Dr Fuhrman: Good afternoon, everyone. My name is Dana Fuhrman and I am a pediatric intensivist nephrologist at UPMC Children's Hospital of Pittsburgh. I have the very distinct privilege of moderating the session today on acute kidney injury and critical care early advances in detection. I'll be talking today along with [00:00:30] two very esteemed professors to start with Dr. Ravi Mehta. Dr. Mehta is a professor emeritus of medicine at the University of California in San Diego, where he is a true powerhouse in critical care nephrology research. Among so many accomplishments, he's a founding member of ADQI and chairs the annual international AKI and CRT conference that just had its 25th year this year. In addition, [00:01:00] fortunate to be working alongside Dr. Anitha Vijayan. Dr. Vijayan is a professor of medicine in the division of nephrology at Washington University in St. Louis, Missouri. Dr. Vijayan serves as the medical director of acute dialysis services at Barnes Jewish Hospital in St. Louis. She's also published extensively in renal replacement therapy and biomarkers, and HAI. And here are our disclosures. So we're going [00:01:30] to start out with a little bit of, we really want to get to know all of you here listening today and see where we stand with things. We know you answered some of these questions in the initial registration, but wanted to get a sense to start with, who is our audience? What is your clinical discipline and specialty? If you could input that information right now. ( [00:02:00] Silence). Very nice. So it looks like we have a wide spectrum, which we'd hope for of different specialties and disciplines. And our goal is to provide information that will support each of you and your different specialties. So another question, just to get to know the group and where you stand. My [00:02:30] institution has guidelines in place for the prevention diagnosis and treatment of AKI. You could just quickly mark on your response here. (Silence). So a wide of responses here as well and excited now to do this talk, because it looks like we have some [00:03:00] things to address. And then lastly, current diagnostic methods for AKI often need to misdiagnose is the way we currently stand. (Silence). [00:03:30] Looks like we have a spread there as well. So without further ado also interested if your institution is AKI diagnosed sometimes delayed. (Silence). Yes. All right. [00:04:00] So let's get into it really brief overview here. I'm sure a lot of you are familiar with this. But I think an important starting point for any talk like this, the KDIGO recommendations or the Kidney Disease Improving Global Outcomes recommendations were put forth in 2012 and really our way of stratifying, acute kidney injury and subsequent iterations of these recommendations still support these interventions [00:04:30] for AKI that we still use today. Importantly, how do we define high risk? How do we catch patients before they fall into the subsequent categories of AKI stages one, two, and three? And really what we're going to get into today is the role of these exciting novel biomarkers for AKI. We may traditionally think of them as really set forth for early injury detection, but exciting new advances in terms of risk prediction patients, even before an injury using these biomarkers [00:05:00] and importantly, looking at prediction of progression and recovery we're going to get into. And then really exciting guiding therapeutic interventions in the future. So I'm going to turn it over to Dr. Mehta who's going to talk about the burden of AKI. Why is it important to determine AKI risk? Dr Mehta: Thank you, Dana, and thank you to the SCCM for the opportunity to be in this symposium. When we think about acute kidney injury, one of the major [00:05:30] aspects to remember is that, it is global. It occurs in every setting, adults and pediatrics, and it is also dependent upon where in the world are you. In high income countries, we know that the instance about 23% and when you go into an intensive care unit population, it's as high as about 32%. But what's more important is the association with higher mortality risk, 23% [00:06:00] overall. And then if you require dialysis almost about 50%, and this is not limited just to adults. Cause when we look at it in the pediatric population, you have similarly a significant number of critically ill patients having acute kidney injury. And then amongst them, there is a significant number who get severe AKI and require dialysis. But what's more important for us to recognize is this epidemiological data over time [00:06:30] suggesting, and this is just the US incidents overall, you can see that in these the risk factor associated with comorbidities. Particularly diabetes certainly increases the risk and the incidence of acute kidney injury. And this is true for those patients who also require AKI and require dialysis subsequently. What we have learned is that kidney injury by itself is not [00:07:00] just an isolated event. It has multiple connotations on different organ dysfunction as goes long. And these systemic consequences can be met at every organ level and can be manifest over time concurrent with the development of acute kidney injury or subsequent to it. And what that translates into is more difficulty on long term consequences. We know for example, that there is a significant change in development of chronic kidney disease, [00:07:30] new onset or progression. If acute kidney injury reflects or is superimposed on underlying chronic kidney disease and the development [inaudible 00:07:39] disease. But new onset cardiovascular problems, having heart failure and or hypertension, and more importantly, rehospitalizations following one event of acute kidney injury are quite common. So all these events actually constitute a major burden because when you look at it from [00:08:00] the perspective of not only the index hospitalization of acute kidney injury, but the downstream effects, you have effects on long term disability, you have increased cost and obviously reduced survival. So it's a major issue that we need to tackle. Dr Fuhrman: Thank you so much, Ravi. And really that leads us to the question is how can early recognition address this