Okay, good morning everybody. Can you hear me okay over there? Thanks. Very moving plenary session we had. So I practice critical care medicine in Clearwater, Florida. It's sunny but not as cold over there. And one of my interests has been quality safety and process improvement in the ICU as medical director, which brings us to the problem with acute kidney injury in the intensive care unit. Disclosures. There's an honorarium for presentation. Acute kidney injury. It's a major issue, major problem, and it occurs quite commonly in intensive care unit. It's more common and expensive than many other acute medical conditions, including myocardial infarction and even sepsis. It occurs in about 57% of patients on day one of their ICU stay in a mixed med-surge ICU. 42% of critical patients with sepsis may develop AKI, and there's an overall 25% mortality rate with moderate to severe AKI. About 23.5% of AKI patients may end up receiving renal replacement therapy. Disclosures vary on the amounts from 7% to 8% up to 23%, 24%, and the annual cost is huge at $5.4 to $24 billion. So acute kidney injury is an increasingly common and potentially devastating complication in hospitalized individuals. Affects nearly 7% to 18% of hospitalized patients, and studies show up to 50% of critically ill patients will develop some form of AKI. AKI is ranked among the top in terms of potential inpatient complications. When the kidney's damaged, there's a very phenotypical process that occurs. You stop making urine, creatinine goes up, you get a metabolic acidosis. Regardless of the type of injury, whether it's just hypertension, sepsis, other forms of shock, or metabolic issues, diabetes, or history of hypertension, complicated by these new events. But the end result is low urine output and increased creatinine, which are late markers. So it can occur quite rapidly, typically within 48 hours of an insult, and progressively worsening loss of kidney function. Only about 6% of acute kidney injury cases advance to requiring RRT, so that's one study showing a smaller number. There's a U.S. study compared to the previous European study showed a larger number. And we stage using the Kodigo criteria with mild AKI, stage 2 moderate or severe in stage 3. The criteria are good for epidemiological studies, but difficult to apply at the bedside. So it's often largely a clinical diagnosis, and retrospective usually when the creatinine hits a higher number than on admission or through the progress of patient stays in the hospital, whether it's on the floor or in the ICU. So it's defined in stage 1 as a 1.5 or 1.9 times increase in baseline, and more than a 0.3 increase in milligrams a deciliter, or urine output of less than half a cc per kilo for 6 to 12 hours. Stage 2, as you can see, increase in baseline 2 to 2.9 times, or reduction in urine output for 12 hours. And then stage 3, a 3 times greater than baseline, or anuria for more than 12 hours. So one in three patients with AKI were readmitted to the hospital or ED, or died within 30 days of hospital discharge. That's a significant problem with 30-day readmission and mortality. And tests assess the early risk of AKI in conjunction with clinical evaluation can improve patient outcomes. AKI is difficult to identify and diagnose before it's staring you in the face. And early detection, as in many other things that we've talked about here at the meeting, that have been talked about at the meeting, time is important. Maybe not as critical initially, like sepsis or trauma, but certainly there is a significant time factor. If you recognize the fact that there is injury going on, a potential injury, then early evaluation is helpful in reducing the risk. So a number of susceptibilities in exposure to AKI have been identified, but there is no single risk factor or disease state that clinicians can use to qualify a clear risk profile. As I said, there are multiple different insults that can occur that can end up with the end result of increasing creatinine and low urine output. As you can see, there are acute risk factors there on the left-hand side, multiple from sepsis, pneumonia, medications, hypovolemia. And as the injury progresses through the course, from injury to developing dysfunction or decreased GFR and overt renal failure and death. Patient risk factors include advanced age, female sex, African American origin, chronic kidney disease is a preexisting problem, chronic heart disease, lung disease, metabolic issues, chronic diabetes, malignancies, anemia, and dehydration can worsen the situation. So in retrospective studies have found about 31% of patients had an avoidable AKI, potentially avoidable AKI, had unexpected delays in diagnosis, about 43% of patients, and 