All right, that's a hard act to follow, so I am going to try my best. Well, thank you so much. I'm Pranav Garimella. I'm a nephrologist at UC San Diego, and over the course of the next 35, 40 minutes, I'm hoping to give you an overview of cardio-renal syndromes. We've spoken about the interaction between the liver and the kidney, the lung and the kidney, and we'll talk a little bit about the heart and the kidney now. These are my overall disclosures, nothing relevant to this talk specifically. This is the outline of my talk. We'll talk about the definition and perhaps pathophysiology of cardio-renal syndromes and how our understanding has evolved over the last 20, 25 years and what has worked, what has not, and perhaps reasons for this. And then I'd like to spend some time talking about creatinine and how we've used that as a biomarker and perhaps some of the limitations associated with it, resulting in treatments that are no longer used or perhaps endpoints that should be re-evaluated in clinical trials. And then I'll get a little bit into the weeds of decongestant strategies, particularly with a focus on diuretic resistance, because that's what we end up seeing first up before anyone else decides to do any more invasive procedures or use extracorporeal therapies. And then I'll close out with two or three slides talking about goal-directed medical therapies in heart failure in patients with kidney disease and why that's important. So what is cardio-renal syndromes? I think we've spoken about the complexity of understanding how to define any of these multi-organ syndromes. Really, there was never really a good clinical scenario. Essentially, it's a disorder of the heart and a disorder of the kidney. One can cause the other. The other can cause the first. How you define it depends perhaps on the acuity, the timing, and the other circumstances that are involved. And so for the longest period of time, we really didn't have a good definition. And like Dr. Kashani said, about 15 years ago, a group of really smart people came together and said, well, how about we give this a framework? Let's classify this such that people have an understanding of perhaps what the driver is in each situation. And does targeting that improve outcomes, rather than throwing the kitchen sink at patients? And so you've got these five types of cardio-renal syndromes that are outlined here. And as intensivists, perhaps the ones that are most relevant to you are the type 1 cardio-renal syndromes, which you'd see often if you're in the cardiac ICU, wherein acute changes in cardiac function result in changes in kidney function. You might also see certain situations where acute changes in kidney function result in cardiac function changes. And then we'll perhaps talk a little later about type 5, where you have cirrhosis, sepsis, and some of these other organ crosstalks that we've already alluded to, and how they play into the interaction between kidney function and the heart. I'm not going to focus on type 2 and type 4, because they're kind of chronic states of the first and third. So if you look at kidney function in people who have cardiac disease, and specifically heart failure, what you'll notice is that irrespective of the type of GFR measure, whether it's MDRD, whether it is CKD-EPI, and these are different GFR equations in stable populations, you have a high prevalence of chronic kidney disease. Over 50% of patients with heart failure have what could be defined as having CKD, and that's a huge number when you come to think about it. Only about 10%, 15%, maybe up to 17% of the general population, even up to the age of 75, have chronic kidney disease defined by these same criteria. And this was a really nice study that looked at about 3,000 patients, and they looked at both men and women, and found that chronic kidney disease, stage 3 and beyond, was presented up to 45 people, if you look at 45% of the population, and 65% had moderate to severe dysfunction. But when you go back and look at these patients' charts, this was by GFR from the database, from the ADHEAR database, and then you go back and look at their charts and see how many of them actually carried a diagnosis of kidney disease, it was 34%. So not only is it prevalent, it's probably under-recognized, and we tend not to refer patients for kidney disease management early on. But this has implications. Chronic kidney disease and chronic heart failure or acute heart failure are a bad combination. This is data from about 2,000 patients who had chronic stable heart failure and a low ejection fraction. So both these are in patients with low ejection fraction, and you see that even if you cut it at a GFR of greater than 75, by the time you drop to a GFR between 50 and 60, you have a decrease in survival up to three years, even patients who have stage 3 or 4 chronic heart failure with a reduced EF. So the lower your GFR, the higher the mortality. And it doesn't matter, this is looking at Cockcroft-Gall, there was MDRD, doesn't matter what measure of kidney function you look at. As long as you have kidney function, the worse it is, the worse your outcomes are in both chronic and acute heart failure. And this is a great association. This shouldn't come as a surprise to all of you. You see this all the time, you know. But a lot of these data that I showed you just now hinge on GFR measurements, which happen in a stable setting and shouldn't really be used in AKI. And the staging of AKI, as we've learned today, has evolved over time. We've had the AKIN criteria, we've