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Welcome to the Talphera First Quarter 2026 Financial Results Conference Call. This call is being webcast live via the Events page of the Investors section of Talphera's website at www.talphera.com. You may listen to a replay of this webcast by going to the Investors section of Talphera's website. I would now like to turn the call over to Raffi Asadorian, Talphera's Chief Financial Officer. Please go ahead.

Thank you, and thank you for joining us on the call today. Today, we announced our first quarter 2026 financial results and associated business updates in a press release. With me today are Vince Angotti, our Chief Executive Officer, and Dr. Shakil Aslam, Talphera's Chief Medical Officer. Before we begin, I want to remind listeners that during this call, we will likely make forward-looking statements within the meaning of the federal securities laws. These forward-looking statements involve risks and uncertainties regarding the operations and future results of Talphera. Please refer to our press release in addition to the company's periodic, current, and annual reports filed with the SEC for discussion of the risks associated with such forward-looking statements. These documents can also be found on the website within the Investors section. I'll now hand the call over to Vince.

Thanks, Raffi. Good afternoon, thank you to everyone joining our call today. It's been less than 2 months since our last update, and we're excited about the progress we've made this year in the NEPHRO study with our ongoing enrollment at current clinical study sites, activation of additional sites, achievement of the 50% enrollment milestone, and consequently, the closure of an additional financing tranche. With this continued progress, we believe we are well-positioned to complete enrollment in the NEPHRO CRRT study this year and file the PMA for a targeted potential approval of Niyad in 2027. As mentioned, in early March, we announced the attainment of the 50% enrollment milestone in the NEPHRO study. With continued enrollment since that date, I'm pleased to report that we have well exceeded this level.

The protocol changes we adopted last year, supported by bringing on new target profile clinical study sites, have positioned us to achieve our goal of completing the study this year. Building on our virtual investor and analyst event in March, we continue to be genuinely excited about completing this study and submitting our PMA for potential approval of Niyad. The KOLs who participated in our March event highlighted the disadvantages with the currently available anticoagulants they're using and their belief that nafamostat will fill an unmet need in this market. These insights, as well as our ongoing discussions with other nephrologists, further reinforce our belief that Niyad could have an important role in anticoagulation for CRRT if approved by the FDA. 9 of our 12 activated sites align with the new target site profile that we set last year.

With nephrologists as the lead, these sites have enrolled over 90% of the patients in the study. The quality of our study sites and the principal investigators and their teams is excellent. Dr. Aslam and I have been actively visiting many of the sites over the past several weeks, all of them are highly engaged and have expressed their desire to have a new CRRT anticoagulant approved for use. In addition, we look forward to welcoming a couple of additional institutions who've been enthusiastic to participate in the study, allowing us to maximize the 14 sites granted by the FDA.

While these new sites will find us further along in enrollment, they've been drawn to the NEPHRO study by a deep appreciation for nafamostat's nearly 4 decades of use outside the U.S. and a strong interest in contributing to the U.S. research with their peers on a potentially new approved CRRT anticoagulant. Adding these final sites helps lay the groundwork for broader clinical awareness of nafamostat, which will serve us well if the FDA approves it next year. With that, I'll now hand the call over to Raffi to update you on the financial results for the first quarter.

Thank you, Vince. Our cash balance at March 31, 2026 was $21.1 million. We believe this cash, combined with future conditional financing tranches, will provide us sufficient capital through at least a potential Niyad PMA approval expected next year. During the quarter, we closed a $4.1 million financing tranche from the March 2025 private placement. There are 2 remaining conditional financing tranches totaling approximately $16 million of additional capital, which, if the conditions are met, are expected to close around the date we release our top-line data and announce completion of the study later this year.

Our cash operating expenses or combined R&D and SG&A expenses for the first quarter of 2026 totaled $3.9 million compared to $2.9 million for the first quarter of 2025. Excluding non-cash stock-based compensation expense, these amounts were $3.7 million for the first quarter of 2026, compared to $2.7 million for the first quarter of 2025. The increase in cash operating expenses in the first quarter of 2026 was primarily due to higher Niyad development expenses, reflecting increased enrollment and an increase in certain G&A expenses. I'll now turn the call back over to Vince.

Thank you, Raffi. I'd like to open the line for any questions you might have. Operator?

Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. Should you have a question, please press star followed by the 1 on your touch-tone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the polling process, press the star followed by the 2. If you are using a speakerphone, please lift the handset before pressing any keys. One moment please for your first question. Your first question comes from the line of James Molloy from Alliance Global Partners. Please go ahead.

Hey, guys. Matt on for Jim today. I was just wondering if you guys are going to announce enrollment at any other milestone, maybe 75%, or is the next update going to be full enrollment and then we're to expect data quickly after? Thanks.

