February 11, 2022 — Dr. Kelly Diehl talks with Dr. Eva Furrow of the University of Minnesota about bladder stones in dogs. Learn more about Dr. Furrow’s research, where the science of urinary stone formation is heading and what that could mean for dog owners.
Resources
https://urolithcenter.org/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032870/
https://www.nature.com/articles/s41585-020-00387-4
0:00:07.5 Dr. Kelly Diehl: Welcome to Fresh Scoop, Episode 41, which I've cleverly entitled Rolling Stones: Understanding Urinary Calculi in Dogs. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation, Senior Director of Science and Communication. And today, we'll talk to Dr. Eva Furrow, Dr. Furrow is an associate professor of Small Animal Internal Medicine and Genetics at the University of Minnesota College of Veterinary Medicine. And welcome, Eva.
0:00:34.4 Dr. Eva Furrow: Thank you, I'm excited to be here.
0:00:36.8 DD: Before we get started, can you tell us a bit about yourself? What led you to become a veterinarian, and then, why did you decide to focus on the urinary tract?
0:00:46.4 DF: Sure, so my story of wanting to be a veterinarian is kind of the classic one, where I fell in love with animals when I was very tiny. I kind of went straight from wanting to be Cinderella to wanting to be a veterinarian, which I'm very glad I made that change. [chuckle] Veterinarian is the right career choice for me. With the urinary tract, it wasn't... I was brought to it somewhat indirectly. So, from research, I had done genetics work and loved it, and so I knew that I wanted to work on hereditary disorders. And from a clinical perspective, I really liked managing endocrine diseases, meaning hormonal problems, where kind of the organs are communicating with each other, and it's a multi-organ issue. And what happened is that when I came out to the University of Minnesota, we have this large stone analysis center here, a really great stone research team, and I learned that one of the common stone types that we see in animals, calcium oxalate, is quite hereditary. And so, it was the genetics research side that drew me to studying urinary stones. And then as I read about them, I learned that they are, in fact, a multi-organ problem, they're really not strictly urinary tract.
0:02:15.9 DF: So, what I mean by that, is that the intestines, the bones, kidneys, parathyroid glands, all of these organs interact with each other to determine what's happening with your blood and urine calcium, which is a contributor to this type of stone formation. So, I got sucked in and then fell in love with stone disease on many levels, research, and clinical side, and that kind of branched out to enjoying other urinary tract disorders as well.
0:02:54.0 DD: Well, that was great. And I think for those non-veterinarians who are listening, we all know that University of Minnesota has been really on the leading edge of research on bladder stones, kidney stones, in both dogs and cats for decades. And I am old enough to be able to contribute to say decades, they certainly were very active when I was a vet student. And that brings me to that big question, and I know this is an enormous topic, but can we start by defining what we mean when we talk about stones or calculi in the urinary tract?
0:03:35.7 DF: Yes, so your urine, or an animal's urine, it's full of dissolved substances. So, it is kind of jam-packed with all these different things that the body has excreted. And stones form when substances that are in the urine that are normally in solutions start to precipitate out into crystals. Those crystals, they then cluster together, they start layering around on top of each other and growing, and they become a solid mass. And that solid mass is what we call a urinary stone. And so, this is forming in the urinary tract, it can be in the kidneys or the bladder, and then we also see problems when it moves from the kidneys to the bladder and obstructs the tube that's called a ureter. Or when it tries to pass from the bladder out of the body and obstructs the urethra. So yeah, that's the basic definition.
0:04:34.7 DD: And what are the most common types of calculi that form in the urinary tract of dogs? And we'll just focus on dogs today. And you alluded to this just in your last explanation, but can you review again why they form?