clear burden that we've seen study after [00:08:30] study and what you just saw. First recognizing that it's a multidisciplinary problem, quite rarely is the first presentation of AKI going to be in the face of a nephrologist. There's a diverse array of healthcare professionals that may be the first to encounter a patient with AKI. Specifically, general practitioners, emergent medicine, physicians, surgeons, cardiologists, geriatricians, pediatricians, nurses. Absolutely, [00:09:00] I saw we have a great representation of nurses in this group. Pharmacists, as well. As I mentioned, many patients with AKI are actually even never seen by a nephrologist. So a lack of awareness of AKI among diverse healthcare professionals can lead to delays in recognition and management, whereas knowledge and recognition and a keen eye for these things can lead to early recognition. So we thought we'd provide a case study. The reason we all care so [00:09:30] much about this is it comes back to our patients. And this is a case of a 68 year old male who is a real patient that was seen in our hospital here in Pittsburgh. I, as a pediatrician, didn't obviously take care of him but one of my colleagues did. Presented with pneumonia and septic shock. He has a history of hypertension and diabetes lives at home, has no recent hospitalizations. A presentation about cultures were appropriately sent and he had a set of electrolytes. A [00:10:00] renal panel sent and his creatinine came back at 1.3 with a known baseline also at 1.3. He was started on antibiotics, very appropriately vancomycin andpiperacillin/tazobactam (pip/tazo). They were started in the emergency room in a timely manner and he was transferred to the ICU on a norepinephrine infusion and his urine output does improve with fluids. So question for all of you, again, if you could select your responses, is this patient at high risk for AKI? (Silence). [00:10:30] Great. So yes. And many of you feel confident, but some not completely confident. No, not completely confident. And certainly more information [00:11:00] is always useful. When we think about putting patients or identifying patients at risk for these, what exposures and susceptibilities put our patients at risk. A lot of these times, these things are right in front of us. Don't require blood testing or biomarker testing. Known exposures that are important to know, certainly sepsis, critical illness, shock, these different exposures that you see listed here. Nephrotoxic medication certainly clearly an issue. [00:11:30] And then susceptibilities, dehydration, advanced age. Sex is a biologic variable. Very interesting. The KDIGO guidelines does list this as a predisposing factor. More recent data has actually suggested quite the opposite, but maybe male sex. So there's probably more to come on this. Race, chronic kidney disease, and other comorbid conditions certainly should open our eyes to patients that are higher risk. But moving into the idea of these [00:12:00] biomarkers and certainly aware of these conventional biomarkers that we think of these, what we term functional biomarkers that get at your kidney function, serum, creatinine and urine output. And then of course, the [inaudible 00:12:14] filtration rate. These biomarkers can be unfortunately quite insensitive and quite inspecific in terms of identifying patients for AKI, which is why much work and much research interest has gone [00:12:30] into exploring these novel biomarkers. And Anitha and Ravi are going to get into some of these biomarkers in more detail and some of more on the weaknesses of the use of these quote unquote functional markers. In terms of the different novel biomarkers, the types thinking about in terms of markers of damage, markers of stress are really markers of inflammation. It's exciting to think about catching these patients sooner. [00:13:00] And really starting to challenge the way we characterize AKI, thinking of it as a moving target. And this four by four or two by two table, you're going to see a different iteration of it later in our talk. We put it here and basically delineating those patients where you may have no functional change or a functional change. And this would be based on your urine output or serum creatinine, for example. And then do these patients have damage based on say a biomarker like [00:13:30] NGAL. Patients may fall into the upper right quadrant where they have no damage, or excuse me, they have damage without loss of function. So a rise in a biomarker and certainly maybe at risk for progressing into that lower right quadrant where they have damage with loss of function, frequently, patients move from different quadrants throughout their course, and really having a knowledge of where patients are rather than just use the creatinine elevated is the urine output down, really [00:14:00] gives us important detail in order of how to treat and prioritize these patients for risk of AKI. This is data from the TRIBE-AKI study which is a study in adult patients undergoing cardiac surgery, showing the biomarker concentration as a percentage of the highest mean value of each biomarker. And the timing of the rise and fall of the listed biomarkers that you see here. I think interesting about this in contrast to biomarkers [00:14:30] like Interleukin-18 increases in liver fatty acid binding protein as shown in that bright blue line. And NGAL during that extension phase of AKI likely represents a response to kidney insult because these biomarkers attenuate kidney injuries. So these changes over time of biomarkers can really give us insight into where in a phase or in a course of AKI our patients are. [00:15:00] So I'm going to turn things over to Dr. Vijayan. She's going to talk about the rationale for early risk assessment and management, and can these biomarkers actually you improve outcomes. Dr Vijayan: Good morning, everyone. Thank you so much for having me at the symposium with Dr. Fuhrman and Dr. Mehta. So from Dr. Mehta, you heard about the global burden of acute kidney injury, and we face this every day in our ICUs, [00:15:30] in the hospitals, and also from Dr. Fuhrman, you heard about the biomarkers, the novel biomarkers that have been available over the past few years. And I