Transcription
Dr. Jacob Torus, you were a researcher over at University of California Santa Barbara. You do a lot in the metabolic health space. Let's talk about some of the organs that we really look at generally speaking when we're looking at metabolic health, metabolic syndrome, and whatnot. I mean, people focus on the liver. They focus on the mitochondria in general, but there are some other aspects that people might not be focusing on.
Can you give me sort of a big overarching view of how some of these other organs might be involved in metabolic issues that people might not be thinking of?
Yeah, that's kind of a funny question. I think, you know, everything is metabolism. Metabolism is just the breakdown of energy and making energy, making macro molecules like making proteins and carbohydrates and whatnot. It's just the sum of all the reactions that are going on in the cell.
Every tissue participates in metabolism in some way, so metabolic health is important to every single organ system. We focus on particular systems themselves, like you mentioned the liver, because it's kind of the one that regulates fats in the body, so we're really concerned about it. Or glucose. It has these general markers that we are concerned with of energy. But realistically, every cell requires these molecules to make energy and perform their own metabolism, and they're all talking to one another back and forth.
So, I think that it's very simple to say it's important to all systems. If you zoom in on any one particular cell type, you're going to find a lot of interplay between all these different systems talking to one another, and that's really what metabolism is: that interplay.
Interesting. Yeah, I think people think metabolism, they just think creating energy, and that's it. They don't think about the actual communication between the systems.
So what do you mean by communication between systems?
I mean, obviously, people are pretty familiar with fatty liver. They're familiar with visceral fat. They're familiar with that aspect of poor metabolic health, right? But how does that play into these systems that are communicating with one another?
Yeah, so the way I always think about metabolism is it's a homeostatic regulator. It's always about homeostasis—finding that balance between signals. The way that cells work is they're not just these on/off systems where something comes in; it's not binary or digital, you know, like we're kind of used to with computers and whatnot. They're analog systems.
A lot of inputs come in to create a baseline level, and it's a sensitization to that baseline that is what the cells are responding to. So if you have a lot of glucose come in, that change in glucose from baseline is what the cell will then respond to. It reaches some threshold, and then that causes a signal. If you have high glucose for a long time, it has to move that baseline up. So the homeostatic regulation is changed, and really, this input that comes in is detected against that baseline. Then the signal will propagate depending on how far away from that baseline it is.
And I would imagine that this signal can be disrupted in a lot of different fashions—not solely by glucose, right?
Oh no, every molecule is performing this function.
What, I mean, in your experience, what are the more common ones? Obviously, glucose is a big one because it's something that's talked about a lot and we see it a lot, but I'm sure fats have a play here. I'm sure specific types of saturated fats have a role. I mean, what are some of the big ones—the bigger levers that people could say, “Okay, yeah, that has an impact on my metabolic health”?
Yeah, the big levers, of course, like you mentioned, glucose and fats are the energy molecules. Of course, they have very big impacts because they're the inputs that are constantly coming in. But, you know, not eating is also a lever, right? Because it's the exact—it's the opposite of that effect, and that's what causes the change in the homeostatic regulator as well. It's either going too far in one way or too far in the other way, and it's kind of those are the interplay between them.
You know, I don't want to get specific, but yes, there are many molecules that perform that function. So the fats, carbohydrates, and proteins—those are all the macromolecules that we're very familiar with studying. But realistically, all of the substances that those are made out of are also playing that same role in regulation.
Gotcha. Yeah. So we start talking— I mean, you do a lot of research in the kidney realm.
Yes, this is very interesting to me. I mean, you don't hear the kidneys talked about a lot in the general, I'm going to call it, the metabolic sphere online. We've got people that talk about metabolic health, myself included. I know, you know, five or six years ago, I did some videos on the relationship with the ketogenic diet and kidney health, and that was about as far down the iceberg as I got.
But the more that I talk to people, the more that people talk to people from your lab, I start to understand, okay, there is a huge play with the kidneys and just our overall metabolic health—not just about your ability to filter and your ability to pee. I mean, there's a lot more going on.
Can you give me just like an overhead view of that, and then we can double click on some stuff?
Yeah, I think it's funny, it's—you know, people like to rank the organ systems as to their relative importance. They all are pretty important; they each have their own functions. You know, the liver, like you mentioned, is very talked about with metabolism, but the kidney is actually a very important part of overall metabolism.
A lot of people don’t know this, but it actually consumes a lot of fat. It’s a very energy-intensive organ because it does so much work all the time, specifically because it has the function of the ATPase. The ATP channel that's involved in sodium and potassium pumping takes a lot of energy because it's always on. It is constantly pulling ions out of a gradient, so it takes a lot of energy.
It's always running through energy, so it has a lot of mitochondria, and it also is regulating fat metabolism as well. For instance, if you eat a very high-fat meal, you have a lot of fatty acids in the blood. The kidney actually will soak up a lot of those fatty acids into lipid droplets and then slowly release them back into circulation to kind of buffer the overall fat content of the blood. So it's really interesting.
