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Intro: The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.

Melanie: Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to listen as we examine the clinical trajectories of acute kidney injury in surgical sepsis. Joining me in this panel are Dr. Tezcan Ozrazgat Baslanti, she's a Research Assistant Professor at the University of Florida College of Medicine, and Dr. Azra Bihorac, she's the R. Glenn Davis professor in the Division of Nephrology, Hypertension, and Renal Transplantation at the University of Florida College of Medicine. Doctors, thank you so much for joining us today. Dr. Bihorac, I'd like to start with you to tell us a little bit about sepsis-associated acute kidney injury and their correlations. Tell us about how it's associated with increased healthcare costs, mortalities, anything you'd like to share about that.

Dr Azra Bihorac: Thank you for having us on your program. So as many of your listeners know, sepsis is one of the most common, expensive and inadequately managed syndromes in the modern medicine. Every year, about 1.5 million individuals in the United States are affected by sepsis, one out of the three hospitals deaths because of the sepsis and more than $20 billion is spent annually on treating patients with sepsis.

Now, the sepsis is really infection that affects other organs and can cause dysfunction of the organs that are not related primarily to infection. One of those organs is obviously kidney, among patients with sepsis, almost 60% of them will experience during the course of the sepsis acute dysfunction of the kidney, meaning that the kidney will not work properly and filter waste products of the metabolism in up to 60% of the cases with sepsis.

We also know that organ dysfunction with sepsis is associated with worse survival. And we also have demonstrated before in our work that among the patient with sepsis and acute kidney dysfunction, inability to recover from the kidney dysfunction can lead to worse survival. And that association was shown by other groups too.

So our interest was really to understand better whether certain trajectories of renal recovery affect outcomes with patients with sepsis and investigate these in more details.

Melanie: Thank you for that. So, Dr. Baslanti, how do you define and classify trajectories of acute kidney injury? And tell us a little bit about the prevalence of persistent AKI and AKI without renal recovery after sepsis.

Dr Tezcan Ozrazgat Baslanti: So we define AKI using KDIGO criteria with the changes in serum creatine compared to baseline. And recent guidelines key criteria, introduces us to use other dimensions, just the severity, how high the creatinine goes, but also duration and renal recovery. They define the rapidly reversed AKI by recovery of AKI within 48 hours of AKI episode start. And persistent AKI is characterized by persistence of AKI more than 48 hours, which may end with or without renal recovery at hospital discharge.

In our cohort, we have seen that 52% of the patients have AKI within the first 48 hours and then, overall 62% had developed AKI. Among those, one third was rapidly reversed AKI, the rest was persistent. So in the all sepsis cohort, prevalence of persistent AKI without renal recovery was 24%. We have seen the worst outcomes, both hospital outcomes and long-term outcomes, being in the persistent AKI group specifically persistent AKI without renal recovery group.

Melanie: Well then, Dr. Bihorac, as you're telling us how important early recognition is as crucial to provide supportive treatment, limit further insults, is there evidence that you can speak to on the fundamental mechanisms that may play a role in the development of sepsis AKI, microvascular dysfunction, inflammation, tell us what we know as of now.

Dr Azra Bihorac: I think we still do not know precisely why acute kidney injury occurs in sepsis. It's postulated that it's multifactorial, that it's a combination of the effect of inflammation and microvascular changes as you have implicated in your question that contributes to this.

I think that, overall, I would like to think about AKI in sepsis as a combination of both susceptibility and exposure. In other words, in other AKI models, we know that underlying kidney health predetermines in many ways how you're going to respond to acute stress of acute illness as an example of sepsis. So for the patients who are older and who have underlying impairment in kidney held, especially among elderly and those with chronic kidney disease, the susceptibility will be much higher, thus resilience will not be the same.

The insult by itself, in another words, how severe sepsis is in terms of infection itself is another mechanism that contributes to the development of AKI. In that sense, the inflammation and persistent immunosuppression that we know now is happening in the early stages of sepsis will be determining the framework of the development of AKI.

Melanie: Such an interesting correlation here. So Dr. Bihorac, sticking with you for a second. Speak about the clinical characteristics, resource utilization in hospital and long-term outcomes. How do they all differ between sepsis patients from different trajectories of acute kidney injury?

Dr Azra Bihorac: So, what we really were interested to understand is within the first 48 hours, most of our intervention for sepsis occur. That is our golden time. Forty-eight hours, we have to administer antibiotics to give fluid therapy. And we were interested to see whether in this first 48 hours, we can distinguish patients with the different trajectories.