will talk about how important it is that we do an early risk assessment for AKI. And also how can we use this biomarkers to improve outcome? So KDIGO guidelines were published in 2012 and as Dr. Fuhrman alluded to not much has changed since over the past [00:16:00] decade or so in how we approach a patient to diagnose acute kidney injury. And we know how limited urine output and serum creatinine are as far as sensitivity and specificity. And of course there's significant delay in diagnosing AKI, as you all said when you respond to the poll question. And so there have been several biomarkers to diagnose AKI, or at least assess the [00:16:30] risk for AKI that have been identified over the past decade. And the question is, are they available at our institution and how can and we utilize those? So serum creatinine, extremely insensitive marker for diagnosing acute kidney injury. And from this figure, you can tell as the injury happens at day zero, the GFR drops from that point onwards. But the rise in serum creatinine is delayed. [00:17:00] And also the rising serum creatinine will change depending on other factors such as muscle mass and volume contraction, fluid overload, et cetera. And so by the time the diagnosis is made, it maybe 48 hours, 72 hours later. And important to note that serum creatinine not an injury marker. So it definitely does not capture tubular stress or structural damage that happens. [00:17:30] So as AKI, the worst stage of AKI, based on serum creatinine and urine output, this also affects outcomes. So patients with stage one AKI are more likely to recover without long term consequences of AKD, which is persistent renal failure for seven days or more. And then CKD, which is persistent renal dysfunction after 90 days. And [00:18:00] patients with stage two and stage three AKI are less likely to recover their renal function back to baseline. And they're very high risk for persistent AKD as well as CKD, including the need for chronic dialysis. And the question is, can we detect these high risk patients even before the AKI happens? So when we try to apply, well, when we try to talk about biomarkers, [00:18:30] we're trying to detect AKI before it happens. So those are trying to identify those that increased risk for acute kidney injury. And once AKI occurs, can we use these biomarkers to figure out exactly where the damage is occurring? And as the AKI progress, can we use biomarkers to predict who might need chronic dialysis or who might be at high risk for death? So biomarkers cannot just be used early on in the course, [00:19:00] but they can also be used later on as well. Biomarkers may also help guide therapeutic decisions. And so in the past, whenever we have tried an intervention for acute kidney injury, now I'm not talking about dialysis, I'm talking about IGF-1 other agents including recently alkaline phosphatase to try and improve the outcomes after acute kidney injury. We've always waited till the creatinine [00:19:30] went up or urine output drops significantly for the, to get KDIGO stage one, two, or three AKI. So the question is if we use the biomarkers, and plus other characteristics to diagnose AKI beforehand, can we intervene? So for example, we can randomize them to no intervention, treatment A, treatment A plus B. We can potentially design studies and look at outcomes. So this is the ELAIN study, that was a single [00:20:00] center study from Germany, that randomized patients to early versus late dialysis, in a sense, it was very early versus early dialysis because patients who are positive with a biomarker NGAL along with stage two KDIGO AKI, they were the very early group. And then the late groups, late group was stage three AKI. And you can see the mortality was [00:20:30] lower in the early RRT initiation and renal recovery was also better in the early RRT initiation. Now this is a single center study, and we know other studies have showed that there was no difference in early outcome with early dialysis, but it just shows that biomarkers can be used to study intervention, not necessarily dialysis, but maybe even medications. [00:21:00] This is a another paper that looked at whether early detection of AKI can improve outcomes. This is from the Pittsburgh group. And this looked at an alert, a serum creatinine change will trigger an alert and will inform the training physician to say, "Hey, this patient is at higher risk for acute kidney injury." And they looked at what happened to these patients over time. And there was a small difference in mortality [00:21:30] after this alert was implemented at this institution. And there may have been potential changes in how physicians manage these patients after the AKI diagnosis based on this alert. And so the absolute decrease in mortality in this study was 0.8%. And if you look at that on the basis of 12% of hospitalized patients in the US getting AKI, that's about 2 million patients per year, which translates to [00:22:00] potentially 17,000 lives and cost savings of 1.2 billion. So the question goes, could integration of novel biomarkers, further improve of outcomes in addition to alerts? So to go back to that slide that Dr. Fuhrman showed earlier, we have to change how we think about acute kidney injury from that pre renal intrinsic damage to functional and structural [00:22:30] damage. And so in this box is where there's no damage, right? This is normal function, no damage to the kidney. This lower left box is what we would typically consider as pre renal because the biomarker is negative, but there is rise in creatinine and decreasing urine output. So there's functional loss, but no damage. This the top right, is where you have biomarker positive. So the damage is beginning to [00:23:00] occur, but it hasn't affected the function yet. So this would be subclinical acute kidney injury. And the box in the right hand side, lower right, would be where you have positive biomarker, elevated creatinine and or decreased urine output. And this is that classic acute kidney injury where you have structural and functional damage. And with that, I will hand back over to Dr. Fuhrman. Dr Fuhrman: Yes. Thank you so much, Anitha. That is exciting [00:23:30] and certainly shows that there is importance in