had the LIFO criteria, and now, as of about a decade or more, we have the KDGO criteria, which essentially talks about a rise in creatinine from 1.5 to 2 times its baseline, or at least a 0.3 elevation in baseline creatinine. And that's stage 1, going all the way up to stage 3, which is 3 times or more the indication for renal replacement therapy. And then you also have matching urine output criteria. This is what's often used in a lot of cardiorenal syndrome studies. That's the easiest to detect, and perhaps you have most power when you look at that as an outcome. But the cardiology literature tends not to call it AKI, they've historically called it worsening renal failure. And perhaps there's a reason for that, and we can argue whether it's semantics or whether there is actually worsening renal failure, or whether there's true kidney injury happening that's driving some of these outcomes, and I'll show you why. So this is a really large meta-analysis of studies that included patients with acute heart failure and chronic heart failure, and looking at the effect of worsening renal function. So in people who actually had sequential measures of kidney function, what happened when they met the criteria of worsening kidney function defined as a rise in creatinine of at least 0.3? And overall, like I showed you earlier, people who have worsening renal function tend to do worse in acute heart failure and in people who have chronic heart failure. And you can see that the effect sizes are not tremendously different. So overall, chronic kidney disease is common in heart failure. Change in renal function or worsening renal function occurs in 20% to 40% of people with acute heart failure, and that too is associated with significant adverse outcomes. So if we take a step back and say, well, what's going on exactly? Why are we concerned about this? The historic view, and perhaps the most common view previously was, well, the heart is a pump. As some of my nephrology colleagues like to say, the most important function of the heart is to pump blood to the kidneys. And sometimes that fails. And so when that fails, you have decreased cardiac output, you have decreased perfusion, perhaps increased congestion, and then you have kidney injury. But we've learned that it's not quite as simple as that. You have cardiorenal syndromes developing in patients who have completely preserved ejection fractions, both in the acute and in the chronic setting. Clearly, it is more than just pump failure. And I think what we have now recognized over the last decade is that there are neurohormonal changes, there are activations in the RAS system, there is an inflammatory cascade that happens between the renal angiotensin system, leading to decreased GFR, there is diuretic resistance, there is increased sodium avidity at the level of the kidney. And then we realize that the venous congestion that is really driving all of this is an important predictor of outcomes. And perhaps that is what we need to be looking at in order to improve kidney and cardiovascular outcomes in this population. So all these axes are really important when we consider the pathophysiology of cardiorenal syndromes. So I like to think about cardiorenal syndromes perhaps not just as cardiorenal syndromes. As we've shown this figure, the goal of this figure really is to show you all the alterations that happen when we think about someone with cardiorenal syndromes. So you have cardiorenal, cerebro, hepato, entero, renal syndromes. Now that's really, really complicated. But the truth of the matter is you never have any one or two organs in isolation. There is crosstalk between all these organs happening simultaneously. And to look at this through the lens of one silo and say, this is the mechanism that I'm going to fix that will result in all outcomes improving, is I think perhaps a little naive. But we know that there are changes in the liver. There is hepatic congestion that happens. At the level of the kidney, you have venous congestion. You have interstitial pressure that's increasing. You have pressure increase in the Bowman's capsule and in the lymphatics. In the gut, you actually have edema. You can have increased intra-abdominal pressure, which is an important driver of worsening renal function when people, or even diuretic resistance, when you aren't able to adequately diurese someone. And then there is the perhaps emerging concepts of the gut-kidney interaction in some of these volume overload states and how the microbiome can affect some of these inflammatory mediators. So again, just thinking about the fact that while decreased forward flow is a component, there are several other things that go into the development of cardiorenal syndromes. And I'll show you a little bit about what I'm talking about regarding forward flow. So this was a study done in the Netherlands. It's about 15 years old now. Wilfred Mullins, who's done a tremendous amount of work, sorry, in Belgium, not in the Netherlands, who's done a tremendous amount of work in cardiac failure, looked at 145 patients admitted with acute decompensated heart failure. And they actually put in pulmonary artery catheters into all of these patients off the bat. And they said, well, let's treat them aggressively and see what happens. So on the left top here, we have worsening renal function prevalence. And that's what is there in all these graphs. So the first one here shows the association between CVP and the prevalence of worsening renal function. And the first thing you note is that as the