Thank you. So just to look at my disclosures, I do have some grant funding from NIDDK. I won't be talking specifically about that or any other one of my disclosures here. So I just wanted to review the objective, and my purpose for that is because some of this is going to be more pertaining to clinical practice, and some of it is about thinking if you're going to do some research and you're trying to identify a drug-related event, you know, what might that look like, or how might you define it, or how might you determine if it's actually related to the drug. So our current taxonomy associated with describing drug-related events is, I think it's antiquated, right? It looks like it's still useful, could be pertained, but it's antiquated and inconsistent. And so what we're hoping for is to be more standardized and contemporary. I say it's antiquated because we haven't aligned our descriptions of drug-related events with the definitions by the Kedegro Group for AKI or AKD. And so the goal here is to try to map our perceptions of that with these definitions. So just in general, kidney diseases and disorders, abnormalities in structure and function that have invocations for health. Now we're talking about AKI. If you know the Kedegro definition, so there's lots. There's rifle criteria, there's AKIN criteria. But in 2012 the Kedegro criteria came out, but I still see infiltration of AKIN and rifle. And Kedegro is really the recommended criteria to use. And so if you look at that, it's a 0.3 rise in serum creatinine from baseline in a 48-hour period, or a 50% increase in a 7-day period. And then there's some urine output criteria as well. So then, how many people have you been familiar with AKD and would know enough to differentiate AKI from AKD? So we have about two or three. Okay. Erin didn't raise her hand, but she would count. So for AKD, it's actually like, okay, so once we get past that 7-day window and suddenly you have your serum creatinine rising, right, and you're now at day 8 or 9, you don't meet the criteria for AKI. So what criteria do you meet? It's not CKD until you're out to 90 days. So we're in this window, somewhere between the 7 days and the 90 days, which is considered to be AKD. And so there's a specific definition for that, which I just said. But there's also functional criteria. And interestingly, the most recent paper on AKD includes AKI. So AKI is actually part of AKD, because what they're saying is three months or less, which includes that 7-day period. Okay. So functional criteria, GFR of less than 60, a decrease in GFR by 35% times the baseline or an increase in serum creatinine of greater than 50% from baseline. So today, since we're talking about critical illness, I'm going to focus just on AKI and AKD and not discuss CKD. Okay. So I'm going to do this by way of example instead of sitting up here and giving you a list of definitions. So if we look at example number one, and we'll go with example number one. Who thinks this is AKI? We have a couple of people who think this is AKI. Well over this 48-hour period, we do have this 0.3 rise in serum creatinine, right. And so we also have a 50% increase in less than 7 days. So this would meet the criteria for acute kidney injury. So what about this example two? Who thinks example two is acute kidney injury? Raise your hand. Okay. We're still at that 0.3 rise in the 48 hours. So this would still meet the criteria for acute kidney injury. So these two would be considered acute kidney injury. Okay. So we're going to expand this out to the 7-day timeframe. And now we're going from 0.8 to 1.3 in a 7-day period. Do we think this is acute kidney injury? A few more. Anybody don't want to guess? Anybody think not? So again, we're meeting this criteria because we have a 50% rise in the 7-day period from baseline which I'm calling at this point in time Day 1 of 0.8. So example two, does it meet the criteria for AKI? Who thinks AKI? Nice and high. Very good. Okay. So again, we're meeting this criteria. But interestingly, I put this one here because it meets it two ways. Not only does it go from 0.8 to 1.4 in a 7-day period, but we also have this 5-6 day where there's a 0.3 increase in a 48-hour period. But you know, because it's meeting the first criteria over the 7 days I would go with that. But I just put that in there to give some considerations to what could or happen possibly to evaluate. Okay. So my suggestion when we're looking for drug-associated events or some type of drug-related event is we go back to what I'm calling the index. The red box here is your index serum cranium. The serum cranium that was the lowest point before it started to increase, right. And so in example one we have this 0.8. And then I say, well, okay, we gave vancomycin and clostridone on day one. And it was started on day one and it was continued throughout the entire 7 days and continues. So I'm getting to thinking about, okay, is this drug-related? Well again, at index, the drug was already be given at least for about 24 hours before that index serum creatinine. So that gets you to thinking. So do you think this is drug-related? So everybody think about this. Do you think it's a drug-related kidney disease? Hands