Okay, as we discussed, we are going to talk about organ crosstalk. So I built this presentation in terms of kidney and liver crosstalk and primarily focused on hepatorenal syndrome. I have no disclosures related to this activity. And our objective for today would be by the end of this talk, we all can appraise pathophysiology involved in kidney-liver interactions, summarize diagnostic strategies for hepatorenal syndrome, analyze evidence-based management to HRS, evaluate indications and post-transplant outcomes in patients with HRS. Going back in history, how to define AKI and how it is applicable to patients with cirrhosis. There have been multiple societies and networks from nephrology and critical care who have been trying to define AKI over years. The intent is, again, as Javier pointed out, for early diagnosis, early capture of this patient so that we can streamline our management of AKI before it turns into CKD. So the first attempt was done by Acute Dialysis Quality Initiative Workgroup in 2004, where they defined AKI as increase in creatinine to 1.5 times the baseline within seven days. GFR decreased more than 25% and has a definition of oliguria and anuria. So based on this, they defined AKI into a spectrum of risk, injury, failure, loss, and end-stage renal disease. This tool had high sensitivity and high specificity, but in terms of application to patients with cirrhosis, the urine output criteria doesn't always hold true in patients with cirrhosis. They have underlying HRS physiology. Their urine output is not always accurate. Secondly, it is talking about serum creatinine within seven days. So an attempt to improve this definition was done by Acute Kidney Injury Network in 2007. They took away GFR from the equation, and they changed the serum creatinine to increase to 0.23 milligram per deciliter within 48 hours instead of within seven days. Better attempt for early identification. Then came, we talked about Kidco Classification Alert with Javier, done in 2012. What it did is actually combined all the good parts from the last two definitions and brought it together. It talks about, again, severity as three stages. Serum creatinine 1.5 to 1.9 fold in seven days or more than 0.3. So it took both, seven days, 48, and also had GFR, again, so that they can capture any patient who is developing AKI. Before I say, all the QR codes are dynamic QR codes. If you scan them, they will take you to PDFs. So my slide set has almost 32 to 35 PDFs, so you can download them. So this spectrum, people were still not happy to identify AKI because we felt we are still late in identification of AKI in cirrhosis. So in that attempt, the International Club of Ascites defined AKI in cirrhotic population in 2015. They better defined baseline serum creatinine for cirrhotic patients. So baseline was defined as serum creatinine obtained in previous three months. So they went far back because these patients have sometimes smoldering AKI. They wanted to capture those patients. The value closest to the admission time to the hospital within previous three months or serum creatinine on admission. So they defined baseline creatinine further down. And then they defined serum AKI as serum creatinine more than 0.3 within 48 hours or a percent increase, more than 50% of baseline, which is known or presumed to have occurred in last seven days. So again, more complex definition to capture patients early. Similar to Aiken staging, it had three stages, but it also included progression of AKI, what happens after once the patient develops AKI, whether they progress or they recover. And also, whether they respond to treatment fully, partially, or there is no response. More robust. So what do we know for AKI in patients with cirrhosis? It can present in three phenotypes, as we know in general, hypovolemic or pre-renal, acute tubular injury, and hepatorenal syndrome. So patients hospitalized with cirrhosis, believe it or not, we will say HRS is the most common diagnosis. Still, pre-renal remains the most common diagnosis when they present with AKI. 19% of the patients present with hypovolemic or pre-renal AKI. Out of pre-renal AKI, HRS type 1, again, this paper was written before the new definition of HRS. So in that population, 25% of pre-renal patients were presenting with HRS type 1. Overall, it accounts for 17% of the cases when patients present to ICU. Let's take it further, why it is important for us to understand kidney-liver crosstalk. What we know traditionally, when AKI happens, we see metabolic disturbances in terms of uremia, metabolic acidosis, hyperkalemia. But those are metabolic disturbances. When we start RRT, these patients should improve. But over decades, the mortality related to AKI hasn't changed. This AKI is associated with systemic inflammatory response. It causes cytokine dysregulation. It causes immune system dysfunction. All those things, in addition to metabolic disturbances, leads to organ crosstalk. When there is a systemic inflammatory response, it affects multiple organs in different ways. And this is not just presence of AKI, but patients die because of AKI and organ crosstalk. When we use the word crosstalk, that means there is a mutual relationship of injury between two organs. We know more about liver-causing kidney