CVP rises, the worsening renal function increases. So a higher CVP, suggestive of higher congestion, is associated with worsening renal function. And you can see here at the bottom, you've got creatinines that aren't too different until they get to about here, where a CVP of 24 actually has a significantly worse creatinine. So in the bottom two graphs here, this is systolic blood pressure, and this is pulmonary capillary wedge pressure. And they look pretty flat. There doesn't really seem to be an association. And when you think about the pump and cardiac index, what you see is that a low cardiac index of 1.4 is actually associated with lower prevalence of worsening renal failure, while a cardiac index of over 2.6 was actually associated with a higher prevalence. And this is how they defined it. So a serum creatinine more than 0.3 during the admission. And in the same study, they said, well, let's look at what are the predictors of developing worsening renal failure. And it turns out that it was the CVP, which was much more strongly associated than baseline cardiac index. So again, the measure of congestion was really predictive of developing worsening kidney failure. And they then used this to risk stratify people and say, well, what is the contribution of the CVP and the cardiac index in conjunction at the time of PA catheter removal? So at the end of treatment, when they thought that patients were perhaps optimized. And you can see here, this is GFR in milliliters on the y-axis. And then these are the four different scenarios. So you had high cardiac index, low CVP on the leftmost. And then you have low cardiac index, high CVP. So these two are high CVP. And the first two are low CVP. And immediately, you can see that patients who have a high CVP, irrespective of their cardiac index, tend to have lower GFR. So again, suggested that venous congestion is a really important driver of worsening kidney function. So this was a much larger trial. This was the ESCAPE trial. And this was done in 575 patients. They all had pulmonary artery catheters right off the bat when they presented. And this is the association of EGFR, BUN, or BUN to creatinine ratio, so different measures of kidney function on this axis. And on this axis here, you have creatinine. So this is the 1, 2, 3, 4. And then you have the different cardiac index tertiles. And what you see here is that, however you look at it, lower cardiac index was not really associated with worse creatinine or with worse BUN. And so it seems that this reduced cardiac index is not always the primary driver of cardiorenal syndromes or worsening kidney failure. And so in the same study, what I showed you was baseline. So we said, all right, let's look at cardiac index across the hospitalization. And you can see this is relative change in GFR. So did the GFR get better or worse? And this is cardiac index at baseline. This is cardiac index on the last day of hospitalization when the PA catheter was removed. This was cardiac index on the day they thought they were optimally optimized. And this was cardiac index change from first day to last day. And however you slice the data, these regression lines are pretty flat, again, suggesting that cardiac index, at least in this population, in this setting, was not the main driver of worsening renal failure. Much larger study, again, 2,500 patients in the Netherlands and Groningen. And you have EGFR up here. And then you have CVP on the y-axis. And you can see that for every cardiac index, with low, normal, and seemingly high cardiac index, as the CVP increases, your GFR declines. So there's really an important role that venous congestion plays in the development of worsening renal function and in cumulative patient survival overall, interestingly suggesting that people who were discharged with low CVPs tend to do better overall at the end. So when we think about what's happening then at the level of the kidney, I think it's really important to recognize that we not only have a venous congestion, but there's also increased interstitial pressure. There's increased pressure at the renal capsule. So you have a decrease in the transglomerular pressure. So the driving force to continue filtration is being dropped persistently as you have congestion that's increasing. And all of this leads to activation of the renin-angiotensin system. You have sodium and chloride reabsorption as well. And the congestion tends to worsen. And I kind of think about this as similar to cerebral perfusion. You shouldn't just be worried about the map. You should really be worried about the difference between the CVP and the map and the driving force in the glomerulus. So again, targeting the map may not be the right thing, because there are other things at the level of the glomerulus that we're not taking into account. And perhaps that's one of the reasons when you look at all these therapies for cardio-renal syndromes or improvement in outcomes in patients who have cardio-renal syndromes, nothing's really panned out. A lot of these are looking at improving, perhaps, not just blood flow, but improving maps. And you have vasopressors here. You've got renally-dosed dopamine, which was a thing a few years ago. But none of them are truly used in clinical practice, because while some of them have shown to overdo and some of them have shown to augment adrenal output, they really have not changed the needle on kidney or cardiovascular outcomes short or long term. And so that brings me to the question, why is that happening? And so when you think