high for thinking it's a drug-related kidney disease. Okay. Do you think it's drug-induced acute kidney injury? Do you think it's drug-associated acute kidney injury? Some people think it's drug-associated. Okay. Not drug-related at all? Okay. There's lots of people who I think are maybe undecided or maybe shy to raise their hand. Okay. So what's the difference between induced and associated? When we think of associated, it's meaning that there's no definitive conclusive reason. I can't say absolutely sure this is drug-related. So I think that it's associated. It could be contributing to the situation. And so that's what I would term as drug-associated acute kidney injury. And it could even be assessed, well I said to go back to the index serum creatinine and assess to see when the drug was given relative to that index serum creatinine. I also think if you give a drug after the serum creatinine is already on the rise, that could also be drug-associated because it could be worsening the condition, right. So it could be contributing drug-associated events. If you have some conclusive evidence that you're sure that it's induced by the drug, and oftentimes, you know, we don't have that additional evidence, but it'd be nice, okay, we know that there's other laboratory values, there's a biopsy that indicates this is drug-related and you have that evidence, we could conclusively say it's drug-induced. A lot of times you don't have that. So what I'm suggesting you do in those scenarios is at least look at the index serum creatinine and go back just before the index serum creatinine to see if those serum creatinines were stable or if they were already increasing. Because if they were stable, then maybe it's drug-induced. So ways to think about and differentiate those two. Okay, so we have kidney disease and disorders occurring in about 30% of ICU patients. And about 30% of that is drug-associated acute kidney injury. And I think some fraction of that is drug-induced. And I'm not sure how much. We haven't gotten really into, everybody's mixed up these terms so much in the literature that they're not differentiated how many cases are drug-induced or drug-associated. And all of these would be drug-related kidney diseases and disorders, right? That's kind of the broader category for all of this. So when we go back to the example, we have the index serum creatinine 0.8. I said the vancomycin, colistin's given, nephrotoxins are given at least 24 hours beforehand. So I think this is clearly a drug-related event based on the data that I have. And it could be drug-induced AKI or drug-associated. I can't really tell. I don't seem to have enough information. And so I believe it's a drug-related event based on this information. Okay. So another example here is, I actually say, okay, day 0, serum creatinine is 0.8. Day 1 is 0.8. Day 2 we give the vancomycin, colistin. Day 3, still 0.8. Then it starts its rise. So if you look at this, it's the AKI based on the criteria. Is it drug-related or not? That's what I'm trying to figure out. And so seeing that there's this stability associated with these serum creatinines before the index, it seems suggestive that this was the factor that not just contributed, could be the reason for the rise in the serum creatinine. And so I'm calling it and saying, go back and look and see if those serum creatinines are stable. And I've given you a definition here of a change in 0.3 in the 48 to 72 hours prior to the drug administration. And then I would say, this looks more like a drug-related kidney disease, because that's the broad category. But it looks drug-induced, right? Based on the information that I have. So then I go through and I say, okay, well, now I'm giving you a little bit more information. Not only were the drugs started, but this person has a history of IV drug use. The reason why they were hospitalized is because they had a motor vehicle collision. They were under the influence, some trauma. The patient has sepsis. Their post-op Day 1 serum creatinine is 0.8. Clearly with everything else going on, you know, vancomycin and colistin are contributing to the cause. But with everything else going on I can't say that's for sure. So I think this is a drug-related kidney disease. And I think it's more of a drug-associated kidney injury because I can't get down to exactly who's to be saying that's due to it, and there's so many other causes that could be contributing. Sorry. I'm going in the wrong direction here. Okay. So we're moving on to look at this example. And we have the fact that here's your serum creatinine over a span of 14 days. Patient starts at 0.9, increases to 1.5. Who thinks this is acute kidney injury? Acute kidney injury? Who thinks this is acute kidney disease? Have some buy-ins for acute kidney disease. And then CKD, not even talking about that today, so don't go with that answer. And none of the above. Okay. So I say go back and look at the index serum creatinine, you know, the serum creatinine before this trend in rising occurs, which is 0.9. And I think it's AKD as well, right. It didn't happen to meet the criteria for the 7-day interval. But it's still increasing. And it's in this 14-day period