may be of more value. The urine microscopically evaluation can be impaired by having elevated bilirubin staining cells and making that interpretation more complicated. So increasingly, I think an emerging field in this area is going to be the application and assessment of complementary biomarkers. Speaking of biomarkers, one of the most promising studied biomarkers is urine NGAL and assessing AKI. This urine NGAL will increase on a spectrum from lower levels in the setting of volume depletion, intermediate levels in the setting of HRS, AKI, and highest levels in acute tubular injury or acute tubular necrosis. This exact thresholds are dependent on what bioassay is used in your local area or referring area. But levels over 220 are generally consistent with acute tubular injury. Some of the strongest evidence to point to this is the responsiveness to terlopressin, which as you know, is a treatment of hepatorenal syndrome. And in low levels, where the urine NGAL was under 220, there was a 70% response rate for terlopressin. And when the levels were over 220, the response rate to terlopressin was lower. Interpretation there is that that latter category was more an acute tubular injury rather than hepatorenal syndrome. Getting more details about the management, the management of AKI and cirrhosis can be personalized based on the volume status. It goes back to those basics I was mentioning earlier to assess the fluid responsiveness and also to incorporate the liver health, the kidney liver health profile. So looking at the overall health of the patient that's coming into this acute kidney injury. Did the patient have MAFLD and now has underlying CKD and has AKI on top of that? That trajectory is going to be a little bit worse than the absence of CKD. Is a patient coming into this with compensated cirrhosis or coming in with decompensated cirrhosis? And then what's the cardiac function? Is there underlying cirrhotic cardiomyopathy that's in physiology that you need to understand there? And also understanding the specific AKI phenotype. So is there volume depletion? Is there ATI? Is there HRS? Or is there a combination of some of each of these? And what's the predominant there? When we think about management in the setting of cirrhosis of AKI, you can think about the general principles of following AKI principles apart from cirrhosis. So I would refer you to the KDGO recommendations for the general population. And include discontinuing or avoiding nephrotoxins, optimizing the hemodynamics and the volume status in the setting of a GI bleed. You'll give blood. If there's volume depletion or sepsis, give balanced solutions such as lactated ringers in the setting of SBP or HRS AKI to consider giving hypertonic intravenous albumin. You have to have careful titration of fluid administration and pay attention to avoiding volume overload. This clinical exam is very important and considering non-invasive as well as even invasive assessments as needed here. When we think about cirrhosis-specific management in the setting of AKI, and if you have 10 societies, you should consider a large volume paracentesis. This can reduce the inter-abdominal pressure. And that alone can help GFR and has been shown to improve GFR. In the absence of cirrhosis, early renal replacement therapy has not been found to be helpful in the setting of AKI. But in the setting of cirrhosis, there may be a benefit to early renal replacement therapy, particularly if there's volume overload that's unresponsive to diuresis, particularly if there's encephalopathy that's refractory to treatment. Importantly, when you begin renal replacement therapy in this context, it's important to understand where your goals are. So is this a bridge to transplant? That's a little easier hurdle. If this transplant is not an option for this patient in front of you, you may want to consider a limited time trial if that's compatible with the patient's goals. And having a definitive end to that time trial, and if there's no option for liver transplant to consider moving more to palliative or hospice care. Tips can improve GFR, can improve refractory ascites, whether or not it can improve mortality in this context is being studied. And there are randomized controlled trials underway that have not yet resulted that might provide an answer there. When we think about more specific HRS AKI therapies, vasoconstrictor therapy with intravenous albumin is the mainstay. And this should be started immediately upon establishing the diagnosis. The delay in treatment here can lead to an impaired trajectory here. And often, you get caught up in this, often you get caught up in this, is this ATI, is this HRS, is there a combination, is there CKD on top of this. And remember that the HRS AKI is not mutually exclusive with those other diagnoses. Terlopressin is a first line therapy as a vasopressor, norepinephrine in my experience has also been quite helpful, where terlopressin is not available or the expense gets in the way. Close monitoring of volume status is very important, given the data that's been shown of volume overload in the administration of terlopressin, they stop IV albumin if there are signs of volume overload. Consideration of increasing the dose of vasoconstrictors every 24 hours if there's no improvement in the serum creatinine by 25% or mapped by 10 milligram mercury. And importantly, to stop the vasoconstrictor if there's a recovery as defined by a serum creatinine, improving to within 0.3 of the baseline. Stop if there's non-responsiveness to treatment, so no improvement after 48 hours of a max dose of the vasoconstrictor. And also stop if there's severe adverse reaction or you're starting renal replacement therapy. Now, just a few words to note about hospital follow-up. In individuals with cirrhosis that have AKI, they deserve close follow-up after hospital discharge. Despite close follow-up after hospital discharge, about a half will be readmitted within three months, and as much as a fifth will be readmitted with acute kidney injury again, anusarca, or hyponatremia. So the close follow-up is really dependent on the severity of the acute kidney injury. These patients definitely deserve to see their PCP early on. They definitely deserve to see you folks in hepatology. If this is a severe acute kidney injury, they should certainly see a nephrologist, and even more so if there's acute kidney injury that has developed. I can't emphasize enough that the inclusion of palliative care early in this process, HRS, and ATI is highly morbid and associated with a high mortality. And regardless of the transplant candidacy, it's my opinion and the opinion of our society that palliative care really can be brought to these patients and improve the circle of care around them. It's also important once the patients get to this stage, hopefully maybe even earlier, that you're considering a liver transplant and the potential benefit of a combined liver and kidney transplant. So I'll stop there. I'll thank you for your attention. And again, appreciate the invitation. Thank you.

acute kidney injury

cirrhosis

serum creatinine levels

urine output

morbidity

mortality

volume depletion

hepatorenal syndrome

biomarkers

therapeutic interventions