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Melanie Cole (Host): Researchers at the University of Florida College of Veterinary Medicine are investigating the potential of a novel biomarker as a tool for identifying animals at high risk of developing end-stage renal failure and hope their findings will lead to improved therapies for chronic kidney disease.

Welcome to UF Vet Med Voice with the University of Florida College of Veterinary Medicine. I'm Melanie Cole. And joining me today is Dr. Autumn Harris. She's an Assistant Professor at the University of Florida College of Veterinary Medicine, and she's here to highlight chronic kidney disease in dogs.

Dr. Harris, thank you so much for joining us today. I'd like you to start by telling us the prevalence of chronic kidney disease in dogs and the significance of these types of studies to canine health overall.

Dr Autumn Harris: So chronic kidney disease occurs anywhere from 5% to 20% of the dog population. It becomes more prevalent as dogs age or get older. And over the last decade or so, there's not been a lot of advances in different treatment options or management options for chronic kidney disease in patients, yet the disease is really common. And so there definitely is a need for new either biomarkers or markers that can help us determine changes in their status, that if we then treated differently would improve their outcomes. And so there's definitely a big need for that right now.

Melanie Cole (Host): Well then, let's talk about that. Tell us about the theory that scientists are hypothesizing, that if the biomarkers work, as they think it will, to assess levels of urinary acid excretion, particularly ammonia, that they may be able to better predict dogs at high risk of overt metabolic acidosis, which could benefit from oral alkali therapy. I'd like you to get into the topic a little and tell us what we're discussing here today.

Dr Autumn Harris: So the kidneys are a really important organ in the body for regulating acid-base balance. And so we eat a lot of proteins in our diet, that when broken down or metabolized in the body, produce acids, and our body then has to make a buffer for that, so that we don't become acidotic, which can lead to a lot of deleterious effects in the body.

And so the main organ that produces that alkali therapy or buffer is the kidneys, which generates the majority of the bicarbonate that is needed to buffer those acid loads. And in patients that have chronic kidney disease, their kidneys may not function as well as they should. And so they may not be able to generate the bicarbonate that's needed. And the way that the kidneys generate bicarb is through generating ammonia. And so that's where, when they generate ammonia, they generate bicarb. And so that's where looking at ammonia excretion in the urine may be really important or helpful in determining patients that may have a positive acid balance, meaning that they might have too much acid in their bodies, before there's abnormalities in some of the other blood work parameters that may be negatively affecting their kidney function, and leading to them to having faster progression of their CKD.

So if we can show that looking at ammonia in the urine of these patients can predict which patients develop more overt acidosis or can predict which patients will have rapid progression of their kidney disease, then that would be really important. And if it does predict that, then we can look at, well, if we give them more alkali therapy, such as sodium bicarb or potassium citrate when we know that their ammonia is low, but before they start to have these adverse outcomes, can we slow down the progression of their disease and have more prolonged survival times without them having some of the complications from their disease?

Melanie Cole (Host): That makes so much sense. Now, why does early detection of CKD and potential therapeutic targets in early stages remain extremely challenging? Has management of CKD in dogs largely been focused on supportive, as it has in humans as well, and symptomatic therapy with very few new therapies available to treat or manage the CKD that have really shown to improve those outcomes?

Dr Autumn Harris: That's true. I mean, right now, most of the recommendations are for us to be doing dietary changes with protein and phosphorus restriction and then providing symptomatic supportive care to any clinical signs they may develop. But at this stage, most patients with chronic kidney disease really aren't diagnosed with their chronic kidney disease until they already lost greater than 75% of their functional renal mass. And so you're kind of already fighting a losing battle. At that point, they've already lost so much function that is irreversible, that they're not going to get back. So it's more about controlling their clinical signs and keeping them comfortable for as long as we can. But if you could diagnose someone with chronic kidney disease, when let's say they've only lost 25% or 30% of their renal function. And then being able to manage them to prevent further loss of renal function, the outcomes should be significantly better at that point, versus when we're only really able to detect or diagnose kidney disease, chronic kidney disease at this point when they've already lost about 75% of their renal functional mass, which is a large percentage. And so they're already much closer to end stages of their disease at that point and it's much harder for us to intervene to improve the outcomes.

Melanie Cole (Host): It's fascinating. It's such important work that you're doing. Can you tell us about your grant through the AKC Canine Health Foundation that was recently funded to evaluate and investigate the potential of that new, but novel biomarker that may be able to predict acid-base balance in patients with CKD?