Yeah, Raffi, I'll start it and then you can give them an idea of kind of the data communication we're planning. We're not planning on any additional enrollment updates, in particular realizing that the balance of the study isn't tied to any tranches until the closure of the study, until the study is being completed. With that said, I think Raffi can communicate to you what our expectation is upon study completion or enrollment completion being last patient out and how we plan to communicate data thereafter.

We'll announce last patient out, but the most important is the top-line data, which should come, you know, within a month after that last patient out. Remember, it's a very quick study, 72 hours at the secondary endpoint, 24-hour primary endpoint. It's a quick study, and we're cleansing the data along the way. It'll be a quick announcement for that top-line data.

Got it. Thank you. Is there any guidance you can give as to where you might be now or timing going forward? Second half 2026 still looking like the most likely for a top-line read?

The second half of 2026. You know, the study goes in ebbs and flows. We're gonna remain on our guidance for the second half of 2026, depending on the flow of those qualifying patients moving forward. We're confident in it being completed this year and announcing those results this year.

Great. Thanks for taking my questions, guys.

Thanks, Matt.

Thank you. Your next question comes from the line of Ed Arce from WestPark Capital. Please go ahead.

Hi, Vince, Rafi. Good to be with you. Congrats on the continued progress. Just a couple of quick questions for me, as we anxiously await full enrollment and top-line data later this year. The first one is these 2 new sites that you expect to come online, pretty soon here, and basically cap out the full complement of sites, would you be able to disclose which sites those are or perhaps give a qualitative description of the type of site and the type of patients that they see? Then the other question is, have you received any commentary from site administrators, that are treating the patients, anyone that is conducting the study? Any commentary that you could share with us about how things are progressing?

Thanks so much.

I'll start with the new sites, Ed, and then I'll turn it over to Shakil to give a little more insight on those sites and the site administrators' feedback. The 2 new sites we don't expect to be significant contributors to the study, but they have significant CRRT populations. I say it not to be significant contributors to the study because they're coming in so late to the study, but they wanted to be involved moving forward. These are study sites that match our new profile with nephrologists being the lead. 1 of the sites in particular is 1 of the top 5 as far as our data suggests CRRT administering hospitals in the country. We'll end up communicating those sites when we update clinicaltrials.gov, dot com on the study sites.

You'll be able to see who those sites are specifically in conjunction with all the balance of the sites we have to round out the 14. As it relates to the site administrators and how it's going, I think Shakil's best positioned to communicate that while he and I have been making our rounds over the last several weeks. Remember, it's a blinded study, but I think what's important about this is the placebo and the product are treated similar in the protocol and the simplicity that comes with it. Shakil.

Sure. Thanks, Ed. Absolutely. When we talk to the PIs, and the investigators and then as well as the nurses who are running this study and who are doing testing and looking at some of the test results, they are all very, very impressed with the ease of administering this intervention. As Vince said, both placebo as well as Niyad, they are administered exactly the same way. Sure, for first 24 hours we have little bit more intense monitoring or blood test to see how patients are responding to it. After 24 hours, you know, that intensity goes down and they basically all are very, very impressed at how little variability they are seeing in the test results.

That's quite a pleasant surprise to them that they don't have to chase their tails trying to keep some, you know, the parameters in within a target range. Once they have somebody stable, at a parameter, lab parameter, they basically stays the same value. Overall, I think.

Shakeel

Everybody is. Yeah. Yeah. Sorry.

Shakil, can you comment on the reach or the conclusion of that stability to get to the proper dose in that first hour and why that protocol works for them? How we're basically controlling that primary endpoint on that first hour?

Right. As you know, this study, we start at a starting dose, which is predefined, and 15 minutes later we check the activated clotting time by a handheld device by the bedside, which we provide, and we provide the cartridges as well. It's pretty standardized test across all sites. Within 15 minutes to check the value and we have a certain range in which we want that value to be. About 70% of the cases, you see the ACT going in that range, right, at the first starting dose.

Occasionally, a patient, that's 25% may need one, and a couple of them may have needed even more than one titration, two titrations, which is, by the end of 1st hour, everybody is in the range in which they are expected to be. Obviously, you know, I'm not gonna disclose for different groups because there's one placebo in which we don't expect the value to change much. As expected, their value doesn't change. In active treatment, the value changes, they remain within that range. This, it's a very, very stable response and which is, which is not a total surprise to us because nafamostat's metabolism is really not dependent on any specific organ. There are other drugs which either depend on liver or kidneys or any other organ for metabolism.

Every time the function of those organs deteriorates or changes, you can see different response, in whatever parameter you're following. The beauty about nafamostat, it really is not dependent on any organ. Most of these patients, they can have fluctuating organ function, which can affect other medications, such as heparin being one example. Citrate is another example. If you have liver failure, citrate will not be metabolized as quickly. Nafamostat doesn't have those issues. That's the reason why once you hit the target level, it essentially remains stable. Does that answer your question?

Shakil, can I ask you.

Yeah. Yeah. Sure.

Yeah, that's.

If you could add a little color.