Does this accelerate in someone that's in a fasted state? I mean, as you have more liberation of fat, is it kind of regulating some of that?
Yes, it is.
Wow, that's wild.
So then, if someone will say—I want to go in a little bit of a different direction with this because it's interesting. If someone would say fat-adapted versus not fat-adapted; someone that is experienced with fasting versus not experienced with fasting; or even the ketogenic diet versus not experienced with the ketogenic diet—like they don't have that level of keto adaptation or fat adaptation—does that change how the kidneys regulate? Can there be enough communication to say, “Hey, these cells have an affinity for fats or an affinity for ketones”? Is it going to regulate and liberate more? Does it communicate that way?
That's a good question. I think that the way that the fat droplets are happening in the kidney is just due to the amount of fat in the blood. So if the serum concentration goes up, then more fats will just end up in the kidney tissue. So, I don’t know if there’s like a specific regulator because that’s not researched.
The data that I know about fat droplet accumulation and fatty acid regulation is very old literature. I don’t know if anybody’s actually looked at it now because, currently, fat droplets are generally considered negative. They’re not considered to be something that’s good; it's a pathology a lot of times because it means fatty acids are very high in the blood, so they end up getting pulled into the kidney or into the liver, like with steatosis and that kind of stuff.
So they end up being negatively associated, but I think that they have a positive function because the kidney needs fats to operate. It's using those lipid droplets for energy or it's buffering the total fat in the blood, so it has this dual function under just normal conditions.
So is there such a thing as a fatty kidney, just like there's a fatty liver? There must be; I mean, I assume so.
I assume under pathological conditions you would probably see lipid droplets that are not just for energy because, over time, as metabolism gets broken down, like if somebody has a defect in mitochondria, they might accumulate these droplets. If they're not able to push them into the mitochondria, they actually go through another process that's called omega oxidation and into a peroxisome—another organelle in the cell that can break down fats—and those can actually cause a lot of toxic byproducts.
Those are known to show up in kidney disease after.
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This is wild. It's actually sincerely fascinating. So does the kidney, in essence, from what you know, does it operate almost as a repository for those fats to drip them out or is it to say, “Hey, we need to bring levels down”?
Or is it both sides of the coin?
I think it's both. It can actually help regulate, saying, “Hey, if energy needs aren't met, we need to release some.” I don’t know if there's any literature on athletes in this particular case—probably not—but it makes me wonder, like, okay, training in a fasted state, someone that's fat-adapted—if you have a higher level of serum triglycerides and you're going to go ahead and pull some into the kidneys—is it going to know how to release them based on intensity levels?
Someone that has a higher, you know, respiratory exchange rate or lower respiratory exchange rate at a higher intensity because they're better at using fats?
I don’t know. You see, you've already... Yeah, this is why research is fascinating, right? Because you get these questions come up like, “What is this actually doing in practice?” and I haven't seen anything like that because you'd have to do like a biopsy—like you'd have to biopsy the kidney during these times to see it. It'd be very hard to study without actually killing somebody or pulling the kidney out and looking at it.
You could look at, like, in animals. It could be done potentially, but it would be a very difficult study.
Yeah, where does this start to come into play with someone that is maybe metabolically deranged or metabolically unhealthy? Like, what does a healthy kidney do in this particular case versus an unhealthy kidney in this context?
Yeah, I think that just the normal way that the kidneys function is using a lot of fatty acids. It's doing a lot of sodium and potassium pumping. It regulates all sorts of other solutes as well, but it's just using that for energy because the mitochondria are such a big part of the kidney. It's just able to do a lot of fatty acid oxidation, so it's just burning through these fats.
Under deranged conditions, it means that these would accumulate because there's mitochondrial damage. If that happens, then you end up having to break down these fats in this alternative pathway, and then those are all oxidized compounds that come out of that. Those can cause inflammation, or they can do a lot of other stuff too.
There are a lot of really interesting things that happen there depending on the type of fat that's getting oxidized in that pathway.
That is wild. I mean, think about it. So if someone is in a low-carb state—and this is going to sound tangential—but it's going to come back, okay? Someone's in a low-carb state, insulin levels are lower, and they have a higher propensity for muscle cramps, things like that.
Is there also a play with the kidneys there? Because I can speak from my own experience: when I am very low carb, I have a much higher propensity for muscle cramps and cramping in general. So I would imagine there's some fluid regulation issue that's happening there, and it doesn’t matter how much salt I take in; that doesn't just solve the issue, right?
Like, the cramping will still happen because there’s clearly some regulatory aspect that may be out of whack. Do things change in a low-carb state with the kidneys or is it an energy...?
You know, there's so much more energy coming from a fat perspective. Can the kidneys say, “Hey, our energy demand is so high that...”? I don't know if you get where I'm going with this.
Yeah, I think what you're saying is... If you do like a ketogenic diet, there’s a tendency to get these cramps because of low sodium or potassium levels—like the disbalance between those two. So, you know, it's a good question. I imagine there’s probably a natriuretic effect.