about creatinine and change in creatinine in patients who have heart failure, one of the things to realize is that not all rise in creatinine is the same. All these situations can give you a 0.3 to 0.5 elevation in creatinine, but that doesn't mean that there's true AKI happening in all of them. Creatinine is a delayed biomarker of change in kidney function. Not only that, but it's influenced by age and muscle mass, as we know, which is a significant component, which a lot of our patients with heart failure have very low amounts of. And then there is this exponential relationship between serum creatinine and GFR. And one thing that we perhaps don't take into account all the time, but which has been spoken of earlier, is the impact of volume overload itself on creatinine. And we know that there is actually a dilutional component and people who come in volume overloaded when their creatinine goes up with diuresis, one of the first things that trainees say is, oh, the person's over diuresis, let me stop the diuretic. And whether that's true, whether the patient is only unmasking their underlying kidney function and is actually decongesting is something we really need to consider when treating these patients with heart failure. And so, Dr. Naira spoke about a renal angina index and we've been in search of that one biomarker for the kidney, what is the troponin of the kidney, and we really haven't come across it because the kidney, like Dr. Kashani said, is so complex that each segment produces different biomarkers and which one do you use in which setting. We've come to the conclusion that some of these biomarkers are better at identifying high-risk patients, but really, we haven't yet come to the conclusion of which set should be approved in which disease state, sepsis versus hepatorenal syndrome versus cardiac disease. But nonetheless, some of these biomarkers show significant sensitivity for diagnosing AKI early, much before creatinine. And so, this was 83 patients who had acute decompensated heart failure and they also had AKI, or at least a 25% reduction in GFR. But when you looked at the association of these biomarkers at predicting this outcome specifically, you can see that their AUCs are pretty crummy, 0.4, 0.5 to 0.65, I mean, that's just better than a coin flip. And you start to wonder, why is that? Why is it that all these biomarkers that have panned out well in sepsis and contrast AKI and other conditions don't do well in heart failure, whether it's predicting AKI or predicting persisting renal impairment? And this was a really nice study. So, this is a post hoc analysis of the Rose heart failure trial where Testania and Amma at Yale really looked at changes in these biomarkers, so NGAL, NAG, and KIM1, which are sensitive biomarkers for AKI. And then they looked at that in comparison to change in creatinine in these patients who have heart failure. And what do you see? There's really no change in any of these biomarkers throughout their admission period. So, whether your creatinine went down or whether your creatinine went up as much as 0.5 to 1.3, your biomarkers don't change. Well, if you then look at people in that same cohort who developed worsening renal function and compared them to those who didn't develop worsening renal function, you still see that the biomarkers don't change. So, even in people who we think are developing worsening renal function, the most sensitive biomarkers for kidney injury and heart failure don't actually go up all the time. And so, that begs the question, are our definitions of worsening renal function and heart failure truly worsening renal function? Are we shortchanging ourselves by using change in creatinine as a criteria for adverse event in clinical trials or to get approval for devices or therapies? And so, when you think about this, you can kind of box patients into this functional framework wherein you may have normal biomarkers or biomarkers are raised, creatinine is normal or the creatinine goes up. And depending on where they fall into this, your treatment may vary a little bit. At patients who have normal function or in people who have loss of function without damage, you might think that you could continue the treatment, but if you're aggressively diuresing these patients and you see biomarkers go up and creatinine go up, there may be a time where you might need to change your therapeutic approach. So, that would be established AKI, really. But interestingly, and the other interesting factor is that these changes in biomarker, these changes in creatinine are actually associated with the loss of, the rise of creatinine or worsening renal function is actually associated with better outcomes. So, this was a study done in patients with, this was the PROTECT study looking at patients with acute decompensated heart failure. About 50% of them had anemia. And interestingly, what was noted was that hemoglobin rise is associated with better kidney function. And so, hemoconcentration is better survival, sorry, not kidney function. So, hemoconcentration is associated with better survival. And they took this further and they said, well, let's look at the diuretic optimization strategies at dose trial. And so, we said at 72 hours, let's look at people who either had stable kidney function, improvement in kidney function, or worsening renal function. And let's see what happened. And what you see here is that compared to stable renal function in the blue line, worsening renal function actually did the same. But those who have improved renal function