That's enough. Thank you. Shakil, a little bit more color. On the administrator site, can you comment to the people on the line how many of the sites are typically using citrate as a primary intervention for anticoagulation and CRRT, and/or heparin as a primary intervention both?

Right.

Anticoagulation and CRRT.

Sure. Of the 12 sites that we have, we don't have any site that uses citrate as a standard of care. There are 2 or 3 sites that will use citrate only if a patient continues to clot. These sites do not use heparin at all. The sites that are using citrate, they don't believe in heparin. They, 2 or 3 sites that have access to citrate, they are not citrate first users, only use citrate as a rescue, as citrate is the only rescue they have. We have 2 sites, only 1 site that uses heparin as standard of care of all the sites that we have. We have 2 or 3 sites that use heparin as a rescue therapy.

They don't use either citrate or heparin when the CRRT is started. If they see clotting, they don't have access to citrate. They go back to rescue heparin. Majority of our sites right now, I would say, you know, 10 out of 12 or 13 that we have, they don't really have any first-line anticoagulant that they use for every single patient. They are really using either heparin or citrate as a rescue. We don't have any site that uses citrate for everybody.

I think importantly, Ed, when they execute the protocol in the NEPHRO study and the titration schedule, they see the ease of use, whether it's placebo or control, doesn't matter. Placebo or active, doesn't matter. It's just the ease of that titration schedule compared to what their historic challenges have been with heparin and citrate. That seems to be the additional feedback.

Right.

is the main comment.

Right. The nurses, even we spoke visiting a site today and the nurses, they were like shocked. "Okay, we don't have to do anything else?" "No, that's it. You know, that's all the monitoring that's required." Yeah.

That's very helpful. Thank you both.

Sure.

Thank you. There are no further questions at this time. I will now turn the call over to Vince. Please continue.

Thank you, operator. I'll just clarify my comment I said earlier about the site names, the additional 2 that will be coming on. That will be on clinicaltrials.gov. Clinicaltrials.gov, excuse me. In our next update of those sites. Again, thank you all for joining us on our first quarter earnings call. We're really very high on what's happening at the start of 2026 and the enrollment that's continuing to move forward. The NEPHRO study progress has been excellent. Our commitment, enthusiasm to bring the potentially new regional anticoagulant for CRRT to the market next year is unwavering. We appreciate your attendance today, and we're very excited about the future for the NEPHRO study, as well as Talphera moving forward. We'll provide you additional updates on our progress and thank you for joining us on the call today.

Operator, that concludes our call.

Thank you very much. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good morning, everyone, and welcome to the Talphera Virtual Analyst and Investor Event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Talphera website following the conclusion of the event. I'd now like to turn the call over to Vince Angotti, Chief Executive Officer at Talphera. Please go ahead.

Thank you, Tara, and good morning, everyone, and thank you for joining our event today. I'm excited to be joined by Dr. Shakil Aslam, Talphera's Chief Medical Officer, and two key experts in continuous renal replacement therapy who are also principal investigators in our Nephro CRRT registrational study. Through their experience and expertise, we hope to provide you with a better understanding of CRRT, the anticoagulants currently being used during CRRT, and how these experts see nafamostat potentially filling an unmet need for anticoagulation of the CRRT circuit.

Our agenda will specifically include first, a very brief business update, so we can move quickly to our key expert discussion, followed by Q&A and closing remarks. Before we begin, I want to remind listeners that during this call, we'll likely make forward-looking statements within the meaning of the federal securities laws.

These forward-looking statements involve risks and uncertainties regarding the operations and future results of Talphera. Please refer to our press release in addition to the company's periodic, current, and annual reports filed with the SEC for a discussion of the risks associated with such forward-looking statements. These documents can also be found on our website within the investor section. Now for the business update. Earlier today, we announced our Q4 and full-year financial results. The Nephro CRRT study is progressing nicely, and as announced a few weeks ago, we reached the 50% enrollment milestone. This achievement, along with the achievement of some other conditions, triggered the closing of the third tranche of our March 2025 financing, generating gross proceeds to the company of $4.1 million.

In addition to the funds received back in October 2025, when two investors waived all their conditions and closed on the second and third tranches of this investment. As of December 31st, we had cash and investments of $20.4 million, which, along with the remaining tranches, if closed, should provide runway through a potential FDA approval of Niyad next year. We expect to complete enrollment of the NEPHRO CRRT study later this year and file the PMA within about three months after study completion. As a reminder, the primary endpoint of the study is measured at 24 hours, so a quick turnaround of data is expected once patients have been enrolled. I'd now like to move on to why we're all here today.