54% had inadequate risk assessment at the time. And about 79% of moderate and severe AKI cases were not identified by reporting physicians. So they're not recognized. The economic and health burden of acute kidney injury is staggering. The numbers are very high, a two to three-fold increase in length of stay, hospital costs, readmissions, development of CKD, especially if those are recurrent episodes of AKI and hospital mortality, six to 13 times worse than if you didn't get AKI. Sepsis and acute kidney injury are often comorbidities. As you can see there with sepsis, 1.6 million patients, about 250 to 270,000 patients annually can be afflicted, whereas in AKI, it's a much higher number, and oftentimes, as we've seen, unreported 3.2 million patients, leaving about 1.1 million patients about to begin to more serious disease. So they have similar economic profiles. Sepsis, very expensive. AKI, very expensive as well, almost $10 billion plus in cost, increasing mortality, length of stay, hospitalizations. And mortality doubles in patients with sepsis and acute kidney injury. So if you have sepsis by itself, mortality rate's pretty high, but then if you add AKI to that, it becomes an even bigger problem. This graphic from Kumar's study from 2006 shows that for every hour's delay in getting an appropriate antibiotic, when shock is developed, increase in mortality rate by 7.6% per hour. In renal failure, we notice that there is a significant increase in mortality as you go further into the time course. For sepsis, we use biomarkers such as procalcitonin, produced by numerous organs when there's a significant systemic inflammatory process developing, and we see an elevation in procalcitonin in the first three to six hours, and over the next 12 to 24 hours, we should start seeing an improvement if the patient's adequately treated and source control has been provided. We know that viral infections don't express an increase in procalcitonin, as has been verified by the COVID pandemic, a great way of distinguishing having bacterial and or viral infection, one or other or both. So we've used procalcitonin as a biomarker for looking at outcomes data in terms of antibiotic reduction, length of stay reduction in the regular floor patients, as well as ICU savings by reducing antibiotic exposure and reducing antibiotic resistance and reduction in C. difficile. All these have been brought out by using a biomarker in the appropriate fashion to monitor, identify and monitor disease process. Going back to AKI, in a parallel, we know it's potentially worse for individuals than maybe an ST elevation myocardial infarction. Mortality rate for MIs is about 14% versus 30% for acute kidney injury. Commonly patients undergoing major surgeries, particularly cardiac surgery, there is an increased risk of AKI following surgery from hemodynamic factors, bypass, and maybe dye exposure prior to surgery with cardiac catheterization, leading to increased, again, mild risk, mortality going up with moderate injury and severe injury quite significantly, and affecting the 90-day mortality as well as the hospital mortality quite significantly. AKI following cardiac surgery procedures certainly causes a significant problem with increased length of stay, cost, and readmissions, as you can see with the three different graphics there on the right-hand side, causing a three-fold increase in cost, length of stay, and readmission rate. Which brings us to the urine test, the nephrocheck test, which is the TIM-2 test and the IGF-BP7, to elucidate on that in the next couple of slides. So the nephrocheck test is a urine test requiring fresh urine sample. It's been FDA-cleared test for the risk assessment of AKI in patients who have been at risk of exposure of an event that could put the patient at risk. It's intended to be used in conjunction with clinical evaluation in patients who currently have or have had within the previous 24 hours an insult that would give rise to a risk for kidney injury. And it assesses the patient for risk of significant possibility or probability of getting acute kidney injury in moderate to severe range at stage 2 or 3 AKI in the next 12 to 24 hours. And it's intended for use in patients over the age of 21. And the two molecules are the tissue inhibitor, the teroproteinase-2 and the insulin-like growth factor, protein binding, binding protein 7, as you can see. And they're elucidated from the proximal and the distal tubules there. And when there's a stress to the kidney without overt injury developing, these proteins are released and it's the product of the two that produces a risk index. And that's been shown to be very predictive of impending renal injury if the issues aren't mitigated. So it's