0:04:49.8 DF: So, there are two common types, and they're... We see them at almost equal frequency. I'll talk about struvite first. So, I haven't mentioned struvite yet, but struvite stones, more than 90% of them are caused by urinary tract infection in dogs. What happens is that there are certain types of bacteria, where as they grow, they produce things that alter the urine environment, and it triggers that precipitation of substances into crystals, and then struvite stones. Because it's associated with urinary tract infections, struvite stones are mostly in female dogs. So, it's the most common stone type that we see in female dogs. The other stone type we see is calcium oxalate, so that's the one that I mentioned, it's at the heart of my research. Calcium oxalate stones are really complicated. I mentioned that they are hereditary, so in people, they estimate that more than half of the risk is genetically determined. Your biggest risk factor for having a calcium oxalate stone is having a family member who had a calcium oxalate stone. That certainly seems to be true in dogs as well. We see really strong breed predispositions, but we know that genetics isn't the full story, so there are also dietary risk factors that interact. It's likely also how much water an animal drinks, how often they urinate.
0:06:13.0 DF: So, it's a complex problem where a number of things kind of come together and determine how much calcium, how much oxalate is getting excreted in the urine. And then also other proteins or factors that might affect the risk that they form into crystals. And that stone type, that's the most common stone type we see in male dogs.
0:06:33.1 DD: Okay, and I think... And we may talk about this a little bit later, is we'll dive a little into... For those of us who are older, it's pretty interesting how we've seen a shift over the years, right, in sometimes what stones are more common. For the non-veterinarians in the audience, just very quickly, what are the most common clinical signs that we see in dogs with urinary calculi?
0:07:02.0 DF: So, dogs present with signs that something is irritating their bladder or urethra. And what we see are increased urgency or frequency of urination. Often that means that they're having accidents in the house. So, they're constantly running to the door to go out. They might have blood in their urine. So here in Minnesota, we have a lot of times where it's, "Hey, the snow just fell, and I discovered in the snow that my dog has blood in it's urine." And then also in emergency situations, if a stone gets stuck and lodged in the urethra, we can see a dog who strains and strains and strains to urinate, and they're not able to pass urine.
0:07:41.5 DD: Okay. And again, I think that also it can... Signs can come and go too a little bit. I think they eventually evolve into being consistent. But I think your explanation was a really good one. When I was in practice, I think straining and blood in the urine, when people finally saw... That was the most common thing that people came to see me about. And what are the treatment options available when dogs are diagnosed with calculi?
0:08:16.1 DF: So, the treatment depends on the stone type. And we don't know the stone type for sure before the stones have taken out. So, we have to do some guess work. So, for example, if it's a female dog and we think that she has a urinary tract infection and struvite stones are most likely, we try to dissolve those. So that can be achieved by feeding them a prescription therapeutic urinary diet that's formulated to try to change the urine composition and make struvite stones dissolve. Those stones, because they're driven by urinary tract infection, we also need to treat with antibiotics to dissolve the stones. So usually, we start both within a few days, just getting the antibiotics onboard. Dogs often feel quite a bit better. But it can take a month or two for the stones to completely disappear.
0:09:07.7 DD: Okay.
0:09:08.0 DF: The other stone type, calcium oxalate, they are very frustrating. We cannot dissolve them. Sometimes, you mentioned, when we were talking about clinical signs, something I didn't mention is that we sometimes discover dogs have stones and they have no signs. So, we were taking an X-ray for a different reason, maybe they ate a sock or something else, and their bladder is full of stones. When that happens, if we think they're calcium oxalate stones, sometimes we'll just leave them, because of the fact that there aren't easy ways to remove them, and we can't dissolve them. If the dog does have signs of discomfort, so the signs I mentioned before, in most practices, it's going to mean that the dog is going to have bladder surgery to take them out. At the University of Minnesota, and some of the specialty clinics, there are other minimally invasive non-surgical options. So, we can go in with a cystoscope, which is a video camera, and we can use a laser and break up the stones and pass them out through the urethra so that they don't need surgery.