So you’re peeing out excess sodium; that's why, you know, adding sodium in is a big part of it. I'm thinking about why that occurs; I don’t know exactly the mechanism of why the carbohydrate part is important there, but there is a sodium-glucose transporter.
I mean, that’s what those the SGLT inhibitors are doing—they're regulating that transport. So I wonder if maybe there’s a necessity for some glucose that’s not being... It’s not doing the job it’s supposed to do to help regulate the sodium-potassium balance.
That's actually interesting. I don't know the answer to that one exactly.
Yeah, it's—I mean, I've thought about it a lot because I find out, though, go back to the lab. I'll figure it out. I'm sure that's known. I'm sure.
Yeah, it’s... I mean, you think about, like, I have a history of kidney disease in my family. My grandpa had one kidney; his father had one kidney removed, obviously, and so I'm aware of that kind of stuff. When I’m—I already have issues with fluid regulation to begin with. I think I have—I don’t want to say I have early-stage kidney issues. I don't— but I've always been aware of that. Like, my fluid regulation is a little bit off.
I've always been prone to cramping, and in a lot of ways, the ketogenic diet was helping me with overall fluid balance. I was finding that I was better because, with the exception of cramping under extreme conditions—that was something that I had a higher propensity at intense, high intensities—then I would cramp more.
But generally speaking, I wasn’t urinating quite as much. Once things stabilized, normally on a ketogenic diet, like you find people start to, you know, there’s less carbohydrates so, there’s going to be less water retention. So people are usually peeing more, especially with insulin levels being low.
So, I’ve kind of found that that low-carb state helps me regulate a little bit more, but there’s also some interplay between—and I know like some of the stuff you've seen in your lab as well—with kidney function, low-carb states, and also the effect of ketones themselves on the kidneys. Can you kind of give me an overview on that?
You want to know about ketones in the kidneys specifically?
Yeah, well, okay, you got a lot of people—first of all, a lot of people that think that being in ketosis is bad for the kidneys.
Oh yeah, which I found in my research over the last, you know, decade. Definitely, or at least it does not seem to be the case.
Yeah, but how do ketones affect the kidneys, both positive and potentially negative?
Yeah, I think that they—I think you're talking about the ketoacidosis issue. I think that that's always been the kind of the issue when we talk about ketones is the association of ketoacidosis, which is the metabolic state of when you're overproducing ketones even though there's high glucose and high fatty acids in the blood. That's what we see with diabetes.
So that's usually when ketones are bad because they’re causing acidification of the blood and all sorts of other negative things. But under normal conditions, like I mentioned, the kidney is a very energy-demanding organ. So it uses fatty acids predominantly—at least parts of it.
The kidney is divided in this, like, you know, what they call the nephron. You have an input, which is called the glomerulus, and things get filtered through that. Then you have a part that goes down and then back up and then back around to make urine. Each part of that tubule has different types of cells that line it.
Some cells are more dependent on fatty acids that are further up at the beginning because they’re doing a lot of the pumping, and then later down, they might be doing more passive collection, so they don’t have the same requirements.
It turns out that, like, the upper part of those cells are actually making BHB. They’re making ketones, and then the ones at the bottom can use it. There's actually changes in concentration along the nephron of BHB.
So the weird thing about nephrons is they're controlling what solutes are in them because that's how you pull water out or pull sodium and other solutes out—it's changing the concentration as it goes down. So you're kind of getting more concentrated, and then you come back up and then the concentration is changing.
This is why it takes so much energy is because you’re trying to create a gradient. It turns out that these cells are making BHB, it's going down and coming around, and there’s a mechanism to pull BHB back across the nephron because there’s a place—it's a junction between the glomerulus at the top and then the late nephron and that pulls it back in.
It actually can increase the flow of things going through it because it's kind of a perpetual energy device. It’s like a weird—it’s using energy, though it uses sodium to do this. So it needs energy put in to do it, but then that kind of increases the GFR, or the glomerular filtration rate—that’s how fast things are going through there.
It can kind of increase that flow, so ketones actually have a role in that function as well. So it’s like one of the just things it does. It turns out different parts of the nephron might be responding differently to ketones, and that's just a very surface-level thing, right? Because ketones also have all these other functions.
So they do more than energy. I think that’s always the big thing that’s hard for a lot of people to understand—they really focus on that energy part, which is a really important function. But in the kidney, it's likely that these other functions are probably more relevant than just the energy because they use fatty acids so much.
So if someone is even not in a dietary ketogenic state, these nephrons are still producing BHB, correct?
Wow, that’s wild.
So it’s just, it’s such an aerobic system that it’s just like, yeah, it’s actually the second ketone-producing organ. The liver is like the primary organ that’s like making the ketones during fasting, then the kidneys is the second organ that makes ketones the most. But those ketones that are produced in the kidneys are not liberated into the bloodstream, are they localizing?
They probably are, yeah. They're probably because they're getting pulled back in through—there's a transporter that's specifically for, you know, the carboxylate. Anything that looks like a ketone that has that same structure will get pulled back in, and those are making a way into the bloodstream.