been a significant improvement in the past 60-plus years of renal testing. Previously, we just had urine output and creatinine, but this marker in the urine mechanistically is a relevant biomarker for acute kidney injury, identified the TMP2 and IGF-BP7 as relevant for early kidney stress. In over 300 candidate patients of AKI biomarkers, including Engal, Sustatin-C, Kim-1 were studied and analyzed via two multicenter observational clinical trials across 37 sites. They showed that these two protein markers had the highest validity for predicting acute kidney injury before you see an elevation in creatinine, which is key. Because once the creatinine goes up, you know, 50% of the renal function has already been affected. So this is an early marker of renal stress predictive of renal injury, and in particular in patients who've been exposed to shock, sepsis, major trauma, and surgery. So the AUC for these markers are significantly elevated, and then the product of those two produces a significant AUC of 0.77 and goes up to 0.8 when you combine the two. The AKI risk is really a product of the tympanomethalonase protein and the insulin-like growth factor in units, in nanogram. If the level is less than 0.03, there is very low risk of going into AKI versus a level of greater than 0.3. The significance of a negative AKI score is the patient is unlikely to develop moderate to severe AKI within the next 12 hours, but a positive level greater than 0.3 significantly increases the risk to developing moderate to severe AKI over the next 12 hours, unless you do something to mitigate the problem. So as you can see here, the nephrocheck test identifies the risk of AKI with a high sensitivity and acceptable specificity. So the urinary tymp 2 IGF BP7 level is greater than 0.3 identified patients at risk. It's a high sensitivity of 92%, and adding the two together increases the AUC from 0.7 to 0.8. The clinical cutoff was selected to identify the majority of patients at risk so you can intervene on those patients. So if you have a test result that shows patients at risk, there are things that we can do to mitigate AKI from developing. And as you can see, the sensitivity there is very high, 92%, negative predictive value being very high at 96%. So you're really predicting those patients who won't develop AKI versus those who will. And patients with a positive AKI risk score have a greater than 25% chance of developing moderate to severe AKI within the next 12 hours. You can see here the specificity is sacrificed for a better sensitivity on the previous slide. Positive predictive value being only 27% in this setting, and 31% in the smallest study. So the AKI risk scores are substantially elevated for intended use patients with AKI. In healthy subjects, patients without any history of kidney disease, and patients who develop renal insult later on, the risk score goes up higher. And patients with stable chronic disease, like chronic renal failure, diabetes, hypertension, or cardiac disease, heart failure, do not have elevated baseline levels. So what we're seeing here is kidney under stress. You see an increase in injury. You see an increase in the TIM-2 IGF BP-7 score. And ultimately, if it goes up higher, you get dysfunction and death. So the FDA has cleared the test as an aid to risk assessment for the acute kidney injury, and specific to AKI. It's an easy, fast. It's got a 20-minute turnaround, and it requires a fresh sample of urine to be tested, not a sample that's been sitting in the collection bag for several hours. So how do we use this? So the early risk assessment has an applicability in the ICU. And our first real experience, the major studies were in cardiac surgery patients, where we know patients at significant risk. So this is a case from one of our patients, a 77-year-old male, post-op aortic valve replacement for aortic stenosis, chronic atrial fibrillation, post-op, comes out on mirinone and norepinephrine. On day one, as is common with most cardiac surgery patients, the weight gain, three kilograms, oxygen saturation's at 97% on three liters. The TIM-2 IGF BP is 1.5, so it's elevated. And because of that, patient received fluids to improve renal function, to improve renal perfusion. Previously, what the surgeons would do, quite typically, would be first of day one, their weights up, there's diarrheas in the patients. But a lot of that fluid's third space, and it probably wasn't helpful to diarrheas on the first day. Patients not having any trouble oxygenating, it's only on three liters of oxygen, no distress. But those patients who were given diuretics on day one, we found a significantly increased risk of AKI over the next two or three days. So this creates a problem with