actually have a higher risk of death at 60 days. And that's really surprising and you start to wonder, wait, why do people with worsening renal function have the same degree of risk as people whose kidney function doesn't change? But when you have improvement in renal function, or what we now call improvement in renal function, they do worse. So again, goes back to, are we really looking at creatinine the right way? And is that our best bet of assessing it? And so then, we go from there saying, well, if we know that congestion is bad and we really want to move on to improve outcomes and we're gonna try and decongest them, this is our goal in heart failure. We're trying to take everyone who looks like on the left and convert them on the right. But we don't have tools other than perhaps diuretics who do them effectively. And there's no randomized control trial of diuretics, right? There is no randomized trial saying, we'll put someone on Lasix versus we'll not put someone on Lasix for acute decompensated heart failure. All the other drugs have randomized trials. Diuretics really don't. But we use them all the time. And the most common problem we run into is diuretic resistance. Turns out that diuretics actually need to bind to albumin in order to get secreted. Most loop diuretics are extremely secreted. They're not filtered. So they need to be protein bound. So in patients who have hypoalbuminemia, poor nutritional status, even getting that drug into the loop of Henle can be a challenge. In addition, they go through the same transporters that NSAIDs go through. They go through the same transporters that uremic toxins go through. So there's competitive inhibition for the drug to get into the tubule and get into the tubule without any kind of action. And so you have multiple reasons why a drug may not work. But still, this drug delivery and reaching the tubule is a small component in developing diuretic resistance as Terramartin and Testanib from Yale have shown really nicely. So this is one aspect of why you may not have adequate diuretic delivery in hypoalbuminemia patients where you have other drugs. Turns out that hypochloremia, in patients with heart failure, is a cause of diuretic resistance at the level of the loop. So that was the proximal tubule. And at the level of the loop, you have hypochloremia. And hypochloremia causes the macular denser which to sense chloride deficiency, which upregulates your adenine angiotensin system and you have sodium avidity. And in this study, that was really nicely done. You can see the odds of low diuretic efficacy increasing as serum chloride levels dropped. And they gave them lysine chloride and then that reversed. These patients, once their chloride, serum chloride improved, you had more urine output, increased loss of weight, and improved decongestion. And you can see here, low sodium, low chloride, the diuretic efficacy was lowest. Normal sodium, normal chloride, the diuretic efficacy was high. Even if you had normal sodium, low chloride, your diuretic efficacy is low. So hypochloremia is a big factor. We've heard about breaking phenomena, which is as you give successive doses of diuretics, the efficacy decreases. And this usually happens within a few hours. And this is thought to be due to increased sodium reabsorption, which can happen with successive doses. But the other thing that happens, which is probably more important, is distal tubule remodeling. And this was a really nice study done to figure this out. It turns out lithium and sodium are coupled in their reabsorption in the proximal tubulin in the loop. So if you give someone a loop diuretic and you see lithium excretion, you should typically see sodium excretion as well. And so in this study, they measured fractional excretion of lithium at baseline pre-diuretic. And you can see that fractional excretion of sodium and lithium is the same. Then they gave a diuretic, and they found that the fractional excretion of lithium increased significantly while the fractional excretion of sodium didn't. And so only about 30% of the increased excretion of sodium, which should be there when you look at lithium, was excreted in the urine. And this is after adjusting for dose of diuretic. So the diuretic was still getting to the urine. It was still getting to its site. But sodium was being absorbed in the distal tubule while lithium doesn't. So lithium is not getting absorbed. So again, there is hypertrophy of the distal convoluted tubule cells, which really leads to diuretic resistance. And then you have some diuretic resistance at the level of the collecting tubules as well. So the question is, now you have all these sites of diuretic resistance. What can you do about it? Is resistance utile? And I think not, because we know how these drugs act. We have diuretics for each of these segments. And so we could potentially leverage that knowledge to improve our outcomes. And I'll show you some data. But before that, when you give that loop diuretic, how many of you here check a spot urine sodium? Can I have a show of hands? Two. Three. We have three people in a room of nephrologists, intensivists, ICU people who really check urine sodium. And I want to emphasize that this is probably the best estimate of whether somebody is going to be diuretic resistance or not. There are multiple studies and prediction equations that have shown that having 50 to 70 millimoles of urine sodium come out at about two hours when the diuretic is at its peak is probably one of the most important predictors of diuretic response. And not having that shows you who's going to be diuretic resistant and who may need additional therapy. So what is this additional therapy? And this is the Yale protocol where they really upregulate, not upregulate, but they uptitrate their diuretics. So you give a dose of diuretic. If that doesn't work, you have diuretic resistance at two hours. The next dose at six hours is doubling the dose of the loop diuretic until you get about 200 milligrams of rosamide. And you can see that when you do that, when you have this protocolized strategy, you really have improvement in the urine output throughout. And the fractional excretion of sodium also increases. So again, you can get past that breaking phenomena if you actually appropriately dose diuretics. This is a much larger study just actually published this month. 