injury, but let's talk about kidney-causing liver injury. So three things we all know traditionally, when AKI happens, there is a volume overload, uremia, and metabolic acidosis. How does that impact liver? We know volume overload and pulmonary edema has been a concept for years. But volume overload also causes right-sided filling pressures to go up, and in return, causes hepatic congestion. Clinically, you see hepatic biomarkers going up because of venous congestion. Uremia directly impacts the cytochrome P450 and impacts drug metabolism. Later, you will hear from Gretchen. She is going to talk about this. Metabolic acidosis has a multitude of impacts. First, it does affect cytochrome P450, and that's why you have to probably re-dose certain medications when patients have AKI impacting liver. In addition, metabolic acidosis diverts ammonium from liver. It depresses the production of urea, and the ammonium gets attached to glutamine and get excreted by the kidneys. In return, it causes deficiency of glutamine in the body, which is an essential amino acid needed for multiple protein synthesis. In addition, with glutamine and ammonia dysfunction, you will see decreased albumin synthesis, which is a hallmark of liver disease. Kidney causes extracellular shift of potassium, how body compensates. Liver and skeletal muscles take up 50% of that potassium, and that's how body compensates to hyperkalemia. Once kidney affects the liver, liver stops uptaking potassium, causes severe disturbances related to hyperkalemia. The things you see in ICU, T wave inversions or cardiac arrest seconded to hyperkalemia can happen when there is a concomitant kidney and liver dysfunction. Metabolic acidosis also alters growth hormone and insulin resistance, causing hyperglycemia. Impaired glucose levels are itself independent markers of increased mortality in patients with kidney and liver disease. So this is what we all know, but what we want to focus also on is systemic inflammatory response, which happens in association with AKI. You see increased markers of IL-6 and TNF-alpha in relation to AKI. Both of these also impact cytochrome P450. They also cause activation of KUFOR cells in the liver, which produces IL-6 and TNF-alpha within the liver. Both of these activates fibrosis and angiogenesis in the liver. It also increases myeloperoxidase activity. Another important cytokine is IL-17, which causes infiltration of neutrophils and macrophages, not only in the liver but also in the intestinal wall, initiates bacterial translocation. So all the things you see in cirrhosis, kidney can mimic that in liver. So you see increased oxidative stress, apoptosis, bacterial translocation, all induced by systemic inflammation caused by acute kidney injury. Let's go to the easy part, which we probably all know, liver-kidney interactions in terms of how liver impacts the kidney. A known concept is a planktonic vasodilatation. There's an overproduction of nitric oxide, carbon monoxide, and endocannabinoids, which cause planktonic vasodilatation, which is a compensatory response to increased hepatic vascular resistance. It tries to increase the portal blood flow, but in return also decreases effective blood volume because there is a venous pooling of blood in planktonic circulation. Decreased effective blood volume causes renin-angiotensin-aldosterone system activation, which in return causes vasoconstriction and hyperperfusion, which we talk about all the time in hepatorenal syndrome. In addition, as we said, do not forget systemic inflammatory response in these organ dysfunctions. When there is bacterial translocation in patients with cirrhosis or there is sepsis, there is pathogen-associated molecular patterns and damage-associated molecular patterns, which causes cytokine strong. You see release of TNF-alpha, IL-6, and IL-1-beta. Again, they cause inflammation, oxidative stress, and nitric oxide synthesis, causing further vasodilatation in the planktonic circulation and precipitate stress activation and further kidney injury. In addition to these inflammatory biomarkers, there is a microvascular injury. You see sepsis. You see ARDS. We all talk about microvascular injury. In all the, as a pathophysiology of all these diseases. So here also, there is a microvascular dysfunction. So all these three things together, PAMP, STAMPS, microvascular dysfunction, inflammation, further causes proximal tubular cell mitochondrial dysfunction, and hence exacerbates kidney injury. So multiple things happening at the same time, initiated by liver injury, will cause AKI. So when we talk about hepatorenal syndrome, we talk about just this part, vasoconstriction hyperperfusion. But there are a multitude of other factors which are causing kidney injury at the same time. So this is just summarizing both kidney and liver injury. That there are two major factors, altered response to activation of vasoconstrictor systems and inflammatory response, which causes further organ failure in patients with cirrhosis. Let's come to HRS, which is the major talk. But I gave you this history to understand HRS a little better. So this is the current definition, which is a revised definition. For the purpose of this talk, we are going to focus on previously called HRS-1, now called