integrating these biomarkers into the way we approach our patients and excited to hear Ravi talk about integrating these novel biomarkers into the diagnostic workup and how we approach patients in this way. Dr Mehta: Thank you, Dana. When we look at the current diagnostic criteria for acute kidney injury, these have been largely related to changes in creatinine [00:24:00] levels and increase over 48 hours or seven days, depending upon whether do you use a absolute or relative change or a decrease in urine output. And I'd like to mention here is there is also increasing recognition that a significant number of patients may come into the hospital with an elevated creatinine. And in which case, if they have a decline in creatinine that also currently can be utilized to identify acute kidney injury. However, as Anitha has shown [00:24:30] you, the two by two framework was what we had presented from ADQI. And the consideration is that if we have access to biomarkers from a functional biomarker standpoint, such as serum creatine, urine output, or Cystatin-C, and we combine them with a damaged biomarker, such as NGAL or KIM-1 or any of the other ones that Dana has shown you, you could then come up a way to classify patients [00:25:00] into those four quadrants. Recognizing that those four quadrants at a cross sectional level would identify one point in time. But if you use the same two biomarkers across the spectrum, you could then see the dynamic changes occurring. Now what's the evidence to support that? So this is a study which is done some years ago and from the emergency room data. And you can see here in panel A is NGAL and panel B is KIM-1. [00:25:30] And in addition, so they combine these two biomarkers measured at the same time in these patient populations. And you can see here is the serum creatinine values are shown in the first row here, and then the biomarker values here. And what you see is that you can classify these into the four quadrants. So these are the low risk patients who had neither elevation of the creatine or the NGAL above the threshold. [00:26:00] You had the next level where there was no change in creatine, but the NGAL level was elevated. And then the next one where the creatinine was elevated, but the NGAL was not. And finally they both were. And as you can imagine from what Anitha had shown you is this is the lower right quadrant of that two by two table. So you see that this is associated with the marked increase in event rates. But what is important to recognize is that this category here [00:26:30] where the creatinine was not elevated and the NGAL threshold was exceeded, you did have a higher event rate. So this is the construct of subclinical AKI. Whereas this is a construct of potentially what we have come to recognize as prerenal where there's a functional change, but damage is not evident as yet. So the key take home from this essentially is that we have patients who fall into one or all of these categories, [00:27:00] and these are associated with different risk profiles and course. Now, how have these biomarkers performed overall? Now we've had access to these damaged biomarkers for many years. However, the utilization has largely been limited to mostly research settings. And when you look at the research data, this is an article which looks at a [inaudible 00:27:23] analysis, 52 studies on urine plasma NGAL, and you can see that the area under the curve is about 0.73 [00:27:30] for urine NGAL, and about 0.83 here. But when you look at the individual database [inaudible 00:27:36] analysis, so this is a literature based, and this is database. You can see that it still is in the same framework about 0.75 of 0.8. Certainly interesting, but not something which led you to real practical utilization. Despite the fact, because this threshold of [inaudible 00:27:54] specificity is at the maximum utility where the area under the curve is 0.75. So if you were to change [00:28:00] this threshold, you would have different parameters itself. Now, does that translate into other biomarkers? So we can see here is the comparison of the biomarker profiles. You have these area under the curves of ranging all the way from 0.6, to the more recent ones of TIMP-2 IGF-Binding-Protein-7 of almost up to 1.8, depending on what which category are utilizing them. And what's important to recognize is that [00:28:30] these biomarkers have different thresholds. And those thresholds also change when you have underlying chronic kidney disease and also in the setting that they're utilized in. So we have to tackle those elements as we go along now, as example of, one of the applications here is TIMP-2 IGF-Binding-Protein-7 biomarkers were allocated in this study where about 400 patients undergo cardiac surgery. And they looked at the framework of reference. [00:29:00] And you can see here is, this is an induction of anesthesia, 30 minutes after, immediately after. ICU admission, six hours after post-op day one, day two, and day three. And he notices that the patients who eventually meet criteria for stage one AKI, they are minor blips in these biomarkers, but in those who develop stage two and three, these biomarkers increase quite well. So the question is, are these biomarkers therefore relevant [00:29:30] for predicting who's going to develop stage two and three? And the framework of reference would be where in the course does creatinine go up? Creatinine might be identified maybe here at post-op day two, while these biomarkers have already been elevated. So that needs to be there. And this is the analysis of the [inaudible 00:29:52] study, which was, if you can remember, was looking at the fluid management strategies in patients at septic shock. And even [00:30:00] though that study by itself was not informative on its own, but a subset of those patients, about 650 patients had biomarkers available at the initiate randomization and six hours later. And you can see that in those patients who had a... This is a cutoff for the TIMP-2 IGF-Binding-Protein of less than 0.3 is felt to be normal range between 0.3 and two is intermediate risk, and then above two is severe risk. But you [00:30:30] can see that patients at our zero could already be stratified into two categories. Those