Dr Autumn Harris: Yeah. We were very fortunate and very excited to get this grant from them that will allow us to look at dogs over a year that have chronic kidney disease, to where we're going to measure the biomarker at the beginning. When they're enrolled in this study, they have to have stable chronic kidney disease stage II to IV and then we're going to evaluate them every three to four months to evaluate how that biomarker may change throughout that year and to see if they have progression of their kidney disease for us to try to see if that marker can predict which patients will have progression of their disease and is there a cutoff that we can use with this biomarker that helps us predict things. And then, we would follow up with that information to use that biomarker to categorize these patients with CKD that may be at risk for faster progression, and then enroll them in a trial to look at alkali therapy to give them a treatment to see if we do that, based off this marker, does it improve their outcomes and slow down the progression of their disease?

Melanie Cole (Host): Can you please just tell us a little bit about how providers and listeners can get involved in this study? You're actively enrolling still now, yes?

Dr Autumn Harris: Yes, we are actively enrolling. This study covers all the exam fees and lab works during the year and provides them with a kidney-specific diet for the whole year. The University of Florida has a clinical trials website that people can go to that they can email if they're interested in the clinical trial, which will get sent to me to look at records. And then, we can contact owners to get them set up for appointments to try to get them enrolled in the study if people are interested.

Melanie Cole (Host): Well, thank you for sharing how providers and listeners can get involved in this study. And as you're telling us the specific aims of this ongoing trial and the main hypotheses that have been identified for this study, can you please tell us about how several clinical trials in humans have indicated that correction of metabolic acidosis with alkali therapy can slow the progression of CKD, even in patients without metabolic acidosis, suggesting that acid-mediated kidney injury might occur even in the setting of normal total bicarbonate in patients with CKD?

Dr Autumn Harris: So there's been a lot of work in human medicine that's looked at acid-base balance. And so what they have found is that ammonia excretion decreases as renal function decreases, so they correlate negatively together. And then, they found that when ammonia excretion is decreased, they were able to determine a cutoff that would predict patients would have much faster progression to end-stage renal disease, it was like 10 times more common to happen in patients with ammonia excretion that was decreased. And then, there have been a number of clinical trials in people that looked at alkali therapy, and that they had patients that improved their chronic kidney disease outcomes even though they were not acidotic on chemistry panels, and that improved their CKD. And so the thought is that ammonia excretion may be able to risk stratify patients with CKD that may have faster progression and would benefit from alkali therapy, even though their biochemistry parameters may be totally within normal limits. And that this would be a big paradigm shift into really focusing on acid-base balance and that it is really important in patients with kidney disease and that we need to do better at managing it, and that this would give us a better tool to assess it and whether it's normal or abnormal in these patients.

Melanie Cole (Host): Have you learned anything exciting as far as advancements that might correlate to human trials that are going on as far as prevention in the first place or very early diagnosis or screening?

Dr Autumn Harris: That's where I think alkali therapy may be helpful. I think there's also some debate about when we should do protein restriction in these patients, and they're definitely looking at that on the human side to where doing more alkalinizing-type diet changes can be really helpful. And so there's still a lot of debate about when patients with kidney disease should be started on these diets. Is it early stages or does that help more than later stages? And I do think potentially alkalinizing therapy may also play an important role and when should we start that? Is it earlier? And if it is earlier, what parameter are we using to base starting that on? And that's where things can get a little bit tricky. And so I think we're trying to move in the direction the same as human medicine, where if we can identify some of these markers that may help identify which patients would really benefit from these therapies versus others that wouldn't, that can be really helpful in tailoring our treatment plans for each individual patient.

Melanie Cole (Host): It certainly would, I'd like you to end with a summary of your study and what you would like other providers to take away the key messages and, again, how they can enroll their patients in these studies.

Dr Autumn Harris: So our study's enrolling. We're looking for dogs as long as they're greater than one year of age that have chronic kidney disease, that are IRIS stage II to IV, needs to be stable, so no more than a 25% change in their serum creatinine during that time. The study would cover the cost of examination fees for the enrollment visit and four recheck visits that would occur three to four months apart. And it would cover the cost of a study diet, which is Purina NF, for the entire duration of the study for the patient. And if there are people that are interested in this study, they can feel free to go to our clinical trials website at the University of Florida College of Vet Med website. And there are some enrollment forms on there that they can fill out, which will get emailed to us. And then, we can contact people to find out more details and to get them set up and scheduled for exams.

Melanie Cole (Host): Thank you so much, doctor, for joining us today. And I hope that you will continue your great studies and come on and join us again and give us an update when you've learned more about this exciting information.

For more information about the UF College of Veterinary Medicine and to listen to more podcasts from the experts at the University of Florida College of Veterinary Medicine, please visit vetmed.ufl.edu. You can also check out vetmed.ufl.edu/ufachievers. That concludes today's episode UF Vet Med Voice brought to you by the University of Florida College of Veterinary Medicine, advancing animal, human and environmental health. I'm Melanie Cole.