increased length of stay, cost, and potential for worsening relationship. They continue to diarrheas just to get fluid off because the weight's up. So on day two, we're seeing a weight gain of 6.4 kilograms. Again, the patient's oxygenating well on two liters. The TIM-2 now has started to come down to 0.84, but there's a poor response to Lasix being started at a modest dose of 20 milligrams twice a day. As you can see, on day three, weight gain continues to go up. Patient's oxygenating well, 98% on Roumere, TIM-2 level has come down nicely, and the patient, because they didn't respond to diuretics, was starting on aquapheresis. But as you can see from the graphic, the stratum came down, creatinine stayed in the normal range throughout that time period. Predictably, historically, what would have happened was they would have given diuretics, there was inadequate intravascular volume, and the creatinine would have gone up, you went into AKI. But the signal tells us to hold off on the diuretics, kidney's under stress, and as the TIM-2 comes down, the patient still didn't respond to diuretics, so then we picked an alternative mode of getting fluid off without sacrificing renal function. That was for 24, 48 hours, and then patient's urine output picked up and started to diuretize well with low-dose diuretics. So multiple patients can be at risk with getting AKI. The average ICU patient, cardiovascular compromise, or patients with respiratory distress, or respiratory complications, ventilated patients, can be at risk. In this case study, it's pre-op patient information showed a 68-year-old female, pre-op body weight 60 kilograms, history of hypertension, COPD, colon cancer, baseline creatinine 0.4, patient underwent abdominal peritoneal resection from malignancy, but then had post-operative signs and symptoms of potential sepsis, just diagnosed from bowel leakage. Patient was on a ventilator, creatinine was still low at 0.5. So what are we concerned about? The patient going into sepsis, maybe significant renal hyperperfusion. The PCT was going up, patient's at risk of antiseptic, is on antibiotics, getting fluid resuscitation. So what can we do to help mitigate in this setting? Well, with dynamic measurements of fluid status, we're using things like passive leg rays to assess fluid responsiveness, get the patients adequately resuscitated fluid-wise, discontinuing nephrotoxic agents, maintaining good volume status with hemodynamic monitoring, oftentimes now almost always non-invasive, and monitoring frequency of serine creatinine, frequently serine creatinine on a daily basis, urine output hourly, and maybe getting a renal consult earlier. This has been shown to be beneficial by using the Kidego kidney bundle guidelines there, using what we talked about, reducing exposure to toxic medications, changing for alternative medications as and when appropriate, maintaining adequate volume resuscitation, blood sugar is being kept under good control, sending more urine studies with serine creatinine, electrolytes, urine microscopy, and maybe an ultrasound at that point, and if the patient is still, despite adequate fluid resuscitation, not putting out adequate urine, then maybe getting a nephrology consult at that point, but certainly not further injuring the kidney if that can be avoided. You can see there in the post-op cardiac surgery patients that following those particular guidelines certainly showed a significant improvement in development of acute kidney injury in those patients. So again, back to that patient. We saw the baseline serine creatinine was 0.4, getting to 0.5, elevated procalcitonin, and on post-op day four, patient is on antibiotics, is TNM, metronidazole, vancomycin, which probably you'd want to substitute at that point. Serine creatinine has gone up to 0.9 from 0.4, so technically AKI on that point. Urine output is still very low, 30 cc's per kilogram on average, just at the 0.5 cc's per kilo, so you want to try and improve on that. Again, volume resuscitation, which is evidence-based using dynamic measurements like changing SVI if the patient's fluid responsive or not to boluses or just maintenance fluid. And so fluid resuscitation, avoiding nephrotoxic agents is key, and monitoring the patients without adding more stress. Over the following 12-24 hours, PCT is coming down, and we see an improvement in patient's outcomes with the interventions. The risk score from the TIM-2 is very elevated, 3.4, so the patient was clearly at increased risk of developing worsening renal failure. So the BRAM's PCT test, bactericepsis, is cleared for risk assessment at the front end, also for monitoring treatment response for antibiotic stewardship and decision-making in antibiotic therapy