who were in a normal range here versus those who were already elevated. And then what happens to them six hours later is some of these people stay in the normal range and some now have an elevation. And on the other side, some of these patients who were elevated, become normal range, and then some stay elevated. But notice that between these two values, the ones [00:31:00] who stay elevated have a high rate of the outcomes, whether they be the stage [inaudible 00:31:06] renal patient therapy or death within seven days. So therefore they suggested there's an opportunity for us to start phenotyping these patients at admission with a biomarker to see, could these stratification allow different intervention strategies for resuscitation with fluid? Because the group who are here are probably quite different from the group [00:31:30] who were here and went here versus those who never had a problem. We need to understand [inaudible 00:31:35] of patients which would be identified and utilized in a different way. Another element on this is simply looking at the opportunity for serial assessments. So if you do one time point, or you do one or two time points, you may not be able to have as good a resolution of what the association is with downstream events. But if you were to look at this with respect to number of test done. [00:32:00] So this is an interesting study looking at patients who had more than one biomarker assessment at baseline 12 hours, 24 hours, and the endpoint is stage two, three AKI in seven days. You can see that those patients who have elevation and are persistent elevations on their biomarker profiles have a higher probability of stage two, three AKI. Now this is obviously an association. There's not a causal relationship here. But [00:32:30] it tends to suggest that there may be an opportunity for us to measure these biomarkers more frequently than just at a baseline value itself. And this is interesting because again, in some respects, this is another study from Jake Joiner's group, looking at patients who they were just assessed one set baseline. And then the one set baseline, you can see that amongst those patients who did not have meet the criteria for acute kidney injury based on serum creatinine criteria [00:33:00] versus those who did. And you can see there's stratification in terms of the levels of the TIMP-2 IG point, they're measured here. But what's happening is this is almost up to nine months after enrollment. You see that there is a, there is a separation in those patients who end up with this composite endpoint of mortality or death at nine months. So some opportunity here for us to look at that part. Now, has this been used for specifically for intervention studies? And there's a few out there. [00:33:30] Amongst them, is this particular study, it was a non cardiac surgery as well as for a high risk major abdominal surgery, where the investigators [inaudible 00:33:38] patients who had a high risk, that means that at baseline, they had the TIMP-2 IGF protein more than 0.3 to a control the standard ICU care versus those where this prompted AKD bundle such as the one Dana showed you in her first slide where there's optimization volume, one is nephrotoxic drugs. [00:34:00] And what they found was although there was no overall incidence between two groups, there seemed to be a suggestion that there was reduced incidence of moderate to severe AKI, [inaudible 00:34:11] creatinine rise, and reduced cost of care. Obviously intriguing, but certainly needs to be developed and checked into a larger data sets. And in that set as such, this is again initial data from Dr. Zorbax group in Germany, where they looked at a similar [00:34:30] aspect of cardiac surgery patients control group standard of care versus KDIGO. Again, the same high risk defined by 0.3 at the initiation of surgery itself. And they were able to demonstrate that there was a significant reduction overall in all AKI and modern severe AKI. We recognized is that in the cardiac surgery group, you have a very standard starting point for cardiac surgery. You can do things very systematically versus in all [00:35:00] AKI where coming in across you don't know when the event has started or what has been happening as such. And what this Dr. Zorbox group did was looked at a similar design to look at a further multicenter randomized study where now they were looking at the primary proportion of patients adhering to KDIGO bundle with the secondary outcomes of incidence of AKI. And here, again, as you can see, is they found in the intervention phase as expected, there was a higher number of patients who follow the bundle. Well, because [00:35:30] you were allocating them to a much more consistent approach saying you have to, we have a [inaudible 00:35:35] bundle. But what is concerning is that in this group only 65% actually followed the bundle. So that means there's opportunity for us to improve, because you would've expected. This should be a much higher number in a randomized study as such. And you can see that the secondary outcomes, therefore, our incidence AKI are not any different, but to moderate to severe AKI, there does seem to be a difference [00:36:00] itself. So again, what we have so far is recognition that the biomarkers may have value in different things. So this prompted an ADQI meeting about four years, about three to four years ago, which is available in this [inaudible 00:36:19] open article. We said, okay, if we now were to think about the opportunity of having damaged biomarkers along with functional biomarkers, [00:36:30] how could we modify the diagnostic criteria in that setting? So if you just look at this right side of the equation, this is basically the current diagnostic criteria, serum creatinine goes up or urine output goes down. And therefore, if we now were to put that framework of the two by two on it. And now if you had a biomarker, a damaged biomarker positive along with this, you could have these different stages [00:37:00] which would represent the four quadrants overall. And so what this has prompted to is an approach which will need to be validated with data. But what that suggests is that we can now have sub stages of the original stage one, two, and three