HRS-AKI. So this is the book definition of HRS-AKI, how do we define HRS. We will focus on this definition and we'll talk about or discuss, either during panel or during my talk, I'll just try to give you hints saying, is this the true definition or does it need further revisions? The AKI definition is again, as we said multiple times in the previous slides, is increase in serum creatinine more than 0.3 within 48 hours or more than 50% from the baseline. It also says should be absence of shock, no nephrotoxic drugs, absence of intrinsic kidney injury, then you make a diagnosis of HRS. Epidemiology, it's hard to interpret because of multitude of studies talking about epidemiology, some of them are using HRS-1 as a definition, newer studies are using HRS-AKI definition. But in general, this is what literature shows, that 17% of AKI cases in hospital are secondary to, are secondary to HRS in patients with cirrhosis. One year and five year probability of developing HRS in patients with cirrhosis is 20% to 40%. With the revised diagnostic criteria, prevalence has changed from 17% to 13% to 45%. Why there's such a big range? Because there are very heterogeneous studies, we are still learning the new definition. Further studies are needed to look at the prevalence. 90-day mortality is almost 50%. It's highest in patients who have more marked sodium water retention and marked activation of vasoconstrictor system. Again, that means patient is in advanced stages of AKI and that's why they are not recovering. Some factors which have been done by multivariate analysis have shown the low sodium, high renin and no hepatomegaly. I don't know why no hepatomegaly but these are the three factors identified as independent factors related to mortality in patients with HRS. Looking at national, nationwide inpatient sample from 2002 to 2012, the light gray line is the incidence of HRS per 100,000 patient and the dark black line is chronic liver disease. Over time in last, from 2002 to 2012, there's increased incidence of HRS. Maybe there's a better definition and we are getting more used to defining HRS over years. Incidence is going up. At the same time, if you compare the chronic liver disease associated mortality or length of stay or hospital cost versus HRS, HRS when it is associated with chronic liver disease has higher mortality, higher length of stay in the hospital and higher cost. No surprise. Another study looking at nationwide inpatient study on HRS population, close to 5,000 patients in the study, looking at various things in hepatorenal syndrome. The first one here is looking at overall inpatient mortality in patients with HRS. From 2005 to 2014, mortality is decreasing. Take that with a grain of salt but probably because we are getting used to understanding diagnosis and managing HRS. Or we are identifying those patients early on for liver transplant because the liver transplant at the same time in HRS is going up. Patients on dialysis with HRS are going up. There were times when we used to say if the patient is not a transplant candidate, RRT is futile in patients with HRS. We are moving away from that trend so RRT rate in HRS is going up. Mean length of stay, almost the same or slightly up, but there's increased cost associated over years with HRS. Let's talk about precipitating factors. We all know them. We are just going to define them in a little bit better way. Infections, large volume parasynthesis, GI bleed or diuresis, volume depletion in any form, whether it's because of diuresis or GI bleed, large volume para, or infections causing severe vasodilatation. Spontaneous bacterial peritonitis, HRS develops in about 15% of cases with SPP. Why? As we said earlier in the slides what SPP does, release of pro-inflammatory cytokines interleukin 6 and TNF. These endotoxins leads to increased production of nitric oxide and other vasodilators causing splanchnic vasodilatation, renin angiotensin stimulation, and vasoconstrictions to the afferent, vessels to the kidney. Sepsis induced cardiomyopathy which is a new field which we forget while we are clinically managing these patients because this remains silent unless a stress response happens to the patient. So underlying sepsis induced cardiomyopathy leads to decreased cardiac output, further causing precipitation of HRS. So what happens to the kidneys after SPP resolves? So there are various factors or variables predict how the HRS will behave after SPP resolves. The factors associated with progression of AKI after SPP are if you have high BUN before you develop SPP, high chances you are not going to recover. If your serum creatinine before SPP is high or serum sodium is low before the development of bacterial peritonitis, less chances of recovery. In other words, if you are sicker before the initiation of SPP, more likely HRS is not going to recover. Large volume PARA without albumin replacement, again volume depletion. HRS develops in 10% of cases after large volume PARA without albumin replacement. It induces circulatory dysfunction in the form of called paracentesis induced circulatory dysfunction. 