401 patients across 18 countries where they looked at this, where they kept increasing that loop diuretic dose until they reached 200 milligrams. And the primary endpoint was efficacy. You can see that in this protocolized dose, the means sodium excretion was much higher. The cumulative natriurosis is higher. And there was about a one-day lesser hospital admission. So no mortality change short term, but you had one hospitalization one day less, which is, I think, an important outcome when you're looking at acute heart failure. We spoke about proximal tubular diuretic resistance. And then so if you can block with acetazolamide, this is the ADVOR trial. So a really large trial published about two years ago out of Belgium again showed that by giving acetazolamide, you can actually increase the likelihood of decongestion. Patients feel better. You have better decongestion at discharge. And you can see that the natriurosis improved as well. This is just a subgroup analysis. I'm not going to focus on that. And this was, again, a recent study looking at the addition of thiazides in an older population with acute decompensated heart failure. 230 patients, and they actually gave them hydrochlorothiazide along with IV diuretics. You can see the weight goes down. The change goes down. What's not here is that they actually had better patient reported outcomes at time of discharge, although the all-cause mortality wasn't different. You'll see that hyponatremia, hypokalemia are more. Impaired renal function was more. But then again, that begs the question again, what is truly impaired renal function when you're decongesting someone? And again, you can use metolazone. You can use tovaptan. You have aquaresis and diuresis above and beyond just loop diuretics. So again, multi-system, multi-segment nephron blockade is key to improving outcomes in patients with diuretics. SGLT2 inhibitors are a great class of drugs. Their diuretic response is a little different. They actually don't induce that degree of a natriurosis like some of our other drugs. But what they do, unlike loop diuretics, is they actually down-regulate the renin. They down-regulate aldosterone. They down-regulate the neurohormonal access. And so they have significant benefit for short- and long-term outcomes when you do that. Again, this is just a very small study, just published, 167 patients, multi-segment nephron therapy. This is in the entire cohort, but this is in patients who had diuretic resistance. So they used that urine sodium, then said, all right, how does that multi-segment nephron challenge work? And you see, once again, that if you can block each of these segments where sodium is reabsorbed, you actually have better outcomes short-term. So why not ultrafiltration? If our goal is just to turn them all into raisins, why can't we just pump them up to a machine and dry them out? Well, the unload trial suggested that there was better weight loss at that time, and then there was some improvement in patients for a risk of hospitalization as well. So this was followed up with the Caress heart failure trial about 12 years ago now, and everyone had to have type 1 cardiorenal syndrome. And they either were randomized to an aggressive diuretic protocol or a fixed UF rate right off the bat. And what you see is that there were actually no significant differences at 96 hours, which was one of the important outcomes. And then all of the ultrafiltration arm had a higher increase in creatinine. And so I don't know about your institutions, and I think that would be a great discussion as to how much of ultrafiltration you practice and what you see. It is making a comeback with a little more nuance to who and when to ultrafilter. But ultrafiltration right off the bat in everyone, perhaps, is not the answer. And maybe there is a subset of patients either based on biomarkers or diuretic resistance in whom ultrafiltration could work. And there is a whole host of targeted devices that are really looking to improve the renal function in patients with cardiorenal syndrome. And I'm not talking about your IABPs and impellers and all those cardiac devices, but really these are looking to decrease the venous congestion here. And these are devices that are put in a balloon in the inferior vena cava. You have arterial underfilling. So again, phenotyping these patients, I think, is really important. Not all of your acute heart failure patients are coming in for the same reason. Their physiology is not the same. So understanding where they fit in and perhaps then targeting devices according to that would probably be a really important part. So I'll close out with a few slides on goal-directed medical therapies, perhaps. And this is a really nice