And interestingly, we have seen that on the sepsis presentation, almost half of the patients already has some indications of acute kidney injury. Part of this cohort that has early sepsis, we think is due to inadequate resuscitation, meaning not receiving adequate fluid and will be very irresponsive to fluid therapy, will respond quickly and will implicate that their course might be less severe than others. This rapidly reversed AKI group actually show themselves in the first 48 hours. Those are the patients that we can recognize as early recoverers, maybe not put any more further invasive strategies of treatment to them and then focus on the group that does not recover within 48 hours. And those are the persistent AKI group.

Among those groups, we have demonstrated that inability to recover from renal dysfunction by the time of the discharge will be associated with need for renal replacement therapy. Almost half of these patients will need dialysis or CVVH and the mortality of 40%. So meaning that patients who do not recover their renal function to their baseline, half of them almost will die by the hospital discharge. Those are the short-term outcomes. These patients will require prolonged ICU admission, will require more mechanical ventilation, more use of vasopressor and so on.

In terms of the long-term function, we also see that amongst survivors, the ability to recover renal function at the time of the discharge will determine what happens to you a year from the discharge and whether you die or develop chronic kidney disease.

Melanie: Wow. So Dr. Baslanti and the message for this particular podcast, how can you translate the findings that you both are discussing today into potential treatment strategies and add to the promising pharmacologic approaches that are being developed and tested in clinical trials? Take this from research to bedside.

Dr Tezcan Ozrazgat Baslanti: So the key points of this research was that we have observed one out of two sepsis patients develop AKI. So the clock starts ticking at the moment of the sepsis protocol being initiated. And after that, two out of the three patients with AKI develop persistent AKI after three days. So this tells us that the initial effort needs to be focused on earlier reversal of AKI. And one out of two with persistent AKI did not recover their kidney function by the time of discharge. And one out of two with persistent AKI without renal recovery died in hospital. And one out of two of the survivors died or had severe functional disability one year after discharge. So this really shows the importance of preventing the AKI development, if not preventing the AKI to be persistent, and if not, try to help the patients recover before they're discharged, because we see that enhancing the kidney recovery is really important and top priority in sepsis research.

Melanie: Can you prevent sepsis-associated acute kidney injury? Do you see that happening in the future?

Dr Azra Bihorac: I think we are in the beginning of these efforts. As of now in our own institution, we have focused a lot of our work on early recognition of AKI and risk stratification of patients who present with acute kidney injury in terms of who is at the risk of developing persistent AKI.

As of now, we have strategies to ameliorate secondary insults in patients who present with AKI within 48 hours of sepsis. That means we can adjust our antibiotic therapy, not to use medications that have potential to induce further kidney toxicity. We also know that too much or too little of the fluid is not good for AKI progression. So we have to develop precision in the way how we resuscitate these patients. And for that, we use some well-proven strategies, like dynamic assessments of volume responsiveness and so on.

But the most important thing here I think is understanding the prognostic enrichment that AKI has in the course of sepsis. In other words, if you can identify a patient who has one of these malignant phenotypes, meaning patients with AKI early is at more risk of having worse outcomes. Three days from sepsis onset, patients who have AKI and is not recovering is now really the most malignant clinical phenotype. And we really need to focus enrolling those patients in clinical trials, as well as using strategies of monitoring or avoiding secondary insult in this specific group of patients.

Melanie: What an interesting study we're discussing today. And I'd like you each to have a chance for final thoughts. So Dr. Baslanti, to start with you, what would you like other providers to take away from these studies and clinical trials and the testing that you're doing and really sepsis associated acute kidney injury, what would you like them to know about this?

Dr Tezcan Ozrazgat Baslanti: I think it's very important to identify AKI and not only severity, but all different dimensions of AKI and trying to take preventive measures as early as possible is the key point. So sometimes the AKI goes undetected easily, so we've been developing some algorithms that can do that and help assist doctors. And I think that would become more common soon and that would help. And I think a really important part is to be aware of the trajectory of the patient and take preventative measures as early as possible.

Melanie: That's a great point. And Dr. Bihorac, last word to you, what would you like other providers to know and to take away from this really interesting episode?

Dr Azra Bihorac: I think that I would summarize this in awareness recognition and precision, meaning increase the awareness among primary providers in ICUs and hospital, awareness of importance of AKI in determining outcomes of sepsis patients. Recognition would be recognizing AKI at any stage of sepsis as early as the time of admission to hospital, very important. And precision means not only to recognize the acute kidney injury and isolated moment of time, but tracking dynamically trajectory of AKI as a complication and understanding which of malignant trajectory your patient is assuming early enough so you can reverse the course and change the outcomes.

Melanie: Thank you so much doctors for joining us today and sharing your incredible expertise in this research. To refer your patient or to listen to more podcasts from our experts, please visit UFHealth.org/medmatters for more information and to get with one of our providers. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.