Great talk, Mahala. So we're going to switch gears now. From ECMO, we're going to go to kidneys and the interaction with the liver. So AKI in liver disease has always been a matter of debate, and we discuss a lot what is what in acute kidney injury and liver disease. So I thought we're going to talk about the short and long-term outcomes in children who have got AKI. Nothing to disclose. So in the next 20 minutes, we're going to talk about AKI in different kinds of liver failure. It's acute, it's acute and chronic, it's cirrhotics, and very importantly, post-transplant group. We're going to define AKI, AKD, and CKD in this cohort of patients, and we talk about outcomes. We're going to talk about short-term outcomes, which might include your mortality, which is within ICU at three months, six months, and a year, and we're going to talk about the long-term effects, which is development of chronic kidney disease, end-stage kidney disease, or mortality thereafter, and of course, dialysis dependence, and in the last part of my talk, we'll talk about outcomes in a special group of AKI in liver disease, which is hepatorenal syndrome. But we have to remember that most data, I know most of us who are sitting in this room are pediatricians, but most data has been unfortunately extrapolated from adults, and children do not unfortunately have this data. This is just to show you different kinds of liver, which we see in pediatric liver intensive care, an architecturally normal liver. You have a completely destroyed architecture here of a cirrhotic liver, and you've got a regenerating liver, as Mihaila mentioned in her talk, liver can regenerate. So these three livers have got a very different pathophysiology, the clinical trajectory, and the long-term and short-term outcome when AKI develops in these patients. So AKI in liver disease does not mean AKI in liver disease as a whole. AKI in acute liver failure, different from AKI in ACLF, is different from AKI post-transplantation. This is the largest study which was published in the New England Journal of Medicine. This is the AKI called the AWARE study. We had about 7,000 patients, and what we found was that the incidence of any stage AKI was about 26%. When we had a look at the severe AKI, we found it was 11%, which means 1 in 10 children admitted to PICUs had severe AKI defined as stage 2, stage 3. But if you look at the outcomes here, as the stage of AKI becomes more, your survival decreases. So higher the stage of AKI, lower was the survival. Then we thought, let's have a deep dive into those patients within the AWARE subset which have got a liver disease. So that's what we did. We looked at these patients with the light blue bars. This is our liver disease. The dark blue bars are the rest of the AWARE cohort, and you would see here whether it is stage 1 AKI or stage 2 or stage 3 AKI, you see the difference. What is the incidence? 59%, i.e. 3 out of 5 children with liver disease will have AKI, as compared to about 26.4% in the AWARE cohort. Look at the mortality, 5.5% in liver disease patients, 3.4% in the rest of the AWARE cohort. So starting off with AKI in acute liver failure, we at King's have just done this study looking at the prevalence, risk factors, and outcomes of severe AKI in patients with acute. I'm underlining the word acute because this does not include cirrhotics, it doesn't include patients with ACLF, and our aim was to look at different things, including outcome. But very importantly, in addition to looking at the mortality, in addition to looking at length of stay, we wanted to look at how many children with acute liver failure with the same severity of illness and the same supportive measures survive without transplantation when they have an AKI versus when they do not have an AKI. Basically what we want to know is what is the effect of AKI on the spontaneous regeneration of the liver. And this is what we found, 125 patients with acute liver failure. We excluded 31 because they were started on CRRT exclusively for liver causes, and you can see any stage AKI, 56.4%. Severe AKI, 39.4%, so 2 out of 5 children with acute liver failure end up having severe AKI. But what's very important is look at day 7 here. You have reached day 7 and you have still got a considerable number of children who have got AKI. Now whether this AKI then becomes AKD or becomes CKD, we do not know. If you look at the various outcomes, you see here the number of children with no AKI, 17% require transplant, whereas with AKI, 35% require transplant. And very interestingly, if you look at the children who survived with their own livers, 71% with no AKI did not survive and others did. So basically what we concluded was that children who have got severe AKI tend to have less regeneration of the liver and therefore tend to have more transplantation. Again if you look at the mortality here, severe AKI versus non-severe AKI, you see there is a difference between mortality after controlling for confounders. So our conclusion was the significant number of children with acute liver failure