As a reminder, continuous renal replacement therapy, or CRRT, is a specific type of dialysis that runs for 24 hours on a slow flow and continues on average between five and seven days while the patient is in the intensive care unit, the ICU. Because the blood clots when it comes in contact with an outside material, the filters used in CRRT machines frequently clog. Therefore, to make sure the patient is receiving continuous therapy that is not interrupted by clotting, international guidelines specify using an anticoagulant to make sure the filters remain functional for as long as possible. As you'll hear today, each hospital currently has a different protocol to achieve the best uninterrupted therapy for the patient, sometimes not using an anticoagulant at all because many physicians don't trust the current options being heparin or citrate.

Other times, physicians select one of the two available options despite their limitations. I'll now hand the call over to Dr. Aslam to introduce our key experts so you can hear directly from them how each of their institutions manage CRRT for their patients and their broad experience with CRRT and currently available anticoagulants. Dr. Aslam?

Yes. Thanks, Vince. Good morning and welcome to an exciting session with our two experts in acute kidney injury and continuous renal replacement therapies. My name is Shakil Aslam. I'm the Chief Medical Officer at Talphera. As a nephrologist, I have had special interest in acute kidney injury, dialysis, continuous renal replacement therapy for over 30 years, first as a clinician and then as a device and drug developer in these areas. It's my privilege to have Doctors McMahon and Teixeira join us on this call. In addition to being key thought leaders in AKI and CRRT, Dr. McMahon and Dr. Teixeira are also principal investigators on our NIAD registrational trial. In fact, their sites are the highest enrolling sites for our study, so we are very excited to have them. I would like to briefly introduce them.

However, I will not be going through their entire list of accomplishments and contributions to this field for the sake of time. First, Dr. McMahon. Dr. McMahon is an associate professor of medicine at the Medical University of South Carolina in Charleston. Her key interests are in the areas of acute kidney injury and renal replacement therapies in intensive care setting. She has published over 50 papers in leading peer-reviewed journals and has written numerous expert opinions, review papers, and book chapters. She is the director of nephrology clinical trials at MUSC and is involved in several ongoing studies in acute kidney injury and continuous renal replacement therapy. Dr. McMahon is also the director of CRRT program at MUSC and is responsible for managing prescription protocols for CRRT and dialysis in the intensive care unit.

She has won multiple teaching awards at Johns Hopkins, MUSC, and University College Dublin. Dr. Teixeira is an associate professor in the divisions of nephrology, primary critical care, and sleep medicine at the University of New Mexico in Albuquerque. In addition to other clinical responsibilities, Dr. Teixeira serves as the director of acute dialysis and continuous renal replacement therapy programs at UNMH. As a critical care nephrologist, his research interests lie in acute kidney injury, CRRT, and septic shock, among others.

He has enrolled over 300 critically ill or hospitalized patients into more than a dozen clinical trials. He has co-authored over 100 peer-reviewed publications, book chapters, and conference abstracts. He's on the editorial boards of three journals. As a director of the CRRT program at UNM, Dr. Teixeira is responsible for overseeing the development of CRRT protocols and quality assurance programs. Welcome to our call, Dr. McMahon and Teixeira. So nice to have you.

Thank you. Good morning.

Thank you. Thank you for having us.

Absolutely. Let's just start off with some basics. As I'm sure you have the same experience, there are just so many different names, acronyms, you know, when it comes to acute kidney injury and the different modes of dialysis. For our audience, could you just break it down to Dr. McMahon, this question is for you. What exactly are the key differences between CRRT, which I recognize increasingly is referred to as CKRT, which, you know, continuous renal replacement therapy, although they mean the same thing. We use CRRT and CKRT interchangeably. You have regular intermittent hemodialysis, which most people are aware of. What are the key technical difference between these two modalities?

Yeah. When we consider out-

Tara, if you have that slide, I think, that will highlight,

The difference.

Sure. Yeah.

Yeah.

Okay. Got it. Perfect. Yeah.

When you think of outpatient dialysis, these are, you know, chronic dialysis patients. Yes, they have organ failure and are attending an outpatient facility in the community. These are usually relatively healthy stable patients. Most of them are relatively healthy other than the organ failure, and they often walk into the unit and attend three days a week for their dialysis therapy, either Monday, Wednesday, Friday for three to four hours, or Tuesday, Thursday, Saturday. When you compare that to the continuous renal replacement therapy dialysis in the intensive care unit, most often these are critically ill patients. Most of these patients will have more than one organ failure in the ICU. Some of them are mechanically intubated, and they're really sick. Some of them are unstable.

In other words, they're hemodynamically unstable and require medications to keep their blood pressure up. The big difference between the two modes of dialysis is one is a higher dose of dialysis for stable patients, but the CRRT dialysis is a more gentle form of continuous dialysis run 24/7 in the ICU at the bedside. It's a more gentle form, a lower blood flow. You can see the setup here in this picture where you can actually see the filter on this continuous renal replacement therapy setup, the machine on the left-hand side. I don't think this picture reflects what we see. Sometimes you go into a room, there's a lot more machinery, like the mechanical ventilator.