I don’t know what amount, though. It's quite a bit. I think this has been done many years ago in dogs—they figured this out, like how much of the kidney contributes to ketone production. It's not insignificant; it’s a very large amount.
Jeez, that’s wild!
So if someone is in a nutritional ketogenic state, do they potentially—I don’t know if there’s any research on this—become even more efficient at producing those in the kidney? Because we know that we've seen that like the liver becomes more efficient, you know. You just develop—in the beginning when someone is doing, say, a ketogenic diet, it’s like they start producing almost too much in the way of ketones. You have a bunch showing up, at least in the urine, and some—you have extra.
And then, eventually, you kind of find this efficiency, and that’s usually just because you're producing it more efficiently. So do you notice that in the kidneys as well?
I don’t know because it hasn’t been—I haven’t seen research looking at that specifically. I would assume so, just because of adaptation purposes. Like, why wouldn't it get better at it?
You know, probably the protein expression of those particular enzymes would go up. That's just a really—that's another one of those homeostatic regulator things.
Yeah, so I imagine they would happen.
Yeah, I find that super fascinating. And you probably don’t know the answer to this, but I'm saying, because this is where my brain is going, I find it interesting because, okay—say someone becomes keto-adapted, or they develop this efficiency, and then they cycle off of a ketogenic diet. And they’ve potentially retained some of that efficiency where these nephrons are still able to produce high amounts of ketones.
Potentially increasing kidney function even in the absence of dietary ketosis?
I would think so. I think that's a pretty well-established function. Whenever you gain adaptations, you generally don't lose all your adaptations just in—you know, with exercise. You know, you work out a lot, you stop working out for a few weeks; it doesn’t just go away.
Or a few months, you know, and you might lose a lot of what you gained, but you still have some adaptations, like structural things, like bone density and stuff. They don't just go away.
That's a good point, yeah. Similar, I think so for kidneys.
And just for the sake of people that are watching and listening, I mean, even from the sake of, like, mitochondrial density. It's like, that doesn't just go away, you know, really quick.
So if you do a lot of aerobic exercise, or you go through a training block for a couple of years where you’ve established really good metabolic health and mitochondrial health, it's not like that just disappears overnight. You've retained some of those adaptations, and it’s going to take time.
The only reason I say that is just so that this doesn’t sound completely Greek to people when they’re thinking, “What adaptations are we talking about in the kidneys?”
Yeah, I just published one of the figures in my most recent publication showing that mitochondrial number goes up. So we were able to count—look at the copy number of DNA in the kidneys, and we were able to show that with BHB, the mitochondrial number increases.
Really?
Yeah.
Do you have you noticed that same thing? Or is there any research on exercise and mitochondrial density in the kidneys?
Not that I can find, but I imagine it has to happen.
Yeah, I’d have to look for it.
My mind is actually pretty blown because it’s like—I just have never thought of, you know, it obviously makes sense when it’s spelled out for you. You look at this, and you’re like, “Of course, it makes sense,” but I’ve never thought of the kidneys as this metabolic arm as such, right?
Like, okay, like you're exercising; it's good for your muscles. It's good for your heart. It's good for the mitochondria, but you don’t think about how it’s improving these independent organ systems and whatnot.
So where in this place could, let's say someone’s not doing a ketogenic diet—because we have a lot of people that watch and listen that do not follow that or have never done it—are there ways to get similar effects?
Like, even the use of exogenous ketones or forms of ketone salts or monoesters or anything like that—does that have an impact? If someone would say, “Okay, I want to have this effect of ketones on my kidneys,” but I don’t necessarily want to do a ketogenic diet.
Like, is there a play there?
Yeah, I think so, and all I have is information from animal research that I’ve done. So I know that there is an effect similar to that. I just presented a poster recently at the APS conference down in Long Beach a few weeks ago.
One of the things I was presenting on was the effects of timed feeding and periodic fasting, and then showing that we were able to give BHB to the animals and recapitulate a lot of those findings. A lot of the same things that happened from the fasting also could happen from BHB as well—look like very similar effects.
We don't know all the effects of fasting or all the effects that are the same, but many of the ones that we're looking at in our disease model—I study polycystic kidney disease, so specifically I’m looking at primary outcomes of that disease model, and a lot of them are recreated by BHB.
So I think that there is a potential for someone to use BHB or a supplement and have a lot of the same effects.
And I know— I mean, even though polycystic kidney disease is a very niche piece to talk about, I think it illustrates the potential that ketones may have because it’s just the tip of the iceberg, right? It’s just like where there has been some niche research there.
Can you explain how polycystic kidney disease and the relationship with ketones might look? Can you explain what polycystic kidney disease is? That’s probably a good place to start and how ketones have that effect on them.
Yeah, so I’ll call it PKD; it’s just easier to say. So PKD is a genetic form of chronic kidney disease. Chronic kidney disease is this progressive disorder; everybody has chronic kidney disease. Just how fast do you progress?
Some people progress much faster. So we’re all going to die eventually, I think, and one of the reasons is because kidney function just, you know, over time gets worse and worse because life is hard. You have to deal with a lot of stuff as a kidney.