75% of the patients develop to some extent circulatory dysfunction after large volume PARA if you do not replace albumin. This is because there is accentuation of arterial vasodilatation. It is initiated by sheer stress because when you do large volume PARA, theoretically your cardiac index improves. Your diaphragm goes down, you have increased thoracic space, your cardiac output increases. The sheer stress of cardiac output causes accentuation of arterial vasodilatation by release of nitric oxide. Decrease in SVR due to decreased intrathoracic pressure and increase in cardiac index. There is a compensatory rise in, again, renin and norepinephrine levels. Increase in hepatic pressure gradient further causing renal vasoconstriction. So if you do not replace volume, paracentesis rather than help can precipitate HRS. Again, the precipitating factors. The group one here, there are comparison between group one and group two. Group one where you have replaced albumin, group two where you haven't replaced albumin. When you replace albumin, you see rise in albumin level. You see improvement in GFR. In group two where you do not replace volume, you do not see change in renin activity. Their renin remains elevated. At the same time, the group two where you do not replace with volume, their BUN, serum sodium, serum potassium, and mean arterial pressure remain deranged. For example, their BUN goes up after you do PARA without albumin replacement. Serum sodium goes down, potassium goes up, and mean arterial pressure goes down in this particular study. Again, showing that the circulatory dysfunction is real if you do not replace albumin. Third thing we talked about is GI bleed. Again, it's purely because of pre-renal effect, because of volume depletion. It occurs in 11% of the patients after bleeding episode. And sometimes in 60% of the cases, once patient develop HRS after GI bleed, they do not recover. The predictors of renal failure after GI bleed is the intensity of bleeding. More the bleeding, less, more chances of developing HRS. Severity of cirrhosis to begin with, like by child B classification. If you are child B, child C, you have high chances of developing HRS and not recover from it. High platelet count, again, no reason for association, but it is associated with HRS during bleed. Can we predict HRS? Absence of hepatomegaly. I said it before also somewhere. We do not know the reason, but this is one of the factor which predicts. If patient has liver cirrhosis, but there is absence of hepatomegaly, there are high chances of developing HRS. Maybe the hepatic vascular resistances are super high, splancting vasodilatation is extra high when you do not have hepatomegaly. Poor nutritional status, presence of esophageal viruses, plus, so these are three independent predictive factors for HRS, plus the things we already know, degree of hemodynamic and renal impairment to begin with, sodium retention, low free water clearance, MAP and plasma run in activity beforehand. These will predict HRS. Interestingly, there is no association with degree of liver dysfunction in terms of liver function test or child peer score. So the major predictive factors are pure nutritional status, presence of esophageal viruses, and hemodynamic disturbances. Let's move on to diagnosis. What do we know about diagnosing HRS, a million-dollar question. Please help me if you know the right way to diagnose. The things in literature are things what we use for AKI diagnosis are the same as we use for HRS with some changes, some differences. Serum creatinine is still used, but we all know it is affected by sarcopenia and also by clearance and liver disease. So in multiple ways, how we calculate creatinine, I think Gretchen is going to go through those in her presentation. So you will know what is the best way, how should we measure creatinine in patients with cirrhosis. Cystatin C is more in market because it has no association with gender, ethnicity, and muscle mass or body mass index. So it's going more into literature and more we are studying about cystatin C as a biomarker of renal function. BUN is still being used. In addition, you will see multiple urine markers in multiple studies being studied for identifying AKI. They all have different ability of discriminating between AKI, HRS, and AKI-ATN. This is where I struggle all the time in ICU. I can differentiate between the two. Cystatin C, again, these are urinary markers, not the sedum markers. At least I can tell you in our ICU, our nephrologists are very keen on getting ANGAL, but it can be elevated in multiple other conditions. So when you look at the literature, it seems so crystal clear. This is HRS. This is pre-renal. This is ATN. But this is the reality, what we feel and see in ICU all the time. I feel like every cirrhotic patient has underlying hepatorenal physiology, and you have to just diagnose whether you can fix pre-renal or ATN. Taking away my field, I will talk about literature, what the evidence says, how to manage HRS. These are the major things we are going to talk about. Medical management, what is the literature behind TIPS, extracorporeal support, and how do we identify patients for transplant. Just general measures to manage AKI and cirrhosis. Discontinue nephrotoxic drugs. That's by every nephrology note. Taper or discontinue diuretics. I have my thoughts about it. We can discuss in the panel and see what you think and what do you do in your practice. Taper