0:10:12.7 DD: Okay. And I think there's also... People may have been familiar with. I think for people, they'll often do... Like they put you in that bath and they put the waves through. My dad had calcium oxalate stones in his kidney. And they did that. Is that available for dogs?
0:10:32.7 DF: Yeah, so you're talking about extracorporeal shock wave lithotripsy. That is available in a couple of places in the country. It's not available at the University of Minnesota. It is used sometimes for dogs that have kidney stones or ureteral obstructions. But most of the stones we see in dogs, they're causing problems because they're in the bladder or urethra. And shock wave doesn't work well in those locations because the stones just bounce around when you try to use it. Shockwave doesn't work well in cats, which is unfortunate because they're the ones who do get a lot of kidney and ureteral stones and really are more like humans and need something for that upper part of the urinary tract. We actually have a clinical trial that's about to start for a new form of ultrasound delivered lithotripsy, which is called burst-wave lithotripsy. They developed it for astronauts, so the astronauts would have a way to treat their own kidney stones in space. So, we're going to see. We have a cat system. We're going to see if it can work for cats.
0:11:40.0 DD: Wow. That's pretty amazing. As you discussed before, you're a geneticist, in addition to all the other things that you do. And so, can you give some examples of breed predispositions for the different stones you mentioned?
0:11:57.1 DF: Yes. So, calcium oxalate are the stone that has the heavy hereditary component. And in the stone submissions that we see at our analysis center that come from the United States, 15% of them come from miniature schnauzers. So miniature schnauzers are one of the top breeds. Bichons are also common calcium oxalate stone formers. Shih tzus are predisposed. Lhasa apsos, pomeranian, Yorkshire terrier. There is a somewhat long list of breeds that have high risk for that stone type. There are some other hereditary stone types, but they're quite rare. So, for some of the other terrier types, the breeds are different. So, one example would be xanthine stones. They are common in Cavalier King Charles spaniels and English cocker spaniels.
0:12:52.8 DD: Okay. And I think a point that people may have noticed is these are typically small breed dogs, though I have occasionally seen calculi in large breed dogs. But not always... Not near as often. Has that been your experience too?
0:13:10.8 DF: Yes. Well, and one of the fun things is we don't know how much of it is body size versus different genetics and large versus small breed dogs. I suspect that it's both. I suspect that larger breed dogs are probably more easily able to pass stones before they grow in size, just because their urethra is wider and it's easier. But if you look at the large breed dogs that are high risk for calcium oxalate. The standard and giant schnauzer are also high risk, not just the miniature schnauzer. Standard poodles are also at increased risk and so are miniature poodles and toy poodles, so that suggests that there really is a genetic aspect and that that might also be part of why we're seeing it in different sizes is just because they're different breeds.
0:14:00.1 DD: Wow, I never knew that about giant and... Giant and regular schnauzer, so that... So, something about being a schnauzer, huh, it's...
0:14:07.6 DF: Those breeds... They are just so much less common that I think we don't see them as often, but they are at higher risk.
0:14:14.3 DD: For sure. And I think it's interesting that when you mentioned about passing, because I often wonder if larger dogs were just... We just didn't see them. I've been amazed. I had a Bichon one time that came in for... They said peeing stones, and I was like, you got to be kidding me. And they brought in a stone and by gosh, that dog really could pass, but it was exceptional, and it just made you uncomfortable, but... Yeah, we had to do surgery on that dog to get all of her stones out, but... Well, that was really, really interesting. Again, the schnauzers are pretty interesting. I didn't mention this before when I introduced you, but of course, you had a foundation grant looking at genetics, so can you walk us through the methodology of some of your studies, and they don't have to be just the foundation study, but how do you approach looking at the genetics of this disease?