develop AKI. AKI in ALF is associated with increased length of stay, prolonged duration, and worst outcomes, and AKI does seem to affect the spontaneous regeneration of the liver. Going to the second category of patient, the serotics. This is a diagram which shows your natural progression of patient with liver disease. You develop a liver disease, you go into compensated cirrhosis, you go into decompensated cirrhosis, you develop portal hypertension, you have all the complications. If you have compensated cirrhosis, the risk of AKI is almost the same as general population. But if you develop portal hypertension complications, your risk of AKI increases exponentially. This is just to give you a concept of ACLF, what acute and chronic liver failure is. You have a child or an adult who is sitting with a chronic liver disease, gets hit by a precipitating event, rapid progression, multi-organ failure. And within this multi-organ failure, you have AKI as a core component. And if you treat them well, there is a chance of potential reversibility. But here, higher the stage of AKI within ACLF, higher is the mortality, lower is the risk this patient actually will get a successful transplantation. Now how do you define AKI in cirrhosis? The International Club of Ophthalmologists took almost the same definition as the KD Gogai said, and said, we're going to look at serum creatinine rise within 48 hours, and we are going to look at, is it two times, is it three times, or you're requiring renal replacement therapy. But the difference is that stage one is also called stage 1A and stage 1B. If you satisfy the criteria of stage one, but your serum creatinine does not go up beyond 1.5 milligrams per deciliter, you have 1A. If it goes beyond 1.5 milligrams per deciliter, it is 1B. And if you look at the staging correlation, how does the staging correlate to mortality, you will see here, higher the stage and lower is your survival. 88% with no AKI, and 31% if you've got stage 3 AKI, so one third the survival if you have AKI. Now what is the prevalence? You can see here that this is a cohort from Italy, 53% of patients with cirrhosis developed AKI. And if you look at the mortality, it is about four times more in patients who developed AKI who had cirrhosis. What are the causes of AKI? We always, I know, when liver and kidney, we start talking about the first thing comes to mind, is it hepatorenal? Actually the most common cause is hyperperfusion, hypovolemia, which could be due to gastrointestinal losses because of renal losses. Then you talk about intra-abdominal hypertension because of massive ascites, and then you talk about hepatorenal syndrome. And you can see here in this cohort of patients, about half of the patients had hypovolemia as the cause of AKI, and about one third had hepatorenal syndrome. Now why is it important for us to say is it hypovolemia, is it acute tubular injury, or is it hepatorenal? Look at the survival here. If you've got a hypovolemia, your survival is 76%. If you have got hepatorenal, your survival drops down to 37%, and if you look at the odds ratio of dying here, it is about seven. You've got hepatorenal syndrome, the risk of death is about seven times more. And if you have a progression of AKI, you don't have AKI before, but then you progress during your stay in the ICU, you see that the mortality exponentially gets more. What are the pediatric specificities in these patients? The first thing is to remember that biliary atresia is the most common cause of chronic liver disease in children, therefore we cannot directly extrapolate data from adults. They've got varying, they've got alcoholic liver disease, and other bits. And the reported prevalence of pediatric HRS AKI is less than 10%, but I firmly believe that this is under-representation, because look at any guidelines, unfortunately pediatric definition for HRS is not there. This is a study which we did in collaboration with Paris and the Netherlands, where we looked at 130 pediatric cirrhotic patients and looked at the correlation between different stages of AKI and the fact that they were having cirrhosis. You can see here, as your stage of AKI becomes more, even children have got a lower survival rate as compared to patients who did not have AKI. Now we talked about pre-renal component, and we said hypovolemia, you give fluids, patients will benefit. Now we have hepatorenal syndrome, it again is a functional component, but you give fluid, things will not get better. And then of course you've got acute tubular injury. It looks like the diagram, they're all three distinct entities, but in reality, there is an overlap. There is an overlap between the functional component and the structural component, and if you look at HRS patients, you have casts in the urine as well, which actually shows you it has got a structural component. Now is there a correlation between baseline GFR in deciding the prognosis of patients on the wait list? This was a study by Lim et al, and you can see here, as your GFR is going below 60, this is 60, you can see