So chronic kidney disease is like that acceleration. Some event occurs, like an injury to the kidney, and then you end up with a lot of scarring, so fibrosis or loss, and that causes loss of kidney function a little bit at a time.
Over time, that kind of builds up, and then you have fewer available nephrons to actually do the filtering, and then it becomes harder and harder for your kidneys to function, and then the end of that course is renal failure.
You end up with end-stage renal disease, and you need a kidney transplant. That’s kind of the end.
Polycystic kidney disease is a genetic form of that progression, so there’s a more rapid progression because of the genetic component. People will live their life not knowing they have polycystic kidney disease, and then at some point, they end up finding out that, “Hey, my kidney function is declining.”
But the reason it’s happening is because they're accumulating these large cysts on their kidneys, and they’re starting to replace the normal healthy tissue, and that’s the loss of the nephron, so they get the chronic kidney disease phenotype where they're slowly progressing as these cysts start to accumulate on the kidneys.
So that's kind of the relationship between the two. It's just a genetic form of chronic kidney disease is the way to think about it.
Okay, so it's just, yeah, almost an accelerated, in a way, accelerated aging—even though it's not actual aging.
So, cyst formation—anybody can make cysts in their kidneys. That’s part of the research: understanding what are cysts, why are they being formed.
Because some individuals, you know, will go to get a scan of their kidneys and there will be a cyst, and they'll be like, “Why did this happen?” It seems to be an injury response. It’s some sort of repair that maybe you need to wall off an area that there’s something that the kidney can’t deal with, so it makes a cyst around it.
It can’t deal with it; it has no other mechanism to deal with it, so it makes these cysts. It’s probably something like that. That’s probably just some aberrant injury response that’s in PKD.
Do I mean in the case of—not in the case of PKD, but if someone’s just developing a cyst, is that usually—that cyst is there, or do they eventually go away, or usually they stick around?
Yeah, I think that—that's the issue; they usually do not go back. Once you have the cyst, you kind of just stay there. It might get smaller or larger, but it’ll just kind of stay in one spot.
But I mean, for all intents and purposes, when you develop a cyst, I mean that is a portion—sometimes, I’ll be at a small percentage of kidney function that you essentially lose.
Yes, you lose some portion of it because that cyst comes from the nephron itself. One of the cells inside that nephron will then start to propagate, and it makes it like a clone of it and makes that cyst.
Interesting. And then it just kind of pinches itself off, and now you have that nephron as a dead end, and then you have a cyst that kind of is off of the side to it.
With polycystic kidney disease, that’s just happening at a rapid, almost genetic mutated rate.
Yes, it’s happening very quickly. I think with our research, the research that I’ve been doing in our lab, we think that injury is the real culprit. It’s not the genetic component alone; you need another thing to happen—a triggering event—to initiate the cyst.
Gotcha. So where does BHB potentially play to this? Is it just making it more efficient for the kidney to operate with less function?
So the way it plays in is there are many facets. The main thing is that PKD is not just a disease of this one mutation. Well, there are many mutations—I’ll just say there are lots of different things that can cause it—but it also causes mitochondrial dysfunction.
So you have a change in the morphology of mitochondria, and you have a total loss of the number of mitochondria, and you have a shift over to glycolysis as the primary energy system that this is happening.
The reason you know that's like kind of like an injury response, all cells kind of do this under injury systems, is because of inflammation. If you have an inflammatory response, cells kind of switch over to this glucose mechanism—that's just kind of like a normal thing that happens—but the cells never kind of go out of that, so they stay in that state.
They kind of propagate inflammation, and it keeps more and more inflammation occurs over time, and that’s what causes, I think, a lot of the injury and then the cyst formation.
BHB or ketones—I guess I’ll talk about primary like BHB—is that it can have a lot of anti-inflammatory effects.
They do this through a variety of ways, and one of them is that it can, you know, affect macrophages. So macrophages are the white blood cells that are, you know, surveilling the kidney. They kind of go around. They're a big part of the inflammatory response; they seem to be really, really critical for the progression of PKD.
BHB can actually affect their switching. They have different modes that they can exist in, so they can exist in kind of like a surveilling mode and then like a very active repair or injury mode, and BHB affects that switch between the two.
It's acting on immune cells in that way; it acts on all immune cells in different ways, but specifically, macrophages, so that can stop progression that way.
Then you have a mitochondrial effect, so it could be helping with, you know, making it easier to make energy through mitochondria. It also seems to have some effects on changing the cell over to fatty acid metabolism by interacting with particular proteins that are called transcription factors, and they kind of turn on the genes that are involved in fatty acid metabolism.
Those also seem to go down in kidney disease, chronic kidney disease, or PKD, and it can actually turn those on genetically, so then they start to be expressed more.
So talking like PPARs?
Yes, exactly.
So that's, I mean, it's just so funny because I've just seen it being in the keto world for, you know, over a decade. Just, you know, “Oh, don't do that; it's going to be bad for your kidneys,” and I’m just kind of like almost laughing on the inside because it’s like this is one of the better things; it's probably one of the better things.