of acute kidney injury where they are being further refined by the data available from applying a damage [00:37:30] biomarker concurrently with the functional biomarker. So then to go back to that two by two framework, you can see here is this is a biomarker negative, no increase, no increase in serum creatine level. This is where you want your patient to live. They don't have kidney kidney problems. And when you go into this phase here, this is the group of patients where the damaged biomarker is showing you an increase, but the creatine has not changed as yet. This is what [00:38:00] we would call stage 1S. This is the subclinical stage where we want to understand what is causing that damaged biomarker to increase. And as a consequence, target that element itself. This becomes very relevant particularly, for example, in patients in oncology, where you give me a chemotherapeutic agent, you might be able to pick this up early and therefore change elements. Whereas in this case here where the biomarker is negative, but the serum creatinine [00:38:30] is going up or you've got some [inaudible 00:38:32]. We call the stage 1A, this is the equivalent of a functional change which maybe related to change in hemodynamics, maybe related to the fluid balance or dehydration could be corrected because this is a section where you may have some early intervention is possible. And then obviously we want to avoid them in here, although we may encounter them in this space which would be stage 1B. And as Dana pointed out [00:39:00] to you and Anitha has shown you is what's crucial is these are interchangeable. Patients will go from one to the other and that's where the value of these biomarkers comes in, is can we identify today where is the person? Is he here? Are they going to go here? Or if they're here, are they coming back into some resolution? And I think that's the more important element that we need to focus on as such. Dr Fuhrman: Thank you so much, Ravi. That is exciting to see all [00:39:30] these research efforts now translating into really use of the bedside and clinical opportunities. I should mention, I'm seeing some really great questions coming up. To the audience, we are going to try to address these all at the end. So thank you so much for your questions. Going to transition over to Anitha for putting it all together in the early diagnosis of AKI. Dr Vijayan: Thank you, Dana. And thank you, Ravi, for really summarizing all the biomarker [00:40:00] studies that shown how beneficial early diagnosis could be. So how can we put this all together? So we still need to take our history and physical and review the chart because we still need to have that clinical suspicion. That patient is probably going to be at high risk for AKI. And Dana showed you previously potential risk factors for our patients. Then we need to look at all the other modifiers, right? The inherent patient characteristics, do they have underlying diabetes, [00:40:30] CKD? What is their socioeconomic conditions? Their environment ICU patient is higher risk than somebody in the hospital floor potentially. And also, patients in developing countries versus developed countries that there might be different risk factors there. So we still need to have all those modifiers in mind. And then we look at our known factors, urine output, urinalysis. And then we do additional testing, if we have [00:41:00] novel biomarkers available at our institution, we utilize that. We do renal imaging as appropriate and then consider a kidney biopsy because a lot of patients in the ICU that we assume have this particular kind of damage may turn out to be something else. So there is a lot more push towards a kidney biopsies as well. And then we come to our diagnosis, which is, do the patient already have AKI or what stage of AKI or are they at [00:41:30] risk for acute kidney injury? And then are they at risk for... Well, so we determine the etiology as well and then we determine, are they at risk for CKD? And for us to get to this diagnosis and management strategies, we really need interdisciplinary cooperation. The pharmacist might be first person to pick up a potential nephrotoxin. The nursing would be the first person to notice a decrease in your output. [00:42:00] So it really is a interdisciplinary cooperation and approach before we diagnose and treat somebody with acute kidney injury. And I'll hand it back to Dr. Fuhrman. Dr Fuhrman: Wonderful. So let's come back to our case. As we talked about early in the talk the 68 year old male who came in with pneumonia and septic shock and has received vancomycin and peptazole for a concern of sepsis and transferred to the ICU [00:42:30] on a pressor and his urine output is improving with fluids. Where might biomarkers be helpful in this case? Where might they not be helpful? An interesting study published by Marlies Ostermann and colleagues looked at a cohort of adults that had been to the ICU with cardiovascular or respiratory dysfunction that developed stage two or three AKI. In those patient that did develop stage two or three, as you can see here, TIMP-2 IGF- [00:43:00] BP-7 or those markers of cell cycle arrest certainly were elevated when patients did develop stage two, three AKI temporally related to the timing of vancomycin administration. So showing that there is an association with the nephrotoxic medications with kidney stress. And wouldn't it be great if we could predict that or see that before we see a rise in creatinine or a decrease in GFR. So in no way, would any [00:43:30] of us be proposing that these patients don't receive the very needed antibiotics to treat sepsis. However, where might a biomarker like TIMP-2 IGF-BP-7 be useful? Ravi talked about these cutoff values that we might propose. And here in Pittsburgh at our adult hospital, this biomarker of NephroCheck is used very readily. And what way one might approach this is you get a level of 0.2. We might consider that in this patient [00:44:00] low risk. So this patient isn't showing evidence of kidney stress on these medications. Based on evidence prior studies, negative predictive value over 95% in thinking this continue for now a weight culture data. However, say you got at the time of admission after the patient