or discontinue beta blockers. Infectious workup diagnostic para because you want to rule out other causes before you call it HRS physiology. Volume resuscitation as per indications, whether it's because of SPP or you're doing large volume para. And bedside echocardiographic assessment of volume status. It is hard to cover what is out in literature, everything, but I'll touch on major points on medical management. In general, it's vasoconstrictors plus albumin. It could be midodrine nocturitide, terliprasin, or norepinephrine. Back in 1919, when there was only midodrine nocturitide, they studied midodrine nocturitide versus dopamine. I'm going to not go into details of the study, just the highlights of these studies. All these studies are looking at HRS reversal or survival or other parameters, what we talked about, what happens to renin-angiotensin activity, what happens to creatinine, what happens to GFR or sodium excretion. So those are the main points when we are going to discuss all these studies. They are looking at it in different ways in multiple studies. So midodrine nocturitide, after 20 days of treatment with these medications, they did see improvement in renal plasma flow, GFR, and improvement in creatinine. So these are multiple patients. All these studies have actually very, very low number of patients. So it's very hard to understand and how we can apply these studies to our population. All these studies have 16 patients, 18 patients, 20 patients. So the plasma creatinine, sorry, sedum creatinine level starts going down by day 10, and it goes further down by day 20. Midodrine nocturitide versus norepinephrine and albumin. So they are looking at what happens when you give midodrine nocturitide or norepinephrine. So this arm on this side is patients getting norepinephrine, this side is midodrine nocturitide. The sedum creatinine value goes down, but not super significant. Urine output and mean arterial pressure goes up in a group with norepinephrine in women much better as compared to a group with midodrine nocturitide. There was no difference in survival in this patient population. When you look at this graph, there is a signal that midodrine, the norepinephrine group has a better survival, but this is not clinically significant. Partly, when you see these crosses, there are a few patients who died. There was one patient with PE in the midodrine nocturitide group who died because of PE. Norepinephrine, three patients died because of septic shock, and three patients died post 30-day. The survival is seen as only 30-day. So again, no change in survival, but biochemical parameters are better in a group with norepinephrine. Our landmark trial, which brought Turley-Presson into market here, is the confirmed study investigators. Here when they gave Turley-Presson in women, they looked at multiple parameters. The first is clinical success, clinical failure, competing events, liver transplantation, or death. They looked at Turley-Presson versus placebo. Placebo is where they gave only in women. Turley-Presson group is where they gave Turley-Presson and in women. When it says reversal, clinical success is called clinical reversal. Reversal is defined in this group as two consecutive serum creatinine values of less than 1.5, at least measured two hours apart, up to 14 days, and survival without RRT for more than 14 days. This is called all these studies when we are going to look forward from this slide onwards. This is the definition of reversal of HRS. Clinical failure, if this patient goes on RRT, underwent TIPS, receives vasopressors because of some other reason, or serum creatinine doesn't improve by day four, all of these are qualified as clinical failures. What they did see is that there's a significant difference in these clinical reversals in the group with Turley-Presson as compared to albumin. They also looked at some secondary outcomes. This one was hard for me to understand, but it says secondary endpoints included in multiplicity adjustments. So there was one patient in the study group where they calculated more than one creatinine. Once they adjusted that value, they still see a clinically significant difference in the group with Turley-Presson. HRR reversal with no renal replacement therapy through 30 days, again, significant in Turley-Presson group. HRR reversal in patients with SIRS response also is better with Turley-Presson. Verified reversal of HRS with no recurrence through 30 days. This is also important. Once they recover, do they rebound back to HRS? Less rebound was seen in patients with Turley-Presson. Predictors of response to Turley-Presson, again, how I interpret this, if the patients are less sicker, they will respond better. Low baseline creatinine, low bilirubin level, increase in blood pressure post Turley-Presson infusion, presence of SIRS, and low urinary engel. So if patients are less sick, they have tendency to get better. What I did not understand is presence of SIRS. Why presence of SIRS is a predictor of response to Turley-Presson. Florence Wong did a study on looking at SIRS. Again, I'm using this term very loosely. We are not allowed to use this term anymore in septic shock. But when the study was done, they looked at SIRS, predictors of response to SIRS. When patient