Yeah, from the inflammatory standpoint, I mean, you've done a lot of research. Just BHB in the first place—is it mainly in NLRP3 inflammasome? Is that kind of the effect there?
You know about BHB also inhibiting the NLRP3 inflammasome then, yeah.
So is that the switching that you’re kind of talking about there or a different element?
So that’s a different thing, yes, but that’s another big part of it. That would be in the cells of the kidney—so the epithelial cells—that would be very important there.
Got it because the NLRP3, if people aren’t familiar, that’s the initiator for like the IL-1β secretion and all that cascade pathway that's involved in kind of like pro-inflammation, secreting the cytokines that then activate the inflammatory response in cells nearby.
BHB directly inhibits the NLRP3, so it prevents that downstream cascade, and so that alone will stop the progression of injury.
That’s one thing. In the macrophages, they actually have a receptor. It’s called GPR109A. It’s a receptor for BHB. This receptor exists on many different cells, but in the macrophages specifically, this seems to be really important for the type-switching effect.
Interesting.
Yeah, is that—the effect of what is it—it's a hard word to say, “beta-hydroxybutyrate”?
Oh yeah, “beta-hydroxybutyrate,” that's the easy way to say it, yeah.
When you start getting into—
So that’s a different—that is a different thing. So I know that was something that was—where you're almost starting to develop an affinity where it can kind of use that.
So I guess my question with this is where I’m interested for years and years in the world of keto I was always interested in the anti-inflammatory effect, right?
And even in my early years, I was probably being a little too cavalier with how I would talk about things. You know, I kind of thought there was this overarching anti-inflammatory effect. But is it pretty localized when you kind of see that happening as far as the inflammasome is concerned?
Like, are you not just getting this general cascade of reduced systemic inflammation in the body? Is it kind of happening in essence where you need it?
No, I think that what you’re describing is the reason that it would reduce it systemically, because you’re targeting the pathway that causes the release of cytokines, and cytokines go into the circulation and go into the tissue surrounding it, and they just kind of make their way throughout the body.
So if you inhibit the cells that are secreting those things, then you can inhibit global inflammation as well because you’re just blocking the source. So it does both functions.
It's well, I mean, because you hear it when you talk to people, right? I mean, it's like sometimes it's in the low-carb space; people come under attack a lot when they talk about like, “Hey, I felt so much better.”
There’s probably a million reasons why people feel better when they go on a ketogenic diet or when they just reduce the processed foods out of their diet in general, but you know when people have metabolic issues and they have chronic inflammation and they see those numbers change and they feel different, I mean, it’s hard to deny that, right?
It’s so—but specifically in the kidney level, I mean, how long does it typically take for someone to start to see pathological differences? I mean, like if they’re actually introducing a ketogenic diet into their life or they're using some form of, you know, ketone salts or whatnot. Is it a pretty quick thing?
Pretty quick change?
That's a good question. I would think it's probably pretty quick. I think that there's no reason to think that this signaling wouldn't start happening pretty rapidly.
I mean, there are going to be differences, of course, between animals and humans. I know that like they’ve done research on metabolic health in people and seeing that within a few weeks of people that are sedentary—those who have very poor metabolic health—they put them on exercise regimens and are like, you know, increasing aerobic work.
They see changes already happening because the proteins they start to change; they start to be made really quickly, they’re involved in doing your metabolic machinery. So I could see pretty rapidly that that would make—make sense that it would happen.
So yeah, I don’t have a direct—I don’t know like an answer like, “This many days” or that, but it makes a lot of sense that it would happen very rapidly.
And as far as—a company called Santa Barbara Nutrients has done some work with this, right? I mean, it’s taken some of the research and it's kind of applied it in more practical applications.
I think that is, first of all, can you tell me a little bit about that? What variation? Because I know it’s using ketone salts, but I don’t know if it’s in a specific mineralized form that is specific for the kidneys.
Yeah, first, a little bit about it, but also just how it works.
Yeah, so we started Santa Barbara Nutrients because of some of the research that I’ve been doing. You know, at UCSB, we found that combining a couple of other projects together into one mega project was a good idea.
In 2019, I had the paper on ketosis and PKD. That was the one paper that we showed that when we gave beta-hydroxybutyrate to the animals, that in that study, it had prevented the progression of PKD.
Then we had another paper where we looked at microcrystal formation in kidneys accelerating PKD. We knew that if you give citrate to animals, you can prevent the progression of PKD. That was a very old piece of literature that I was working off of there, but we just have a mechanism.
So we took those findings from those two papers and put them together to combine beta-hydroxybutyrate and citrate together. We hypothesized that if we had them together, maybe we could lower the amount that you would have to give them in order to create a synergistic effect.
That paper got published last in December, so I worked on that for quite a while. During that time, we had a patent with UCSB, and then we have a license to commercialize that patent.
So we made Keto Citra, and Keto Citra has been on the market for a few years now. It’s formulated to have beta-hydroxybutyrate and citrate together, and the ratio is based off of the research that we did in the lab.