You can see at the bottom of the machine, you have these bags, these replacement fluids, and often the citrate anticoagulation is contained within those bags, and they require infusions of calcium to run to maintain that filter lifespan. The filter is really everything. It's really important these patients get really good quality dialysis in the ICU. You do not wanna interrupt their dialysis. It's really important for the patient.

Great. To summarize, intermittent hemodialysis is done mostly outpatient, though it can be done inpatient as well. Patients are typically more stable, walk into dialysis, very high speed, quick three to four hours dialysis, and they go home. Whereas CRRT is patients with life-threatening disease, many of them on ventilators, multiple comorbidities. They are in medical ICUs, critically ill, multiple machineries and interventions, and the dialysis is very gentle and slow, but since it's not as quick, it has to be done over extended period of time, 24 hours a day, and can go up to five to seven days as long as the patient needs it. Thank you. That was very helpful.

That's it. Yep.

Yeah. Dr. Teixeira, you work as a director of an outpatient unit as well as you're the Director of the ICU. Are you seeing any interesting epidemiological trends in the incidence rates of end-stage kidney disease or which is what most these patients get dialysis for as an outpatient versus acute kidney injury, which you see in ICU in a patient like that shown in this picture?

Yeah, absolutely. The chronic dialysis, you know, population in the United States is kinda, you know, historically over the first 20 years of this century has gone up and up and that's been a kind of big topic in nephrology. But it's starting to level off. If anything, you know, during the pandemic, you know, although, you know, these are somewhat more stable patients, you know, they are somewhat vulnerable to things like infection, like with our dialysis population locally, and I think this reflects national data too, dropped somewhat. To some degree, the chronic dialysis population, you know, may be stabilizing.

In theory, with some of the treatments that we've developed to help sort of prevent progression of chronic kidney disease to end-stage kidney disease, that will, you know, continue, I think, that trend that chronic dialysis may become a smaller part of our practice. The opposite is true of the acute kidney injury. You know, ICU populations in general are just growing across the United States. There are some kidney-specific things that can happen to land someone in ICU. But most of the time, this is a complication of some other severe illness, like septic shock, for example, being a very obvious one.

The incidence rates of septic shock and acute kidney injury severe enough to require dialysis, often continuous renal replacement therapy, has only continued to go up. This is becoming a bigger problem, a more frequent problem, and, you know, over time, I think it's gonna be dominating the practice of your average nephrologist, not to mention someone like myself who's kind of a dedicated critical care nephrologist. I think the patient population that this issue is relevant to is only gonna continue to grow.

Right. Dr. Teixeira, as fewer patients are progressing to end-stage kidney disease and going on dialysis, that means that the proportion of patients who have chronic kidney disease but not on dialysis, that portion of patients is gonna expand, I presume. Those patients are very high risk of acute kidney injury, and so is that what you're seeing as well, that there's actually more patients to develop acute kidney injury?

Yeah. To some degree, I mean, these things relate. That's absolutely fair. The patients with chronic kidney disease that you know not yet requiring dialysis, that population is not going anywhere, and they are more at risk of acute kidney injury. To some degree, the proportion of patients with what we call end-stage kidney disease or chronic kidney failure that are requiring maintenance continuous dialysis outside the hospital, the proportion of those patients that originally developed their kidney failure due to acute kidney injury that usually gets better but sometimes does not, especially in those with underlying chronic kidney disease-

Yeah

... in other words, those who previously had kidney disease and have a superimposed kidney injury, the proportion of those patients that account for the total chronic dialysis patient population size is going up over time, slowly starting to compete with things like diabetes and hypertension that are thought to be the most common causes of end-stage kidney disease in the United States. Yes, absolutely. The-

Mm-hmm

... the patient population, just as the United States population is aging and developing more chronic kidney disease, the patients at risk of acute kidney injury are increasing, which I think is part of the reason why we're seeing more of it along with, to be fair, I think just, you know, a gradual explosion. It seems like it to me, an explosion. Over the course of my 20 years since I was a med student, you know, messing around in ICUs long ago, the expansion of critical care in the United States is just, you know, it's only going up and up and up. You know, the

Yep

... the complexity of the patients that we're supporting, the amount of, you know, devices that we are using to keep people with, you know, impaired circulation, you know, whether it's mechanical circulatory support and, you know, ECMO, extracorporeal membrane oxygenation. These complex life support devices are being used more-

Yeah

... and more, and not just in academic medical centers, spreading to sort of, you know, community hospitals, you know, and more and more to sort of somewhat less subspecialized centers-

Yeah

... the complexity of, I think, the life support that we're offering across the United States is only increasing.

Yeah.

As a result of that, acute kidney injury to some degree is kind of the collateral damage that can happen with some of these really-

Right.

...high levels of life support. You know, patients that, to be blunt, may not have survived, you know, 10, 15, 20 years ago are being, you know, supported by some of this more complex level-

Sure

... of critical care that we can provide. A lot of them along the way, unfortunately, are suffering some degree of kidney injury, which is often a consequence of this underlying severe illness.

