Podcast: Play in new window | Download
Welcome to season two of Kicking Gout in the Acid. This season will dive into additional topics of importance to not only those with gout, but for those treating the disease as well. Whether you’ve been recently diagnosed, care for someone suffering, or are a medical professional treating the disease, the Kicking Gout in the Acid podcast can help you learn more.
This episode of Kicking Gout in the Acid features a conversation between Dr. Larry Edwards and Dr. Richard Johnson, board-certified nephrologist and member of the Board of Directors for the Gout Education Society. The two explore the connection between gout and kidney health through topics like uric acid regulation through the kidneys, treatment options, and considerations for medical professionals in charge of care should keep in mind.
Key Takeaways:
- The kidneys play a central role in uric acid regulation. About two-thirds of uric acid is excreted by the kidneys, and one-third by the gut. When kidney function declines, uric acid retention occurs, increasing gout risk.
- Kidney disease and gout are closely linked to one another. Chronic kidney disease (CKD) is a major cause of gout because impaired kidney function leads to uric acid buildup. Conversely, high uric acid may contribute to CKD progression, creating a vicious cycle.
- In those with kidney disease, treatment can look a bit different. Notably, NSAIDs may not be an option due to their harmful impact on the kidneys. For those with kidney disease looking for pain relief from a gout flare, options like steroids should be considered. Also, historical dosing restrictions for allopurinol in CKD have led to undertreatment, but recent evidence supports gradual titration to higher doses when monitored.
- For medical professionals, it’s important to screen those with gout for kidney disease and vice versa. Medications known to raise uric acid should also be reviewed, namely, diuretics. Comorbidities should always be considered when treating gout.
Start your journey with gout today via the Gout Education Society website and sign up for the monthly newsletter.
Follow the Gout Education Society on X and Facebook
Looking for nearby gout specialists? Find rheumatologists, nephrologists and more via the Gout Specialists Network.
Educational Materials:
Kicking Gout in the Acid is sponsored by Sobi.
Podcast Transcript
Ian Ponitz
Hello, and welcome to Kicking Gout In The Acid, a podcast from the Gout Education Society. My name is Ian Ponitz, and I’m your host for this series. Kicking Gout In The Acid features conversations between Dr. Larry Edwards, chairman and CEO of the Gout Education Society, and experts on the disease.
Each episode will dive into important topics that you, the listener, should know about gout. The goal? To feel empowered to get gout under control.
In this episode, Dr. Edwards is joined by Dr. Richard Johnson, board-certified nephrologist, professor emeritus at the University of Colorado Anschutz Medical Campus, and board member of the Gout Education Society. Today, Dr. Johnson and Dr. Edwards will discuss the connection between gout and kidney health, how uric acid is regulated, and the challenges patients face when both conditions exist.
Dr. Edwards, take it from here.
Dr. Larry Edwards
Thanks, Ian. I’m happy to be joined today by Dr. Richard Johnson, who’s a board-certified nephrologist, an internationally recognized researcher, and a member of the board of directors of the Gout Education Society.
Welcome to you today, Rick. What I’d like to do is ask you to just briefly here talk about your interest in gout, how that came about, gout and uric acid.
Dr. Richard Johnson
Yeah. Well, first off, thank you, Larry, for inviting me to be on this podcast. It’s a real delight to see you again and to interact with the people who are interested in gout.
I’m a kidney doctor, and gout is very common in kidney disease. And so, just by nature, I’ve seen many patients with gout. But what happened was, in my research, where I was investigating mechanisms of kidney disease and high blood pressure, I became interested in the role of uric acid in kidney disease and blood pressure.
Over the years, I have studied this with National Institutes of Health (NIH) funding and other grants to try to understand if uric acid might have a biologic role in diseases, not just gout, but in diseases such as high blood pressure, chronic kidney disease, metabolic syndrome, and so forth. It’s a controversial topic, but that’s where I’ve spent much of my research career over the last twenty-plus years.
Dr. Larry Edwards
You’ve certainly been at the forefront of that area of investigation over that time period. Can I get you to just do a brief overview of the role the kidneys have in regulating uric acid?
Dr. Richard Johnson
Yes. It’s a very important role for the kidney.
Uric acid is a breakdown product of purines, which are nitrogen-containing substances that are in our cells, DNA, and other RNA. And just as we have to get rid of waste, when the purines break down, they form uric acid. In many animals, there’s an enzyme that degrades uric acid, and so that’s the main way you get rid of uric acid, you know, like most mammals do.