The idea is that we have no sodium because sodium is involved in, you know, worsening progression—at least in a lot of studies done with PKD. We use calcium, magnesium, and potassium.
Potassium is in there because that’s, you know, very important for kidney function. It’s actually—potassium is, I think, woefully under-supplemented. People usually have very low potassium when they actually need much more than they think they do.
Magnesium and calcium are in there because those can bind to compounds in the gut that can cause kidney stones—like oxalate, that's a big one—or phosphate.
We think that those are kind of able to prevent the formation of these crystals in the kidney. Together, you know, the idea is that not only do they provide alkali base—BHB is a salt, so the salt will increase the amount of alkali in the urine—so that’ll raise urine pH as well to prevent crystal formation.
All those things together are kind of, you know, it has BHB and citrate. Citrate also binds to calcium in the urine, so that prevents the crystal formation. We have kind of like all these different approaches. The BHB has all the mechanisms like I was talking about before plus many more that are undiscovered, but it seems to be like those together cause a synergistic effect in the animal models.
Gotcha.
So originally it was really sought out to be something for PKD in the first place. I mean, really just, but is there an application potentially independent of that just for general kidney health?
I think so. I might be biased, but I think it has the application just because potassium has already been shown to be beneficial to kidneys on its own. I think there’s lots of research on just supplementing potassium chloride as being beneficial for kidneys, so that data already is plentiful.
A lot of people know that. The other part of it is the alkali, so if you just removed all the other ideas by just adding alkali and potassium alone already would be significantly improving kidney health on them by themselves.
When you add alkali to kidneys, you actually increase the amount of NADH that can be produced because you’re changing the barrier—you’re lowering the barrier to making more energy by increasing the alkali in the cells.
There’s a lot of interesting research that’s shown that where you just add bicarbonate to cells, and they start to make like tons of more NADH.
Really?
Yeah, just because of that alone!
So adding increasing the alkali in the urine is already good—that’s already a good thing.
And then you add on top the, you know, the prevention of microcrystals, which I think we’re all making these crystals. That’s just part of the kidney’s job is to filter and make the—and you know, get rid of these solutes.
In that process, you’re going to make some of these crystals. So having citrate available should just prevent that from being an issue, so you’ll prevent kidney injury on itself.
And then the BHB has all of these functions that are just like—they’re very numerous. So I think there’s no reason not to believe that that would have benefit in just normal kidneys.
I mean, I don't see why not.
Yeah, you're getting, I mean you're getting almost the energetic benefit, the anti-inflammatory benefit, the potential lesser effect, right? Just by...
Is the crystals themselves that actually have an injury effect?
Yeah, so the crystals have—they have a few different ways that they cause injury. They have—you know, there's probably a receptor for oxalate. I haven’t seen—nobody knows exactly what it is, but it probably has a receptor specifically that causes the effect that causes a lot of free radical damage because it just blasts off free radicals as soon as that thing gets makes contact with cells.
Then it activates the inflammasome and then has all of these effects of causing tubular dilation and kidney injury just on itself, just the crystal itself.
So yeah, I think that that’s a big thing.
I want to come back to oxalates in just a second because that’s something that people talk about a lot, but I went ahead—I put a link down below for Keto Citra as well.
So I mean, and where can people find it in addition to the link that's down below if this is something—if they were looking for it?
Yeah, SantaBarbNutrients.com is our website; that’s where you can find it.
Cool. I’ll link out to all that stuff down below so you guys can check it out.
And again, like, it’s something that—well, for what it’s worth too, there’s also just the flat-out effect of exogenous ketones that you would get out of this too.
So even if you were looking at it, saying like, “Hey, this kidney health isn’t necessarily my focus; maybe it’s a secondary focus,” there’s still the effect of having, you know, actually a non-salt form of BHB, which is actually kind of nice because I know some people want to take exogenous ketones but they don’t necessarily want a thousand milligrams of sodium or something like that, right?
So, okay, coming back to oxalic acid or oxalates for a second.
I know this might not be your wheelhouse, but there's a lot of people—obviously you’ve got the carnivore community that is very anti-oxalates.
Is the evidence strong or is it really, really in its infancy when it comes down to consuming oxalates and how those can impact your kidneys and in turn have an effect on ROS and whatnot?
Oh, the data is out there. It’s definitely not good.
Really?
Yeah, oxalate is terrible for your kidneys.
So even coming from like just raw vegetables, kind of thing like that?
Yeah, any—oxalate, you know, it’s... The kidneys have evolved in such—I mean, we’ve all evolved to deal with oxalate because oxalate is just this—it can’t get rid of it because it's—when you take all the carbon, you take carbon, you take—the only way to get energy out of it, you strip all the electrons out of it, and when you’re done with it, you end up with an oxalate skeleton.
So this thing has just been around since as long as there have been humans; this thing has been getting created. So all the systems of the body have had to deal with this thing.
So we have all these different mechanisms of dealing with oxalate. Citrate, one of its probably evolved to help with that function as well—the kidneys are just pumping out citrate all the time. It pumps out these other—there's another compound called osteopontin.