and discontinuation, and that's been well-born out in the literature for antibiotic therapy for patients in the emergency room going through the hospitalization, and even shown to benefit from community-acquired pneumonia as well as COPD exacerbations and sepsis. So the nephrocheck, in comparison, also is an early tool for testing for patients at risk before the creatinine goes up, so you can implement a care plan to resuscitate the kidneys and prevent further deterioration of kidney function, which has its significant problems in morbidity, mortality, length of stay, and cost. So with the early identification of patients at risk, there is an opportunity for management strategies that may attenuate AKI severity, thereby impacting morbidity, mortality, length of stay, and cost associated with developing AKI. This patient from our service, a 68-year-old female seen post-op in the cardiac surgery ICU, had a left atriotomy on bypass for excision of left atrial mass, history of atrial fibrillation, mass have been seen on TE prior to an ablation for the AFib, so it's an incidental finding. Post-op day one, significant fluid weight gain of five kilograms. Creatinine was normal range. The TIM-2 was elevated 0.94. Patient was needing 10 liters of oxygen for oxygenation on high-flow oxygen. Post-op day two, 8.5-kilogram weight gain. Creatinine's going up. TIM-2 is elevated to 2.23, so we weren't going to stress with increasing diuretics, but still adequately oxygenating in 12 liters. By day three, creatinine's still in the stable range. Oxygenation's gone to 60 liters per minute, 70% FiO2 heated high-flow, and the T-2 has gone up to 2.49. As you'll see, weight gain continues, and what we're seeing is a significant change in the TIM-2 level, again, not stressing the kidneys by further diuresis, but then by day three or four, once the risk has been mitigated, as you're seeing where it reduced TIM-2 level, we can start diuretics. If diuretics don't work, then we go to aquaphoresis or CRRTs to remove the fluid. So if the patient's relatively stable, not getting into worsening hypoxic failure requiring we want to avoid intubation ventilation, then you're monitoring the patient for respiratory distress or not, and then once you're able to safely get the fluid off, get the fluid off. Diuretics work, that's fine once the marker's come down significantly, otherwise we saw that if we added diuretics too early, then you start getting an elevation in creatinine, and then you're forcing AKI development, which is what you want to avoid. This is an algorithm that's put together by our pharmacy department, it's a little difficult to read, but basically the key points there is if the patient's hypotensive or not making adequate urine, fluid assessment, non-invasively, you're looking to see whether getting the fluid adequately on board helps improve urine output, we stick to urine output, and if there is no significant urine output over the next four hours, despite adequate fluid bolusing and resuscitation, then you start the other mitigation, things like avoiding nephrotoxic agents, doing hourly urine outputs, and controlling diabetes, and getting a nephrology consult, and then alternative modes of getting fluid off if and when necessary. Putting this protocol into place, we're seeing a reduction in AKI, we've certainly seen it in the cardiac surgery patients, where it's more almost on a daily basis we're preventing this from happening. On the med-surg side, it's a little bit more difficult because it's such a different variety of patients, but we're trying to put this into place to mitigate renal failure in these patients. It's a strategic goal across our system for the next year. So to summarize, biomarkers can help improve disease management, whether it's in sepsis or in renal failure. Renal failure creeps up on you, sepsis may be, even as we've already discussed in many meetings, sepsis isn't always so easy to identify early on, it's very difficult initially sometimes, it's not always straightforward. The renal failure creeps up on you, on patients you kind of expect it, but you don't see it until it's there, and then when the creatinine's going up, as I've said, you've got 50% of kidney function already gone, so that can be a problem. So the earlier you detect it, the better, and we're feeling that using this marker in our system certainly has helped in the identity, identification of patients at risk, and mitigating the risk by putting in the Cadego kidney resuscitation guidelines earlier than we would have done otherwise. That's the disclosure slide. That's the end of the talk, any questions?

acute kidney injury

intensive care unit

kidney damage

early detection

nephrocheck test

biomarkers