got the vancomycin and the peptazol, TIMP-2 IGF-BP-7 value 1.3. So this patient's more high risk kidney stress may be due to sepsis, but nephrotoxin [00:44:30] may also be paying a role. As we mentioned, these are both exposures and susceptibilities. Certainly you wouldn't want to hold vancomycin as a medication, but this might be a patient that you think I'm going to look at levels more closely. I'm going to wait to dose again based on the level. And we all have those patients that maybe we didn't do this in. And the vancomycin level comes back at 30 in the face of what looks like a normal serum creatinine. And then in contrast, you might have a patient [00:45:00] or this patient may have a biomarker value that's very high risk, 4.4. This is a patient that you're certainly... And I'm seeing some of the questions coming up, very good questions. About other things that we can do in terms of mediating or mitigating this kidney stress. So very close attention to hemodynamics in this patient, very close attention to fluid status, monitoring this patient closer from a kidney standpoint, looking for other contributors to kidney stress. And certainly maybe considering if you were choosing [00:45:30] peptazol, something like serophene, something that maybe has a little less nephrotoxicity. So a careful attention in that case. So, and we, again, address this in this conversation. So the questions and we're going to get into your questions in particular, as a group. Really interested to hear, do you have access to biomarker assays at your institution? ( [00:46:00] Silence). So most of you either a no or unsure. So clearly there are some barriers to a biomarker acquisition in the clinical realm. [00:46:30] So if not, which a lot of you mentioned that's the case, what are the barriers to using these biomarkers? (Silence). So simply [00:47:00] the access costs may be an issue, infrastructure, lack of laboratory support, maybe lack of evidence to support. So clinical buy-in just people not being aware of the evidence out there in terms of use in the ICU. So we're going to touch on of these things as we address your questions, just didn't want to miss the opportunity. I'm excited. We have a little over 10 minutes to get into these questions. Some concluding remarks. And thank you so much [00:47:30] to Ravi and Anitha, this was a really fun conference to put together and your input. On this in terms of what we're all conclusion AKI, hopefully we've conveyed is common and associated with poor outcomes including mortality. And that these novel biomarkers can improve the early detection and clinical management of these patients. I should mention, we touched on it, and not the focus of this, but there is certainly room and opportunities [00:48:00] and research for looking at biomarkers in patients who've had AKI in the recovery phase. Novel biomarkers of kidney injury should be combined with traditional functional biomarkers in no way are we saying we don't [inaudible 00:48:13] serum creatinine and urine output are not useful. They're extremely useful markers of function. And overall using that group of biomarkers and functional markers or novel biomarkers to improve our patient management, which is obviously our goal [00:48:30] here. So in moving forward, we're going to get into the QA session of our time and we have a perfect about 10 minutes. I'm going to pull up some of the great questions that the audience and throw some of these out to my co-presenters here. There's quite a few. So I will say in advance, if we don't get to all your questions, feel free all of [00:49:00] us are very obviously interested in this space and are excited to talk over email or anyway, if we don't get to your questions if after the session, you want to talk more. So question, I'll pick one here, that's coming up. So this is very relevant, I think, to ease of use. And one of [00:49:30] the criticisms you might get with maybe trying to introduce a biomarker at your center, how readily available are the biomarkers and what is the typical turnaround time for results? So I will answer, I guess, in terms of my center and then I'd love to hear what the other group members here have to say. We in Pittsburgh and our adult side, we have started using, or we have been using for a few years now, the NephroCheck, and that comes [00:50:00] back within an hour. I think that's absolutely key to have the biomarker available to you to actually make clinical decisions. I'm excited to report that at children's hospital here in Pittsburgh, we're going to be starting to use NGAL. And with that test, usually within an hour, we will have a result, which is absolutely important in terms of interpreting the results and acting on the results in a timely manner. Wondering if Ravi or Anitha have anything to add on that. Dr Vijayan: So [00:50:30] the turnaround time should be about an hour. The actual test is I think it's just 20 minutes. But getting the specimen to the lab, running it, so probably a turnaround should be in about an hour, I would say. Dr Mehta: I think that the difficulty is the type of test while some of these biomarkers are designed to be point of care done in the room itself, just like an AVG or other elements. They require a lot of clear certification in [00:51:00] other regulatory aspects. So in essence, they have not really been adopted as point of care, at least in the US, which they and translates into however, your stat labs work in these situations. In our center, we do not have access to these biomarkers largely for the same reasons. I think it's related to cost coverage, administrative reasons, figuring out what the burden will be to the lab in terms of performing these tests and what we reimbursement they would get. [00:51:30] And it all depends on who is the champion for it, who is pushing for these biomarkers and which group is taking that responsibility. So it's highly variable in that setting. Dr Vijayan: So just a word about the cost. When we looked at this data as part of the ASN advisory group for the NephroCheck each test cost, I believe about $70 every time you do it. The platform might be expensive to start out with. But interestingly, we all used to do urine [00:52:00] eosinophils for a long