instead. So I agree. It should be AKD. So I said go back and look in the previous 24 hours and see if a drug could be contributing or they've received a nephrotoxin that we need to assess to see if it's contributing to this situation. And so I say, yep. Okay. Well we gave some vancomycin. And, you know, there's a nice long list to go through. Do you think it's a drug-related kidney disease? Do you think it's drug-induced acute kidney injury? Or drug-associated acute kidney injury? Drug-induced AKD? Or drug-associated AKD? Well, again, all these terms, if you're thinking it's due to the drug, say that it's drug-related kidney disease. And we already agreed that it's AKD. So that means B and C can't be an option. And so now we're down to drug-induced and drug-associated. Always hard to tell. We're difficult to commit. This looks stable before the rise begins. So I think that it could be a drug-induced AKD based on the information that I have. Okay. So now, if you look, we are saying, okay, vancomycin was started on Day 2. But now they also got some NSAID on Day 6 or 7. What do you think about that? Well, I already think it's due to the vancomycin. Now I have this ibuprofen on top of it. What am I going to do? What's going on here? So think about it. Which one do you think, the ibuprofen, what would you call the ibuprofen? Okay. And let's just make sure. We think, and I'm bringing this up because of nephrotoxic burden. If a patient in the ICU was uncomplicated, we would all be surprised, right. No situation is ever uncomplicated. The patient is never going to be on one nephrotoxin, right. It's always on more than one nephrotoxin. And it gets difficult and more complicated to evaluate. So that's where you have to start thinking about your nephrotoxic burden. Instead of just isolate yourself to thinking about what's going on with this drug. I'm starting a new drug. It's okay to start this drug. You know, how many other nephrotoxins are they on? Can you take them off before you start the new nephrotoxin that you have to start? So then you evaluate and you say, okay, there's a calculation for this which is a cumulative days to evaluate nephrotoxic burden. You look at the number of drugs given times the number of days those drugs were given and that's your assessment for nephrotoxic burden. That's the current one study that exists on this topic. That's how they defined it and calculated the nephrotoxic burden. And I'm also saying, yeah, that would be great, except sometimes I don't know when they started the thoracomide. I'm not sure when they started the Nalpro. Maybe you have some history on the Ketorolac. Maybe you should know when the vancomycin started. So maybe sometimes you only can evaluate it as an aggregate assessment. And then sometimes, you know, okay, well 12 hours ago the Ketorolac was stopped. So maybe there's still some remnant effects. So don't just think about the one drug. Don't just think about nephrotoxic burden when you're assessing the kidney-related event. Okay. So what do you think about the ibuprofen? You know, this looks more like it's due to the vancomycin because the rise started before I even gave the ibuprofen. But I'm sure giving the ibuprofen, which was probably unnecessary, is not helping, right. And so I think, and I would call this, you know, if you're asking me specific about the ibuprofen, I'd call that a drug-associated acute kidney disease because they already have AKD, right. And remember that AKI is part of AKD. So I would have called it a drug-associated acute kidney disease. But overall, that's what this patient has, I think, anyways because of the vancomycin. Again, our scenarios are never usually this easy because I get to make up any scenario I want. That's why it's part of the presentation. But you know, I'm trying to get you to think about how you might differentiate these. Okay. So again, we have kidney disease and disorders, currently about 30% of ICU patients. We have drug-associated acute kidney disease. I have no idea how often that occurs. We haven't looked at that. We didn't differentiate that. First of all, we haven't done good in the literature about differentiating drug-associated versus drug-induced. And we certainly haven't thought about drug-associated AKD. So I don't know how often that occurs. And the literature says about drug-associated acute kidney injury or drug-induced kidney injury occurs in about 30% of the time. Although I think that's the larger portion and there's less to drug-induced acute kidney injury. And all of these events are drug-related kidney diseases and disorders. Okay. I'm going to give you a scenario for why drug-associated AKD might occur. Okay. You know, what would, you know, when would we might start thinking about this? So here's a few options. Option 1, the increase in serum creatinine is delayed following nephrotoxin exposure. I like to call this one the slow burn, right. If you, if everybody, I'm sure there's lots of pharmacists in this room, we go back and like, yes, vancomycin takes some time to accumulate in the tubule. And guess what? It doesn't occur in your perfect little 48 hours or 7 days. And technically if you look in the literature it says somewhere