had more than two criteria of SIRS with SIRS, they had better reversal with the Turley-Presson group. Confirmed SIRS, here the definition HRS reversal versus confirmed HRS reversal is when you see creatinine less than 1.5 after starting Turley-Presson, it's called HRS reversal. Once you see two values 48 hours apart being less than 1.5, it's called confirmed HRS reversal. So both these population had more than two SIRS. If they had SIRS response, they had better response to Turley-Presson. Also they had better response to change in creatinine. Underlying physiology is not clear, but more likely the SIRS initiates vasodilatory response overall in the body, and probably helps Turley-Presson a little bit to cause vasodilatation in the renal vessels. Again, then they kept on studying Turley-Presson. Every single year there are multiple studies coming for Turley-Presson now. Turley-Presson plus albumin versus albumin. Again, incidence of reversal with Turley-Presson is much better. So these are two different phase three trials. The reverse is done in here and Canada, U.S. and Canada. OTO-401 was done in Germany. Again, very little population, so that's why they combined these studies. They saw independently in both studies that Turley-Presson had a better response. When they combined the population in Germany, Canada, and U.S., they still saw that Turley-Presson group had a better response. In terms of reversal of HRS. Similarly, the mean change in creatinine from baseline to the end of treatment was much better in Turley-Presson group as compared to albumin. Again, making a case for using Turley-Presson. Now we are looking at other outcomes in the study, Turley-Presson plus, again, Turley-Presson albumin versus albumin. Overall, when you look at survival distribution function, how the survival happens, there is no difference. Transplant-free survival in both group is the same. Overall survival, no change. So all these studies, when we are talking, there is not a single study which has shown improvement in survival, including this one. But once you see this population as a subgroup, the patients who showed the reversal of HRS in both population, whether Turley-Presson or albumin, the top one, the top two graphs are where they showed reversal. If, by any means, they had a HRS reversal, they had a better mortality. I mean, they had a better survival. So survival depends on reversal of HRS, not Turley-Presson versus albumin. Also, compared, Turley-Presson versus midodrine and octeotide. Norepinephrine did better than midodrine and octeotide. Of course, Turley-Presson is doing better than midodrine and octeotide. Complete or partial reversal is better with Turley-Presson group. But there is no change in mortality. People who do respond, they have better survival. But the people between two groups have no change in survival. But the responders have better survival. I think I went too far into these studies, but I'll try to conclude. So Turley-Presson versus norepinephrine, right? This is what we want to see, probably. Because before Turley-Presson, we were using norepinephrine as the drug of choice. I promise only three more slides on Turley-Presson. So Turley-Presson versus norepinephrine. Both of them have a good response. Sorry. Can you go back? This is a head-to-head comparison. But what it's showing is that both of these have good response. Both of them improve creatinine. Both of them changes urine sodium. Both of them increase urine output. Both are equally good by other means. At the same time, there is no change in survival. Cumulative survival between two groups is no different. Then started, after all these studies, multiple meta-analysis. And they have different results. It depends on what time and what studies are involved in those meta-analyses. Partly it could be there's a very heterogeneous population in this meta-analysis. And the HRS definition is different in different studies. That's why we are not having a solid answer about whether Turley-Presson is better than norepinephrine. For example, this study done in 2012, comparing multiple studies and doing a meta-analysis, is in favor of Turley-Presson in 2012. On the top, they are comparing Turley-Presson with Albumin. And below, they are comparing Turley-Presson with norepinephrine. Turley-Presson is clearly better than Albumin. This is equivocal, equal response of Turley-Presson to norepinephrine, done in 2018. 2012 versus 2018. Again in 2018, another meta-analysis came comparing Turley-Presson and norepinephrine. No difference. Both are equally good. So, in panel discussion, we will discuss whether you want to use Turley-Presson. Of course, the word is going towards Turley-Presson. But more likely, what we want to know is, what is the prognosis of patients with HRS? This, again, study was done in 2015, where HRS1, type 1, type 2 were the definitions. Showing that if patients have cirrhosis with ascites without HRS, they have a better survival, better prognosis. In some patients, the HRS1 has the worst prognosis. If we have to quantify prognosis in HRS, I would say, look at the trends. Change in meld skull over time, change in serum creatinine, change in bilirubin, and change in serum albumin, rather than the absolute numbers. How quickly they are worsening, that