approach, which I think is a goal-directed approach to worsening renal failure in patients with acute heart failure. And I cannot emphasize the importance of a repetitive evaluation, whether that is urine sodium, whether that's clinical evaluation, or other biomarkers that you would use. And if you have occurrence of renal failure, I think it's important to assess diuretic response. Is the patient really diuresing? Are they decongesting? Are they having hemoconcentration? Is their albumin going up? And if all that is the case and the patient is doing better, I think there is probably the rationale to continue these therapies. If you have evidence of hyperperfusion, and I think this is where the intensivists and other cardiac intensivists kind of need to talk about, when do we put in these pulmonary artery catheters? When do we need to use inotropes? When do we need to use something other than decongestive therapies? And yes, there is probably a role for them. But we know, for instance, from ESCAPE, that not everyone coming in with acute decompensated heart failure needs a pulmonary artery catheter. You can get away without it. But that is when we, I think, have to really understand what's happening to the hemodynamic status and decide on pressors versus other kinds of circulatory support that you may have. And reassessing this diuretic therapy, using that urine sodium. Reassess that diuretically. Are you having adequate response? If you're not having adequate response, go up. Double the dose of the diuretic. If by 12 hours, if your diuretic response is still suboptimal, then you might need to add the combination therapy. And if all of that fails and you still have persistent decongestion, then you really have to worry about whether you need to call in for dialysis or isolated ultrafiltration. But these are ESC position papers on heart failure. I think they're a great read and go through this algorithm really well. And I'll close out by saying that while all that is an acute heart failure, it's really important to remember that we can actually affect change in the hospital when we start patient on some of these medications that are really cardio and renal protective in the long term. So this is Get With The Guidelines Heart Failure Registry, 365,000 hospitalizations. And this is the proportion of patients with heart failure reduced EF who were given these important classes of medications, ACE inhibitors, beta blockers, mineralocorticoid antagonists, ARNIs, or triple therapy. And then you can see that as GFR declines, the proportion of these patients getting these drugs decreases as well. And mortality increases. And in this really nice study of 4,300 patients, compared to all, so this bottom line here is ACE inhibitors, beta blockers, MRAs, either initiating or escalating their doses compared to stopping them or de-escalating them. And mortality is higher even in acute heart failure if you continue all these things. And I know that Dr. Naira said the KDGO bundle says stop the ACE inhibitors. But again, I think we need to be cognizant of who these patients are, what is the timing of starting or stopping these medications, and what is the impact on them. You know, if you already have established AKI, your creatinine is three, you're worried about hyperperfusion, do you really want to start someone on an ACE inhibitor at that time? Perhaps not. And we know that even outside of patients with kidney disease, just continuing these medications really is associated with better outcomes. And so the level of evidence in patients with kidney disease to use a lot of these medications is strong to prevent cardiovascular death and hospitalizations, not so much for all-cause mortality, but up to stage three and maybe even stage four, we have a fair degree of evidence to suggest better outcomes. So I think it's important that we re-evaluate our processes, our best practices in our hospitals, and make sure that patients who are appropriate to get these medications should get them even in the acute setting. Because there's evidence to show that if you started in the acute setting, the likelihood of that being continued is higher. I have seen numerous times, and perhaps I'm guilty of it too, saying ACE inhibitor at follow-up in the kidney clinic or with primary care. The number of times that patient is going to get readmitted before they can actually make it successfully to a kidney clinic or to a heart failure clinic is really high. And so again, if we can affect that change in-house, the likelihood of that being carried and having an effect is probably much higher. So I'm going to stop right here. These are my key takeaways right now. Congestion is an important factor. Worsening renal failure doesn't really always mean true kidney injury. And creatinine can sometimes be misleading. So think about that when we are assessing patients and look at them to see if they're actually decongesting. Distal tubal hypertrophy is really a major driver of diuretic resistance. And I think using a multi-segment blockade will really improve outcomes in patients with heart failure. We're seeing the first trials come out this year with multi-segment blockade. And I really expect that to explode over the next few years as we decide which of those segments are perhaps superior or do we throw all these medications at the patients. And we really need to optimize goal-directed therapy. So thank you so much.

cardio-renal syndromes

heart failure

biomarkers

diuretic response

nephron blockade

acetazolamide

goal-directed therapy