0:15:09.1 DF: Alright, we'll see if I can explain this in an understandable way. There are two main approaches that I currently use to try to discover genetic risk factors. The one that I got experience with first, it was part of my Morris-funded research, is called a genome-wide association study or people will abbreviate it as GWAS. And with a GWAS the concept is that you sequence about half a million genetic markers of a dog, so it's not all of their genetic information, but you're testing many, many markers, and it gives you a picture of the dog's genetic ancestry. And then what you do is you take that kind of genetic pattern information for a whole bunch of dogs that are stone formers, and you compare them to a bunch of dogs that don't have stones, so controls and have never formed a stone in their life. And by comparing them, it allows you to pick out what pattern is shared by all the stone formers, what little ancestral region did those dogs inherit that the control healthy dogs didn't. And then we can look at that specific genetic region, we only have it kind of tagged, or flagged right now by markers, but once we know where it is, we then sequence that region more thoroughly to try to identify a mutation that's causing risk for stones.
0:16:41.9 DF: So, the analogy that I like to give is it's... If you know that there was some address, visiting that house was responsible for causing stones, and you had a bunch of people with stones and a bunch of people without, you could start by asking them to put pins on a map of every city they visited, and then look to see what city showed up as more common in kidney stone formers, and then once you know that city, then you could say to those people, Hey, in this city, give me a list of all the addresses you went to. So that's essentially what we're doing, but rather than looking across a map, we're looking across the genome, so all the genetic information. And a city is like a chromosome and the address is a specific genetic region. So, the other approach that we've moved to because it's become... In part because it's become a lot more affordable and we have better tools available to do it, is to just sequence the dog's entire genomes, so not just do markers, but get all two and a half billion base pairs of genetic information on the dog. It's an enormous amount of information, but what we do is take all that data and then we filter again to see what is showing up as more common in stone formers than controls, and that can directly label mutations that are different.
0:18:13.0 DF: The advantage there is that we can also include information as we're kind of filtering and looking at all the mutations about, Hey, does this make sense? Is this a mutation that affects calcium excretion? Is this a mutation that might logically play a role in disease? So, this would be more like starting off, if you've got people with and without stones, asking them to give a list of every single address they've ever visited and starting with all the addresses, so way more information rather than trying to first narrow it down to a city. So, there are advantages and disadvantages of both approaches. The GWAS is less expensive, it works well when you have a lot of dogs available and works well for complicated diseases, but it requires more steps and follow up. The whole genome tends to work really well when we have kind of severe, really onset disorders, so things affecting puppies or young dogs, and generally we have fewer animals involved in that type of study.
0:19:19.0 DD: And for those listening, we... And Eva touched on this, we have done more, so a lot more genetic work. And I think you emphasized, and I'm going to emphasize too, what makes this now possible for us because you might say, Well, why... I know it sounds hard, but why didn't you do it to begin with? One was the cost, which has come down astronomically, probably in the last decade, to do a full sequencing and also the computer power that required to... It sounds silly, because we all think of computers as being all knowing and big things, but we need computer power to be able to compare these full genomes in dogs. So, for a long time, we just didn't have that, and I think we're entering a whole new era of genetic analysis now. And it's really exciting. What did you find, Eva, with your research?
0:20:20.4 DF: So, with the GWAS approach, where in that approach, I was really targeting kind of our typical stone former. And what I mean by that is that most of our dogs that we see with stones, they're middle-aged dogs when they form stones. Schnauzers and Bichons, I said before, they're our high-risk breeds. And so, the GWAS helps, it works well for kind of picking up risk factors in those complex populations. In those studies, we have repeatedly confirmed that there are certain genetic regions that are associated with stones. It's like we found the city, we've even found the right block. However, it's unclear what specific mutation is driving stone risk. So, it's like figuring out that final address and being certain about it, it's harder.