Yeah. I presume that you're seeing similar trends in utilization of CRRT for management of these patients. It seems to be growing pretty rapidly.

Yeah. Yeah, absolutely. Like I think the use of CRRT is only gonna continue to rise over time. We're seeing it locally and across the country.

Right. Dr. McMahon, tell us about the risk of clotting in two totally different modalities of treatment. You have very fast high flow acute dialysis and obviously filter can clot, and then you have slow, you know, dialysis for a long period of time, low flow, and patients who probably are much more sick and inflamed.

Mm-hmm.

How do you compare the risk of clotting between these two?

Yeah. It's a good question. The risk of clotting by far is a lot higher in the intensive care unit patient. I think we can say that for sure. These are a different cohort of patient. The majority of the time we're starting CRT, for example, for septic shock, and that means patients are really inflamed. They have these inflammatory markers. A lot of those markers will stick and adhere to the filter, reducing the efficiency of the filter, predisposing them to clotting. It's not just with sepsis or septic shock. We're a big liver center. Our liver patients have bilirubin, these other proteins floating around that can affect the filter. There's a lot of risk factors that exist in the ICU patient that makes them vulnerable to clotting in the ICU on CRT.

Preventing that clotting is paramount, and delivering good dialysis is really important. We do use some anticoagulation, typically heparin, a very low dose heparin in a small proportion of outpatient chronic dialysis patients for some patients, but we don't see that level of clotting in the outpatient compared to the ICU.

Yeah.

Yeah.

Yeah. Dr. Teixeira, I've seen you even on national holidays, you know, running off to the ICU and, you know, putting those fires out. What happens? General, I think many people take a very simplistic view. Well, okay, the filter clots, you pop the filter out and put a new filter in and, you know, keep going. Could you just walk us through what exactly are the implications when a filter clots? You know, implications for you as a clinician, for the support staff that's taking care of those patients and the patient themselves. What happens? You know, what is, you know, life like when you get a call in the middle of the night, "Hey, gee, Dr. Teixeira, this filter has clotted off"?

Yeah. I mean, there's implications kind of, you know, at many levels, and it affects sort of both the patients as well as the healthcare system, I would say. You know, very simply, if you are not on the machine, you're not getting the therapy that sort of, you know, life-saving kidney replacement therapy, whatever you're trying to fix with the machine, whether it's a buildup of, you know, potassium in the blood, which can be directly life-threatening, acid buildup in the blood, excess salt and water that you're trying to remove to say, let's get someone off of mechanical ventilation because they have too much fluid in their body. None of that happens when the machine is down.

It takes at least, and I say at least because, you know, sure, if the nurse has absolutely nothing else to do and this patient on, you know, multiple forms of life support, they drop everything that they do. It you know maybe takes just an hour, but takes at least an hour. Like, I think on a practical level, it's often an hour or two, sometimes three, before they get the nurse has the kind of bandwidth and time to sort of reconnect everything and get everything going again. That's valuable sort of time that the patient's not receiving the therapy, and that ends up reducing the effective delivered dose, which is, you know, not the goal of this sort of life support modality that is indeed meant to be continuous.

Like I already alluded to, the nursing time is extremely valuable that we're sort of kind of cutting into here, and there's all sorts of costs as well. Like each of these hemofilter sets, as we call them, costs hundreds of dollars. You know, just thinking from an equipment perspective, you know, that's obviously extremely sort of counterproductive for kind of efficient patient care. Occasionally, like usually not, the nurses are able to often identify that the filter's about to go down before it completely clots off, and rinse back the blood, as we say, to prevent as much blood loss that would typically occur with one of these filter sets.

Occasionally they don't and the net result of that is they lose all the blood in that tubing in that filter. These filters are pretty slick, but they still have about 150 ml or perhaps a more you know kind of intuitive way to think about it. Basically about a half a unit of blood is in these circuits at any given time to allow this therapy that you know cleans the blood to be going on continuously. It's not infrequent, it's the minority, but still a substantial number of times, they're unable.

The issue, the clotting or whatever issue that causes it to stop all of a sudden is sudden enough and catches the nurse by surprise that they actually lose half a unit of blood, which is obviously the exact opposite of what you wanna do for a critically ill patient, many of which, you know, already have active bleeding or because of their sepsis or some other disease process, they're already very anemic.

Mm-hmm

The implications of that, you know, are, you know, definitely, you know, not helpful to the patient or to the healthcare system.

Yeah. Briefly, what exactly are you doing to prevent the clotting? What is your anticoagulation of choice right now to prevent those filter clottings?

Is that for me? I can answer. You know, I've been at the University of New Mexico now about seven years, and when I came in, we didn't have a specific protocol about how to approach it, and we haven't really evolved beyond that. In part, like, you know, to some degree I think the guidelines suggest that we should, but there is no hard data suggesting that these other options available improves outcomes, and none of them are free of major issues or complications. In other words, heparin, we can talk about a lot. In short, I'm not a huge fan of heparin.