here, this is 40, this is 20, the risk of mortality is 2.5 times more when you have a GFR less than 20. So lower the GFR, higher is your mortality in these patients. But once the GFR crosses 60, you can see almost the mortality remains the same. We know MELD predicts the mortality, and in this particular study, they looked at various models. They looked at MELD, they looked at MELD, and plus they added your GFR in the third model, they took out creatinine, and in the fourth model, they added in sodium. You can see here, when you have got GFR added, things get better, but when you remove the creatinine, things remain the same. So a fully measured GFR, if you can, is better in predicting survival as compared to serum creatinine. Now what are the outcomes? The outcomes in AKI is known, but outcomes of AKI in patients who've got liver disease probably is not known. Look at the three different, four different categories. You've got all-cause mortality, early, late. You've got cardiovascular. You've got hospitalizations, which can take place either because of AKI or other causes, and very importantly, chronic kidney disease and end-stage kidney disease. So this cartoon shows you how the AKI progresses and what different terminologies we use. The red is a normal kidney, the orange is acute kidney disease, and your green one is a chronic kidney disease. You get hit by a precipitating event, you get AKI. This AKI could be stage one, two, three. If your AKI goes away in 48 hours, as you can see here, it's called transient AKI. If it persists from day two to day seven, it's called persisted AKI, and if it progresses beyond that, now that's a nebulous area. If it persists up to 90 days, we have coined a term called AKD, acute kidney disease, but if it persists more than 90 days, we call it chronic kidney disease. So you've got AKI, which is transient and persistent. You've got AKD, you've got CKD. What are the definitions? These are definitions. They're all dependent on the duration of renal dysfunction, less than 48 hours, 48 hours to seven days, seven days to 90 days, and beyond. That's how you define AKI, AKD, and CKD. Now people might say transient AKI, what is the effect of it? If you look at patients with transient AKI versus without AKI, there's a difference of 20% in survival. So any AKI which takes place does matter. Now AKD, this is a paper published by Patidar, and they looked at the incidence of AKD, and they also looked at 180 days, what happens to these patients with AKD, and you can see here that out of the patients, 6,000 patients they looked at, there were patients, one third of them who developed AKD. And the incidence of mortality, both at 90 days and 180 days, was tremendously high as compared to patients who did not have AKD. And if you look at the de novo CKD, how many patients with AKD go on to develop CKD, the hazard ratio was much higher in those patients who did not progress to AKD and just had persistent AKI. Now what about the probability of survival? This is a study from Italy, again, looking at AKD patients, so patients who had AKI beyond seven days, they looked at five year survival, you can see here, 88.8% in patients who did not have AKD, the survival, and the five year survival of those who had AKD was 34%. So almost a decrement in survival by about threefold if you have AKD. Does the pattern and trajectory of kidney injury matter? Does it matter you have AKI? Does it matter you have AKD? And you can see here very clearly that if you have mild AKI with full improvement, your hazard ratio of dying is only 1.1, but if you have severe AKI with minimal improvement, the risk of dying is threefold. If you have got AKI on CKD, this is the cohort which will have the worst prognosis as compared to patients who have either AKI or got either CKD. So definitely the pattern and trajectory of AKI matters in prognosticating patients with cirrhosis. When kidneys recover, they recover with adaptive repair, but they do not recover, they have maladaptive repair, and these are some of the risk factors. And we know there's inflammation in cirrhosis, we know it's age which matters, and the kidney condition, HRS, matters, because HRS, the risk of maladaptation increases, and there are many risk factors which progress from AKI to end-stage kidney disease. And very importantly, if you develop AKI within the hospital setting, and the severity of AKI, these are two determining factors whether this kidney disease is going to progress. Now this is a study from the Spanish group looking at the cirrhotic patients, 140 patients looked at AKI patients, and of the AKI patients who survived, about one-fourth of them developed cirrhosis. So if you look at this particular cartoon, you see patients who develop CKD here, they already have, these are the black dots here, they already have a low EGFR as compared to patients who did not develop CKD. And if you look at their presentation, the next 12 months, that EGFR never recovers in patients with CKD, whereas in patients who do not develop CKD, the EGFR nicely recovers. So they