But humans and some other species, like apes and also birds, and reptiles, lost this enzyme. And so we have to get rid of uric acid from our body a different way. We don’t have the enzyme to degrade uric acid, and so we have to get rid of it typically through the urine. And about two-thirds of the uric acid we get rid of goes out through the kidneys into the urine. One-third is removed by the gut.
So the gut, or intestines, especially the large intestines, have bacteria that degrade uric acid. There’s some movement of uric acid in and out of the intestines, and about one-third of uric acid is removed by the gut. When people start developing kidney disease, they’ll start to have some problems with excreting uric acid through the kidneys because with less kidney function, there’s less filtering, and it’s harder to get the uric acid out. And so the intestines increase their workload to remove uric acid a little bit in response to that. But it’s usually not enough, and so uric acid starts to be retained in our blood.
As the uric acid levels go up, we become at risk for gout and other complications associated with high uric acid. But when the kidneys are not working, the uric acid levels tend to go up. In people who start dialysis, for example, about half of them will have a uric acid level of greater than seven.
It’s very, very common to develop gout with kidney disease because you’re retaining the uric acid. So, kidney disease is a major cause of gout because as you get worse kidney disease, your uric acid tends to go up, and as the uric acid levels get over seven, the risk increases for the uric acid to crystallize into joints and to cause gout. It’s been known for a long time that you can develop gout because of your diet, you know, from eating foods very rich in purines. Beer and alcohol will generate uric acid. Sugar can generate uric acid.
So you can raise your uric acid by diet, but the two other major risk factors are genetics, if you have a genetic predisposition to have gout, and the other is if you develop kidney disease, because as you develop kidney disease, you retain uric acid. So, kidney disease is very important in people with gout, and everybody with gout should have their kidney function tested.
Dr. Larry Edwards
And genetic mutations in these transport systems, both in the gut and in the proximal part of the kidney, I think, are very important and have been researched extensively here for the past fifteen years. I have always been impressed over the last thirty, forty years that I’ve been looking at these things that uric acid was so tightly regulated by multiple transport systems in the kidney transport systems in the gut that you talked about.
Why do you think uric acid has that much influence as far as the body is concerned?
Dr. Richard Johnson
Well, you know, there is this problem where if the uric acid levels go up really high, and this is particularly seen in some animals that also lack this enzyme. So we lack this uricase enzyme that, if we had that enzyme, it would protect us if our uric acid levels go up. It would degrade the uric acid, and it wouldn’t matter if you had kidney disease or not.
But in some animals, especially reptiles and birds, for example, if their kidney function gets worse, they can retain very high levels of uric acid, where the crystals don’t just form in the joints, but also in the kidneys and in the heart and throughout the body, and it’s actually got the name visceral gout. It’s fatal, basically. It’s really massive crystallizations associated with aneurysms and severe high blood pressure. Visceral gout is a problem.
Now, in humans, we rarely see visceral gout, but there are reports. I was on a paper that described a couple hundred cases of uric crystals forming outside of joints. And usually these are people with kidney disease, and the uric crystals just overwhelm. You can find them in the heart, in the blood vessels, in the kidneys, in the skin, in the eyes. And I’ve seen a few patients with this over the years, and it’s really a horrible syndrome often associated with uric acid levels of fifteen or higher.
So the kidneys, though, become so important for getting rid of uric acid. And it’s controlled in the tubules. So what happens is after the blood is filtered in the filters of the kidneys, we have millions of filters called glomeruli. And then the urine runs down tubules until it gets into the ureter and then goes into the bladder. It’s full of urine, and then you excrete it. But the urine is initially partially filtered. It’s first filtered, and then the tubules have this big action to reabsorb sodium and all other kinds of things. And it’s very regulated because otherwise you would quickly become volume-depleted or dehydrated, because you have to reabsorb much of the water that’s filtered, and you have to reabsorb salt.
Uric acid is tightly controlled with all these transporters that are in the kidney to help reabsorb and secrete uric acid. And there’s two transporters that are particularly important in reabsorbing uric acid. One’s called URAT1, and one’s called SLC2A9. If you are unlucky enough to have a mutation that knocks it out, you can’t reabsorb any uric acid, and you end up with a uric acid level of one. And so you’re protected from gout.
But interestingly, now you have another problem, which is that the uric acid levels tend to be very high in the urine, especially after exercise or heat stress or after a big meal, because there’s no regulation, and it just all goes in the urine. And recently it’s been shown that that can cause kidney damage, and especially in people who exercise a lot, because the uric acid levels get so high in the urine that they form crystals there and irritate the kidney, the tubules, and cause inflammation.