0:21:15.6 DF: And a lot of dogs seem to have a layering of different problems, so they might have multiple different genetic regions that are contributing to their risk. We're still working on that, we're kind of at the level of fine-tuning what we've found to more precisely identify what's happening. We also, with the whole genome sequencing, that approach we've applied to some juvenile stone formers that were unusually young, they were one or two when they first formed stones rather than being seven, eight or nine years old. And they had had multiple recurrences, every six months or a year they were coming in for stones again. When we studied those, we somewhat quickly discovered their genetic mutations, and we found two so far that are very strong. We'd call them kind of monogenic, which means just having that one mutation and that one gene is enough to cause very high stone risk.
0:22:17.5 DF: One of them is in a urinary protein, so it's secreted by the kidney into the urine, and it both regulates urine calcium excretion and then also crystallization. And so, dogs, if they have two copies of that mutation, if they got one from each parent, they form calcium oxalate stones when they're about two to four years old, and they form them recurrently. Of course, that mutation turned out not to be present in the breeds I had first started researching, so it's not in schnauzers, or bichons, or shih tzus, but it's in English bulldogs, Boston terriers, American Staffordshire terriers, rottweilers, mastiffs, a few other breeds. It's actually kind of in the unusual breeds, where if those breeds form calcium oxalate stones, it's almost always this mutation that's responsible.
0:23:05.4 DD: Well, that sounds really interesting. Were you surprised that it's like, "Oh, it's not in these guys but it's in... "
0:23:13.4 DF: Yes, I was so excited and then frustrated at the same time, that our breeds that are making up the most of our stone formers, that I'm still working on, hopefully, we'll have more information and have them solved soon too.
0:23:32.4 DD: So, based on the outcome of your studies, where are you heading next now?
0:23:39.4 DF: I have a couple different directions. I mentioned already that for those complicated breeds, the schnauzer, bichon, shih tzu, Yorkie, some of those other ones, we are still working on trying to identify the specific mutations. For the ones where we already know the mutation, we're trying to understand what does that mean for their individual care, and that's the ultimate hope for all of this work, that if we can... All general dogs that form a calcium oxalate stone, if a dog comes in with calcium oxalate stones, they have about a 50% chance that they're going to form them again in two or three years. And that's awful, especially if it means bladder surgery every couple of years.
0:24:25.2 DF: So, the goal is that, if we can understand why they're forming stones, maybe we can come up with better or more targeted ways to prevent the recurrence, or identify those dogs maybe even before they form their first stone, and prevent the first stone from ever happening. So, for the urinary protein mutation that's in English Bulldogs and other breeds, we're looking at exactly what's happening with some of the kidney proteins that transport different electrolytes in calcium. We're looking at exactly what's happening with crystal formation, and looking at is there anything that we can give that kind of allows the mutated protein to start functioning better again. Or is there anything that those dogs need to avoid, so do they need a different diet than our general calcium oxalate stone former? I suspect that right now, we kind of use a blanket approach of all calcium oxalate stone formers, here's what they need.
0:25:27.0 DF: I'm hoping that in the future we'll instead say, "Hey, this subset, based on your genetic profile, this is the best way to prevent stones for this dog, but a different dog would be better off with a different approach." And maybe a different dog, their risk is so low that we don't have to stress as much about having a whole bunch of preventative therapies or regular visits for them. That's kind of tailoring to the individual patient's genetic background, that's kind of the concept, if you've heard of personalized or precision medicine, that's my pipe dream. I also collaborate with researchers of urinary stones in humans. I work a lot with a team at Mayo Clinic, and also some researchers at the University of Minnesota. We very much have a One Health approach where we kind of go back and forth and say, "What are you discovering, what can we share, how can we help all the species that have this problem with our kind of combined work?"
0:26:26.4 DD: I'm really excited about that. I think for those of us who practiced, and veterinarians listening and the veterinary students, it is so hard when you have dogs with calcium oxalate stones. And owners try to do everything right as far as diet, and they show up again two years later, and the owners are often not very happy with you because here the stones are back, and why are the stones back? And I'm really excited because sometimes it works like a charm and sometimes it doesn't. And I'm excited about your work because I think it can help a lot of dogs that... Especially the recurrence. Those are really, really tough. They're financially tough, they're tough on the animal and the owner. So that's awesome. If you could look into your crystal ball, which I see you having there in your office, [laughter] where do you think research on this problem is heading? It's really taken a genetic turn that nobody was really looking up when I was a student or early practitioner. Then I think we were just trying to figure out diet stuff. And where do you see this going?