As a heparin first center, I've definitely never had the thought that term becoming a heparin first center made sense, so we haven't done that. Then citrate, you know, can work well if I'm sitting at the bedside managing it. I joke that I love citrate because it gives me job security 'cause I'm perhaps the only nephrologist in the state who understands it well. It's a little bit perhaps arrogant of me to say, but it's complicated. The reality is that it's complicated.

You know, citrate nominally has been recommended as first line for CRT in the United States or worldwide, I should say, for over a decade, and it still accounts for only a fraction of practice, you know, in other words, only you know less than 50% of centers across the United States are citrate first because of the complexities and issues related to that. We are a nothing first center, which is like arguably not-

Okay

You know, adherent to the guidelines, but it's because the options available, you know, are basically neither of them are fully satisfactory.

Right. Okay. Dr. McMahon, what is your strategy for anticoagulation?

Yeah. We're the same. If you clot more than once in 24 hours-

Yeah

You automatically start citrate anticoagulant.

Yeah.

We have ACD-A.

Okay

2.2% citrate in our institution.

Okay. Wonderful.

You know, like my last institution, they didn't have citrate because.

No

the director of CRRT there just didn't wanna take it on board.

Right.

Because, like mentioned before, it's the complexity and the burden.

Mm.

It's quite fascinating, you know, when you talk to your colleagues in the division, some of them still aren't 100% familiar with the protocols. We-

Right.

...see these events occurring. Safety is an issue, especially as-

Right

... the director of CRT. Your job is to keep things safe for the patient while delivering good dialysis and modifying these protocols as we go.

Right.

Yes, we do use ACD-A, and it is not reliable.

Yeah.

It is a job security.

Right. Life expectancy of these or useful life of these filters is around-

Yeah

72 hours. When you are not using anticoagulation, you know, what kind of lifespan do you get for these filters?

Yeah. If you actually look at the data, the data has been published on this, a third of filters that start go down in the first 12 hours.

Yeah.

Another third will last 12-24. Most institutions are therefore not getting 24 hours with their filters.

Yeah. Okay.

Remember, these filters are expensive.

Yeah.

Dialysis is expensive. The filter alone-

Yeah

...is a connection fee at our institution about $2,300+ the nursing fee.

Yeah.

It's not cheap, and then the cost of anticoagulation, the cost of the connection, the cost of blood should it go down, and then the implications obviously for the patient.

Yeah. Sure. Sure.

Yeah, so it's not cheap.

Dr. Teixeira, what kind of filter life do you get at UNM? You're on mute.

Yep. Yeah. No, I just like pulled up some of our most recent data. This is actually skewed by pediatrics, which is a little bit different.

Sure

Situation. Their filter life tends to be better than ours. Our filter life tends to be, you know, our median is 13 hours. I'm just looking at some data.

Yeah.

This is a few months ago.

Mm.

We have some that, you know, extend a little bit longer. Our mean is a little bit longer than that, but still less than 24 hours.

Yeah. Yeah

That is, you know, suboptimal. Again, I think part of the issue with that is that, you know, the options available to us to improve that are limited.

Right.

We haven't sort of, you know, implemented any, you know, major changes based on that other than trying to remind people to like consider, you know, heparin or citrate, you know.

Right

Upon, you know, premature filter loss.

Right.

Yeah, our data, you know, locally matched, you know, the sort of more global data that Dr. McMahon just said.

Heparin has been used forever, and it's FDA approved. But there is, you know, a lot of, I would say, you know, disagreement on, when to use it, if to use it at all. Does it really, you know?

No

... offer a favorable benefit, you know, to the risk profile to the patients. Dr. McMahon, you tend to, looks like, avoid heparin altogether. So-

Yeah.

What is your beef against heparin?

Well, I used that at my last institution for seven years, and I can tell you it just is not as efficacious as citrate. Okay? The data on it is about 26 hours with heparin. It's not like these filters are supposed to last 72 hours.

Right.

If you're getting 26 hours with heparin, it's just, that's just not really good enough. More importantly, it's not regional. It doesn't stay in the circuit. You're affecting the systemic thinning of the blood, and your bleeding risk goes up with heparin. If you've got someone in with a big brain bleed post-op, the surgeons don't want you to start it, you know?

Yeah.

It's a huge problem. It's lack of efficacy, well, reduced efficacy, and then the risk of bleeding with it. Yes, it's cheaper, but that, you know, it, the cost doesn't come into it at that point, you know? Yeah. Even though it is approved, we actually-

Right.

We don't have a heparin protocol at our institution for that reason. We actually did bring one in for research because it was a requirement for a protocol, but we don't use it. We don't use it at all.

Right. Do you see any issues. At least I felt that titration with the heparin was never a straightforward thing, you know? So-

No. We think this with regular patients too, right?