concluded that one-fourth of patients who present with AKI will develop CKD, and you will never get a recovery to baseline of the EGFR in those patients. What about pediatrics? Do we know ACLF in pediatrics? This is a study from All India Institute of Medical Sciences in Delhi, where they looked at about 600 patients who had chronic liver disease. They took only ACLF patients, which were about 84, and about, I would say, 22.6% of the patients developed AKI in this cohort of patients. They clubbed together death and liver transplantation within three months of developing AKI as a poor prognostic factor. One-third of these patients had hepatorenal syndrome, one-third had sepsis, and the remaining had nephrotoxic drugs. And you can see here that the hazard ratio for death or liver transplantation in children who have ACLF with AKI is about 7.7%. So if you're a child, you have AKI, you have ACLF, the risk of dying is about 7.7%. And this is King's College Hospital data for ACLF, exclusively secondary to biliary atresia. And you will find here that the survival of ACLF is much lower than the patients who actually got a transplantation just with chronic decompensation, not with ACLF, but independently, hepatorenal syndrome, and the fact that they received CRRT was a poor prognostic factor. The last group of patients, the post-transplantation group, we know a lot of things take place pre-transplantation. Pre-transplant AKI leads to post-transplantation AKI, but a lot of things happen intraoperatively. A lot of changes take place. And you can see here within the first six months, the GFR decreases by 30% to 50% of an average. And by six months, kind of stability goes. And post-transplantation, you expose these patients to nephrotoxic antibiotics, nephrotoxic calcineurin inhibitors, and all these things lead to post-transplantation AKI. Now, what are the risk factors? You can see here that if you compare this in these 1,400 patients where they looked at mortality, higher the stage of AKI, lower was the survival in these patients. And if you received renal replacement therapy before liver transplantation or develop AKI post-transplantation, that was a very high risk factor for mortality. So AKI post-transplantation can have long-lasting consequences. What is the incidence of CKD? About 60%. You can see here is a cumulative incidence of death, GFR less than 60, and the graft loss. And you can see as it's about six years, your risk of CKD is about 60%. So after five years of transplantation, if you've got an AKI, your risk of developing CKD is about 60%. So monitor these patients for kidney health and for liver health. Does the severity of GFR matter? And you can see here, as your GFR is getting lower and lower, your chance of survival is getting lower as well. Your GFR more than 60, your survival is 91%. Your GFR less than 30, it's about 30%. So meta-analysis shows seven-fold increase in mortality in the wait list if there's renal dysfunction. Similarly, creatinine clearance, very important. Lower your creatinine clearance, higher is the mortality, both within 30 days and at two years. So creatinine clearance, eGFR matters. So lower the eGFR or the creatinine clearance, lower will be the survival, both short and long-term. What about hepatorenal syndrome? We know that it causes mortality. It does have an effect on mortality, that's short-term. What about the long-term impact of patients who responded to terliprasin versus who did not respond to terliprasin? You can see here that the risk of developing chronic kidney disease in patients who respond to terliprasin, the survival is much better as compared to patients who did not respond to terliprasin. So response to terliprasin, a key factor in determining the short-term outcomes as well as the long-term development of CKD. So response to terliprasin, very important. Now, do we have a tool to measure properly the GFR in patients with liver disease? Because there are lots of confounding factors here. So in this particular patient, they looked at GFR measurement and something known as GRAIL, which is glomeral filtration rate in patients with liver disease. And you can see here, sorry, I'm going to go back. You can see here, when you compare the red one is the GRAIL, the comparison of GRAIL measured versus estimated, the difference is much lower. So probably GRAIL is the way forward, and I'm going to quickly skip that. So this is my last slide. In summary, we say kidney dysfunction matters in liver disease. You need to understand which liver disease are you dealing with. There's a spectrum, AKI, AKD, CKD, and there is a pre-transplantation kidney dysfunction which leads to post-transplantation problems as well. And what you need to do is to have a holistic picture in mind, patient susceptibilities, kidney health, liver health, and make sure you have a holistic assessment of the patient when they come to you in your nephrology or hepatology follow-up post-transplantation.

acute kidney injury

liver disease

children

transplantation

portal hypertension

kidney dysfunction