time. And the urine eosinophil testing was actually probably more expensive than doing a NephroCheck testing. And of course now urine eosinophil have gone out of the favor, rightly so, but I thought it was interesting that we would consider this test expensive. But it was not really an expensive, more than expensive than doing a urine eosinophil testing. Dr Fuhrman: That's very interesting. I wasn't aware of that. And there are a number of questions in regards [00:52:30] to cost, so thank you, Anitha, for pointing that out. And yeah, it probably will vary a lot based on institution. And an individual asked about insurance coverage and certainly, yes. If institutions are using it, there is coverage for it, but it's going to be quite individualized in that regard. And I like Ravi mentioning the need for a champion in this regard. I think that's key. Showing the data, presenting the data. It's exciting that we have so many people [00:53:00] here on this meeting that are hearing the data maybe for the first time to bring back to your centers. I will say at my center, we're a big liver transplant center. And then looking it from a research standpoint, the use of novel biomarkers in predicting AKI in that patient group in particular, and then the association with outcomes after even leaving the ICU really got people excited about the need for these biomarkers. So I think making it [00:53:30] personalized can really help. Touch on another kind of theme of questions I'm seeing here managing patients in terms of blood pressure and hemodynamics and how that is important in terms of mitigating kidney damage. One individual asks, we usually maintain patients blood pressure, systolic blood pressures greater than 90 or MAPs greater than 60 or 65 in patients with chronic hypertension is this enough? And [00:54:00] if so, how should we address the deleterious issues of pressors versus kidney damage? I will say, as a pediatrician are my MAP values and SPP values may vary greatly based on age. But I absolutely agree that maintaining adequate perfusions of the kidney, even if it does require pressors is necessary for AKI prevention and preventing progression and having a knowledge of that is absolutely important. I don't know if Anitha or Ravi [00:54:30] have anything to add to that. Dr Mehta: I think the one thing to remember is that the studies which have been done in critical care, looking at target MAP pressure by itself did not demonstrate any specific threshold. However, in those patients who were hypertensive before, had chronic kidney disease before there was a clearer [inaudible 00:54:55] need to have a higher blood pressures. And generally the principle is trying to keep it in MAPs of higher [00:55:00] than 65, if you can. There is enough data now from anesthesiology and in the operating room demonstrating that the duration of low MAPs correlates with the development of acute kidney injury and long term aspect. I'm not aware that there have been any studies which have specifically looked at a damaged biomarker profiling in relationship to hemodynamic management to say, could those biomarkers then [00:55:30] be used as targets? To say, where do you stop or where do you enhance? And I think that's sort of the question which comes up is we have access to these biomarkers, albeit in the research setting mostly at the moment, but could they be utilized for actually guiding patient management better than what we currently do? And that's an open question, which I think the audience, all of you will be excited to see how you might want to use that. Dr Fuhrman: Thank you, Ravi. One of the [00:56:00] questions was I presume you don't believe LASIK stress test is useful. Yes, we didn't talk about the first amide stress test within this is a biomarker. It could certainly be thought of as such or is. And there's some exciting data coming in the pediatric world in terms of combining the use of some of the damaged biomarkers that we talked about today in combination with the furosemide stress test to predict need or to stratify patients based on need [00:56:30] for renal replacement therapy. So absolutely I think we all think, and if Ravi or Anitha want to add, that the use of the furosemide stress test can have additional information in terms of marking patients that are higher risk for progression or risk of needing renal replacement therapy. Dr Vijayan: Yes. I completely agree. The furosemide stress test along with the novel biomarkers would be a great addition. And I think J. Joiner's data already shows that for adult patients as well. So I definitely [00:57:00] recommend continuing to use furosemide stress test as a [inaudible 00:57:05]. Dr Mehta: I think I would just put a word of caution there, is that the stress test should be done in the way it is designed to be. Not simply just add a bunch of diuretics and then see what the output is. You really do want to do it as a stress test and not continue to persist if you're not getting the response. [00:57:30] And I think that it translates into the broader context that I was, showing you is that when you look at creatinine or urine output as a representative of kidney function, then you are trying to combine the functional evaluation with a structural evaluation. Cardiologists are really great at doing this. They have specific biomarkers [00:58:00] for structure like troponin and they have specific functional assay such as a chronic echo. And I think in the nephrology realm, we have not used them in combination, which is why it's important for us to recognize we have these tools. We should start using them, but we should use them appropriately to generate the evidence so that we can manage patients rather than just sometimes using them and sometimes not. Dr Fuhrman: [00:58:30] That is a perfect concluding remark by Ravi. I think it's been exciting even in my relatively shorter career to see these changes in how we categorize AKI and how we're moving towards a much more detailed and careful approach. And yeah, I think we're at the top of the hour now. But really again, if we didn't get to address your questions, please don't [00:59:00] hesitate to reach out to us individually. And we thank you for your time and thank you both to Anitha and Ravi.