between 4 and 14 days, right. So vancomycin takes some time to accumulate and it doesn't, you can't even detect this rise in serum creatinine until somewhere after the 7 days. That's the slow burn, right. So that's one option for why you might see a drug-associated acute kidney disease. What if you have a person who has AKI, either drug-associated or drug-induced acute kidney injury, the renal pathophysiologic process continues, is ongoing, due to lack of recovery, guess what? You took away the offending agent. And some improvement happened, but the person never got back to their baseline, right. And they're still meeting the criteria for AKD, that could be an option, right. And what about if this situation where the renal pathophysiologic process is ongoing, because you continued the exposure, guess what? You couldn't discontinue the vancomycin, it wasn't an option in this patient, you had to continue it. Or guess what? Somebody missed it. It was unintentional. You know, you didn't realize it was a drug-related event, the nephrotoxin wasn't discontinued and continued to contribute to the situation, and the serum creatinine continued to rise. Okay. When I get into differentiating drug-associated versus drug-induced, I don't want people to minimize the word associated. I want people to think of it in a way, if it's drug-induced or drug-associated, do something about it, right. Treat it, manage it, think about it. So here's the scenario for Option 1. The vancomycin starts on Day 2, looks relatively stable, slow rise, the slow burn rises over some duration of time, again because the vancomycin needed some time to accumulate, right. And so this would be Option 1 or how I would describe Option 1. Now let me describe to you Option 2. The vancomycin was started. You realize and you think it's drug-induced, you remove the vancomycin because you're able to in this patient. The serum creatinine was still on the rise slightly, you know, then it starts to come down a little bit. It starts to come down a little bit. It never gets back to baseline and still meets the criteria for AKD. That could be another option. Or Option Number 3 is, you have a scenario here where you had to continue it, right. You had to continue the vancomycin. It's some type of endocarditis. You have to continue it. You can't stop it. The duration is going to go longer than the 7 days, even the 14 days potentially. And you know, the serum creatinine continues to rise over some duration of time. So in summary, I'm suggesting we adhere to the AKD, CKD definitions. A lot of us have tried to come up with different definitions. If you look in the literature, people like the serum creatinine rise of 0.5, I don't know over what time frame. Just if you get the drug and there's an increase in 0.5 or some time frame, it's acute kidney injury related to the drug. I don't know why you're picking 0.5. Because if the serum creatinine starts at 3.7, I go up to 4.2. That's much different than if we're at 0.8 and I have a rise of 0.5 to 1.3, right. So 0.5 is this nebulous thing that's been used in the literature. So I'm suggesting, look it, kiddico people took a lot of time thinking about what AKI and AKD and CKD are. Stick with their definitions. And then go back and figure out if it's drug related. So go back and figure out if this drug exposure, see at the time of the index serum creatinine what the drug exposure was. Make sure they received it for at least 24 hours. Because a lot of our assessments in literature, we don't actually make sure that it's at least 24 hours. And remember, if you damage the kidney in some way, the serum creatinine doesn't rise two hours later. Right. That's not going to happen. So you need to at least, if you're going to call it related to the drug, at least make sure they've received it for about 24 hours. Then look to see they're still continuous. I said go back to the index. If you go back to the index and look at the nephrotoxins, you want to make sure that the drug was still being administered as the drug continues to rise and see and assess if it wasn't recovery or if it was continuing to rise, maybe it wasn't drug related because the drug was discontinued. And then even after, even while the serum creatinine is rising, if you give a drug, it could be worsening the situation. Right. So that's a drug-associated event. Determine nephrotoxin causality. Think about, you know, in an ideal world we'd have a lot of ways to figure out in the test to see if the patient actually has and is drug-induced. But look, we don't do biopsies on everyone. So you're not always going to get to your answer. Maybe you have some additional laboratory tests that could help you. But you're doing this retrospectively for research. Maybe you don't have all that information. So you're going to have to work with what you have. Sometimes the only thing you have is to figure out if the serum creatinine is stable or unstable prior to the indexed serum creatinine. Consider nephrotoxic burden and realize that induced or associated management is necessary. Okay. Thank you for your time.

standardized taxonomy

acute kidney injury

acute kidney disease

diagnosis criteria

nephrotoxic burden

evaluation