Right. Right.

They get super therapeutic, and you have to hold it, and oh. It's a mess.

Yeah. Yeah, Shakil, I can add to that too. Like, you know, just more globally, you know, thinking out of my practice as intensivist, the use of heparin is no longer the only thing that's FDA approved for CRRT. I hope that changes soon for obvious reasons-

Right.

...considered first-line for anything. It's no longer

Right.

You know, regular and fractionated heparin is no longer considered first line for DVT/PE-

Right.

....for clotting in the lung. It's no longer-

Right.

...considered first line for heart attacks. It's because, in addition to the fact that, like Dr. McMahon just pointed out nicely, it doesn't really work that well, like the benefit-

Yeah.

... you get in terms of prolonging the filter, it's pretty marginal. You have the risk of bleeding that comes with it, but also it's, it has to try to phrase this in a non-medical term, it like both overshoots a lot-

Right

...in terms of its blood thinning effect, and then-

Right.

... sometimes it doesn't work. It doesn't adequately thin the blood when it's supposed to.

Right.

You know, the technical term has got unpredictable pharmacokinetics. So basically like it's hard to get it on enough, and then some patients it's hard to prevent it from overshooting. It's just a pain in the ass. It's like a drug that I think even outside, if you set aside CRRT, I think is eventually gonna fall away to newer agents that are just kind of easier to use. It is not either very good at doing what it's supposed to do, which is get the blood, you know, thin quickly-

Right. Right.

...nor is it good at preventing overshoots and bleeding risks-

Sure. Sure.

....associated with thinning the blood too much.

Yeah.

It's really just like an inferior agent.

When you overshoot, it's not like you just turn it off and it just, you know, goes away. You know, in many patients it can linger on for hours, and sometimes you have to reverse it with using, you know, fresh plasma, you know, and all that. It's dirt cheap. Do your hospitals incentivize you to, you know, "Hey, use it. This costs us-

No.

... pennies, and why not? You don't buy into that-

No

...incentivization, right? Okay. Great. You talk to other people, and this obviously is your experience with the heparin, and is that the general consensus you get? I know, you know, you guys go to all these meetings, and as we are going to the one at the end of this month, you meet all the, you know, main people in CRRT world. When you talk to them, is this experience with heparin universal across all, or do you have some, you know, real strong supporters of heparin out there?

No. I mean, citrate still is superior, a higher incidence of use across the United States.

Yeah.

Compared to heparin, it's definitely not used despite the cost advantage. Just you wouldn't sacrifice patient safety or efficacy over you know. It's just not used. It's not used as much.

Okay. Okay.

Yeah.

Makes-

I've never met anyone who's a strong proponent of heparin. Heparin hasn't been recommended as first-line for the last, you know, 10-15 years.

Yeah.

Right?

Mm-hmm. Mm-hmm.

You know, despite the fact that it's the only thing that's approved technically for this use, nobody's pushing for heparin to be-

Yeah

...you know, first line.

Dr. McMahon, you do use citrate-

Yeah

... in select patients. Tell us what is life like?

Well, how long-

Using citrate.

How long have you got? Because I can

So-

If I can tell you, it's an absolute. As the Director of CRRT at MUSC, it is an absolute pain in the ass for me, because it's constant. I mean, I'm not gonna bash citrate, okay?

Sure. Sure. Yeah.

It does its job, but there's issues with its use.

Right.

You know, I think we talked about complex protocols, and it has a huge burden on nursing staff and also on the medical staff.

Yeah.

This monitoring of labs, the iCals, the post-filter calciums, the lactates, the CMPs, and then this titrating of this calcium infusion that you have to give the patient. There are certain cohorts of patients that you can't even use citrate in. Well, you gotta watch them really closely. Liver patients, for example.

Right. Right.

They can accumulate it and get some degree of toxicity related to it, and then you're stopping-

Yeah.

...the citrate.

Right.

Because you're starting a calcium infusion, my protocol starts at 60 cc an hour, and if you have a decompensated heart failure, you can't even pull off that 60 cc. You're going in there with your machine, and then you're overloading them with this infusion.

Right.

Don't even mention now because the Regiocit, the 0.5%, got pulled by the FDA 'cause they didn't have an emergency use authorization, and then we moved to ACD-A, this higher percentage. I'm seeing a lot more metabolic disturbances with it while they're not therapeutic. So it

Dr. McMahon-

Yeah

...for some of us who may not know, what exactly is ACD?

It's just a higher percentage of citrate that we use-

Okay. It's a highly concentrated citrate solution.

...concentrated citrate, 2.2%.

Okay.

It's like this alkalotic drug, and it changes-

Yeah

...the pH of the blood-

Right

....you have to monitor for that.

Right

We see a lot, you know. I get a lot of the safety events that come back with its use, and it's all the time, to the point now that we actually have to do citrate rounds when we start citrate.

Oh.