That's just—it’s just putting it into the urine all the time because that binds a lot of these crystals and stuff, so we have all these mechanisms to kind of deal with crystals all the time.
And normally, I think we probably existed with some bacteria that ate oxalate, so we probably didn’t have the same effect in the past, but since, you know, antibiotic use and all sorts of other things, soil bacteria seem to be kind of depleted from our microbiome.
So, you know, we kind of are exposed to more oxalate than we probably should be, and then that’s—yeah, so that’s—so oxalates are for sure a problem; like they're definitely a thing.
Preventing their, you know, the crystal formation is almost certainly going to be beneficial.
Yeah, so even for just the effect of, okay, let's say you're someone that eats a lot of spinach; you consume a lot of oxalates—consuming citrate can actually help with that, correct?
So does a lot of the—and this may be outside of your wheelhouse—I'm curious if we could almost film another topic on this all together, but oxalates, is the main driving negative impact of them—does it start in the kidneys?
I mean, is that where—and then the kind of the reactive oxygen species that drives up from there? So is it really a kidney-centric issue where most of the literature is focused?
No, oxalates are everywhere. They go all over the place. They end up in the connective tissue; they end up in the thyroid; they end up all over the place.
So they can just show up in tissues and make crystals anywhere. So they can be in the kidney because that's like kind of the place that, you know, kidney stones or people know about kidney stones.
So most of the research on oxalate is focused on kidneys, but there's a lot—I mean, they’re everywhere.
Yeah, so cook your vegetables.
Yeah, cook your vegetables or you have some calcium with it!
With it, yeah.
If you're—that's wild, man. I mean, that's because, like, it’s so—it’s nice to hear it from someone that is well-versed in this because I feel like the more that people that are not scientifically minded talk about it, the more people kind of want to tune it out.
And also, just when you have people that fear-monger around vegetables, it makes it difficult to want to believe them in the first place.
When you think, “But when you actually, okay, well, there’s practical ways that you can sort of reduce this oxalate buildup.”
I mean, that's just wild, that's so—so calcium or citrate along with it can make a difference.
Does cooking actually break it down?
No, you can't break down oxalate.
So you can break down phytic acid, but not oxalate?
Yeah, oxalate is just inert, essentially.
Yeah. It can survive in just, like, sediment and stuff. It's just these little crystals; they just—heat—they don’t break down from heat or anything.
Yeah, they’re really hard to get rid of.
How do you—I mean, is citrate like the only way you get rid of them? How do you actually excrete them?
Can you ever get rid of them?
Well, citrate binds to the calcium part, so it just prevents them clustering into crystals.
Yeah, you can't get rid of the oxalate necessarily. So like if you have a—if you have calcium with your meal and you have free oxalate, then the free oxalate will bind to the calcium, and then you can just kind of poop it out, so it just never kind of makes its way into the body.
That's the—that’s one strategy, but if they’re free oxalate, then it will just diffuse and make its way into the blood, and then now your kidneys have to deal with it.
So like if you get a spinach, it has a lot of free oxalate.
Yeah, it’s a lot.
Do you happen to know—again, this may not be your wheelhouse—but while we’re talking about this, I mean, what—so there’s a difference between having high oxalate content and free oxalate content, is that?
Yes, because there’s—the soluble and the insoluble oxalate are different. The plants, you know, they use oxalate crystals for defense purposes. Some plants do; some of them use it for like just storing calcium.
They have no bones, so they need to have a way to store calcium. So they’ll frequently have these—like phytic acid binds magnesium, and so that’s why people are worried about, like, “You’re going to suck all your minerals out.”
Well, the plant's using it for, you know, holding onto minerals and for defense. It’s the same thing with the oxalates. So you end up with these soluble oxalates, which are the free versions that can easily make their way into the blood, and then you have the crystalline form that are the insoluble stuff.
The research on this is actually kind of annoying because there's no real good table, like, “Here’s all the stuff that exists.”
So I talked to Sally Norton; she’s a—oxalate. She’s like the oxalate queen. She made a video with her because that’s all she talks about is oxalates. That’s her whole thing.
She’s actually put together some—you know, all the resources that had the different tables of oxalate-containing foods, and had it in one place and like referenced all these things. It’s really nice; it’s worth finding.
But it’s not good because the food companies are the ones that are looking at the oxalate, not independent people researching this stuff.
So they have all these values all over the place, so people have to go by whatever that has, and some things have never been tested or looked at.
Yeah, or just hard to decipher for the layperson in the first place. They don’t really know what they’re looking at.
Yeah.
Is there—and I don’t want to, you know, put you into a corner of making a claim, but is there an element of Keto Citra that could help with oxalates as well?
I mean, just this citrate and stuff?
Well, that's why we put the calcium and the magnesium in, yeah. Those are bound to oxalates in, you know, in the food and in the gut, and hopefully, they won’t get absorbed.
I mean, that’s why one of the things we’re hoping will happen.
Yeah, yeah. Well, Dr. Torres, I appreciate it, man. Thank you very much.
Well, thanks for talking to you!