will tell us the prognosis. Increasing serum creatinine, increasing bilirubin, urine sodium more than 5, independent predictor factors for prognosis of patients with HRS. Are we still in time? Two minutes? So let's talk quickly about the other therapies which have been studied in HRS. TIPS. The indication or the hypothesis behind why TIPS will work is by portal decompression, refilling of central venous system, less activation of renin-angiotensin activity because you are doing portal decompression. But it can cause transient ischemia in ACLF patients. So this is sort of a caution while doing TIPS. Studies have shown that TIPS have some change in survival. But at the same time, when you look at those studies, they were very picky about the population. Because the population, like when we call an ICU, our hepatologist to do a TIPS or IR to do a TIPS, the first thing they ask is, what is the MELD score? They do not pick sicker population for TIPS. High mortality. They also look at heart function on those patients. So these studies were very selective in picking those patients. That's why they did show that they might have a better survival. Not change in mortality, but maybe better survival after TIPS. See, they excluded any patient child's PEW score more than 12, a little bit more than 15, or severe encephalopathy for reasons we know. It can, so that's why the conclusion is it can improve survival, but in selected patients. It can improve renal function. It can resolve ascites. It can result in reduction in sodium. Acetambranin, aldosterone, and norepinephrine levels can be used as a bridge to transplant. Again, those patients will be too far from transplant in these studies. Let's skip this. RRT, bridge to recovery, or liver transplant. It does not improve mortality. A meta-analysis I think, Javier, you pointed out that indicates similar outcome in patients receiving pre-transplant CRRT and transplant recipients without renal failure. So, if you do CRRT pre-transplant versus a patient who do not have kidney injury before transplant, they do equally good. MARS therapy, again, it can change creatinine significantly, but it has no change in mortality. Liver transplant and SLK, that's a hot topic. We see that in ICU. We call nephrologists, hepatologists, and critical care physicians together to make this call. It's considered curative. Effective pharmacotherapy with vasodilators and vasoconstrictors and albumin can lower the mild score and increase the wait list time. SLK is on the rise since a unified network for organ sharing in 2002 defined SLK. HRS AKI patient survival post-SLK is significantly superior to those who have non-HRS AKI. So, type 1 versus type 2. Type 1 do better after RRT. So, indications, these are per guidelines. You can read from the bar code, but this is how we define these patients. Mainly sustained AKI patients, six consecutive weeks on RRT, or GFR less than 25 for six consecutive weeks, a combination of A and B for six consecutive weeks. So, if the patient has HRS and meet these criteria, you should be calling in if those patients are SLK candidates, simultaneous liver kidney. Pre-transplant predictors of recovery of renal function. Again, how long the patient was on RRT before transplant. That predicts whether these patients will recover longer the time the patient was on RRT before transplant, less chances of recovery after transplant. So, again, this is showing survival. No change in survival depending on how long you were on the RRT before, but if the patients recover spontaneously after transplant, they have a better survival. Prevention. I think last two slides. Prevention, we all know. I just put it in just as a completion of HRS. Treat SPP, right? Albumin infusion with antibiotic therapy with initial dose of 1.5 gram per kg at the time of diagnosis of infection. And repeat after 48 hours with the dose. SPP primary perflexis is needed for other patients also. For example, we know GI hemorrhage, but this is also needed for patients who have acetic protein less than 1.5. Significant renal dysfunction and the child peer score more than 15 points or a little bit greater than 3. So, these are the indications for the patients who require SPP perflexis to begin with. Large volume PARA, give albumin after. Lastly, there are emerging therapies as vasodilators. One of them is serolaxin. It's a recombinant human relaxant too. Increases renal blood flow, again, not studied in humans, but on mice. It increases renal blood flow by reducing renal vascular resistance and reverses endothelial dysfunction. A randomized phase two trial has been done where it showed significant reversal of kidney injury. Again, more to come. So, in summary, what we say is kidney organ crosstalk contributes to AKI-related mortality. Inflammation has been recognized as a major factor in development of HRS in addition to splanchnic and circulatory changes. Critical illness complicated by hepatorenal dysfunction portends a poor prognosis. Preventative measures, early identification, vasoconstrictors, and albumin can improve outcomes, not the mortality. Thank you.

organ crosstalk

kidney-liver interactions

hepatorenal syndrome

acute kidney injury

cirrhosis

HRS physiology

medical management strategies

liver transplant