0:27:35.9 DF: Well, genetics, I think, are going to continue to be a big part of this, but I've seen a lot of branching into other areas that it never would have initially occurred to me to look at. So, one that's kind of become a hot topic is the microbiome. So, all the bacteria and other microbes that normally are supposed to be living in your body, they live in your intestinal tract and your skin and other places. They also live in the urinary tract, so you do have some bacteria that are normally hanging on the urinary tract, that's true of people and dogs. And now there's growing evidence in people and humans that are stone formers, that microbial population, both in the intestinal tract and the urinary tract are different in stone formers. And we don't know whether or not that's kind of a marker of how the environment has changed or whether or not those microbes are actually contributing to the risk for stones.
0:28:36.7 DF: Are they somehow helping those crystals precipitate out? Are they affecting how much urine calcium or oxalate ends up in urine? So, I don't know, but I do think that that's a new direction. I have a graduate student right now who is quite brilliant, and she is passionate about microbiome research, and so she's starting work on the urinary microbiome and dogs with stones. And then we're also looking at how does that relate back to their genetics? So, are there things about a dog's genetic that affect what microbes live in their urinary tract? And are those kind of two interacting to determine stone risk? So that's one area. Metabolomics is another one, which is just asking what the body is producing and also what the bacteria are reproducing and releasing that might affect stone formation.
0:29:31.4 DD: That sounds really exciting. As a GI person, of course everybody knows the GI tract is just filled with bacteria and stuff. I'm really excited. Obviously, people look there first, but I read all the time about there's a blood microbiome and probably a... You know what I mean? And urinary. So, we're not sterile, like places we thought are sterile, but they're not necessarily harmful. They could be good guys, so that's super exciting. As we wrap up, Eva, what's your kind of take home message for our listeners?
0:30:05.4 DF: Well, I think the point that you made is the big one. You mentioned how frustrating it is that urinary stones, particularly the calcium oxalate type, they are complicated, and so we do not have a reliable way to prevent them. They're frustrating. They come back and that can happen even if you follow every recommendation, because really we need to find better ways to reduce the risk of recurrence. Even our best right now is only okay. And that is in part because there are genetic factors that are probably very, very hard to overcome. There are just things about that particular animal that they were born with and that we're not going to be able to change necessarily. That said, that is my focus and hope that we might find creative solutions to get around it to solve problems. Even if we can't correct their genetic mutation, can we use it to understand what's best for the animal?
0:31:19.9 DD: Well, that's great. Well, thank you so much. So that does it again. That was so fast. Thank you, Eva, for coming on Fresh Scoop and joining us today, because it was really fun. As everyone knows, we'll be back with another episode next month that we hope you'll find just as informative. The science of animal health is ever-changing. This was a good example today, and veterinarians need cutting-edge research information to give their patients the best possible care, and of course, that's why we're here. You can find us on iTunes, Spotify, Google Podcasts and Stitcher. And if you like today's episode, we'd sure appreciate it if you could take a moment to rate us, that will help others find our podcast. And a big thanks to everyone who've been listening and recommending us to your friends, because we just passed our third anniversary, and we are among the top 25% of podcasts in the world. Whee! Which is hurray, and we're hoping... We want to really get good science out there. To learn more about Morris Animal Foundation's work, again, go to morrisanimalfoundation.org, and there you'll see just how we bridge science and resources to advance the health of animals. You can also follow us on Facebook, Twitter and Instagram.
And I'm Dr. Kelly Diehl and we'll talk soon.