So it’s not that you necessarily want a higher uric acid in your blood, but if the kidneys are excreting all the uric acid, the problem is that the uric acid can get too high in the urine, and that can be a problem. So the kidney wants to regulate it so that there’s not too much uric acid in the urine, so it can handle it, while at the same time it wants to maintain a certain blood level. And when the kidneys aren’t working, the uric acid levels classically are retained, and you have an increased risk for gout.
Dr. Larry Edwards
Yeah. Well, about 90% of the uric acid that first gets filtered by the glomeruli ultimately gets reabsorbed in the body, so we’re only excreting about 10% of that that reaches the kidney.
There’s a lot of flexibility there and probably a marked gradation of what’s actually normal in any given individual. I think the genetic diseases are interesting because they, of course, are with the person since birth, essentially, and may be accumulating uric acid at a much earlier stage than, say, somebody who is obese or has other problems with dietary intake or even chronic kidney disease itself. So I think that when we see those patients, they really do have significant increases in reabsorption and uric acid deposition problems.
Dr. Richard Johnson
Yes. Actually, there’s been one fairly significant breakthrough in the last few years. It was discovered that some people, especially in Japan and other countries in Asia, can carry genetic polymorphisms or genes that reduce the excretion of uric acid in the gut.
What happens is when you reduce the excretion of uric acid in the gut, the kidney has to take on the burden. And so what happens is the uric acid tends to be high in the urine of these individuals. They have a high fractional excretion. And oftentimes they used to be called overproducers, with the idea that they were making more.
Now we know that there are overproducers, but actually they’re underexcretors in the intestines, so the kidneys have to make up for it. And this group in particular is known to be at risk for developing kidney disease. And here’s the paradox, Larry.
We know that kidneys regulate the excretion of uric acid, and we know that when you develop kidney disease from whatever cause, it’s often associated with retention of uric acid. But there’s also a story that uric acid itself may be a cause of chronic kidney disease. So we might have a circle where chronic kidney disease raises uric acid, but then a high uric acid may snap back and make the kidney disease worse.
One of the reasons is that when the kidneys have a higher uric acid burden, there’s more risk for urate crystal formation, and that can occur in the kidneys as well as in the joints. And actually, you can get a thing called gouty kidney disease or gouty nephropathy, where urate crystals can be found in the kidneys. But there’s also this thought that uric acid may cause kidney stones, and that also can lead to crystals in the urine that may cause kidney disease.
There’s interesting new data that’s really supporting that when you get acidic urine, like from eating meats and so forth, or being dehydrated or heat stress, such as with climate change, that that causes low-grade dehydration. Dehydration causes a concentration of the urine as well as an acidification of the urine, so the urine tends to become acidic. Urate loves to crystallize in acidic environments. You can make uric acid crystallize if you drop the pH or make the urine more acidic. So when people are working hard in the heat, their urine becomes concentrated and acidic, and if they have a genetic predisposition or a diet or other means that leads to high uric acid in the urine, they can get not only kidney stones, but they may get crystals that can damage the lining of the tubules and, over time, cause kidney disease.
Dr. Larry Edwards
That kind of buckles into going back a couple of hundred years. There weren’t very many things that were done well for gout. Most of them were mistakes.
Dr. Richard Johnson
Ha ha.
Dr. Larry Edwards
I think staying hydrated was always one of the recommendations, even back in the Ben Franklin era.
Dr. Richard Johnson
Yeah, there is no doubt, Larry, that hydration is underrated as a way to help people with gout and kidney disease, and kidney stones.
Hydration is so important, and we’ve actually done studies that show that drinking eight glasses of water is beneficial in so many ways, in many different settings. And people with chronic kidney disease can excrete water fine, so drinking eight glasses of water a day is fine for most people with chronic kidney disease. But if you have any questions or issues, talk to your doctor. But yes, keeping the urine dilute is a very healthy thing.
Dr. Larry Edwards
Rick, we’ve discussed how gout and the kidneys are related.
Let’s talk for just a few minutes about the connection between gout and the kidneys. Uric acid is a risk factor for kidney disease itself, and then the treatments that we use a lot of times, like the anti-inflammatory drugs for the pain of gout, talk about how this enters into problems for the kidneys themselves.
Dr. Richard Johnson
Oh, yes. So it’s a complicated question, but let’s just first begin with the typical person presenting with gout. They want to control their pain. So it’s very common to take nonsteroidal agents like ibuprofen and indomethacin.
Dr. Larry Edwards
Naproxen. Yeah, mm-hmm.
Dr. Richard Johnson
Yeah. And these drugs can really help reduce the pain and are super valuable to the patient with gout because other types of treatments are more complicated, like steroids or colchicine. It’s just so much easier to take a nonsteroidal.
But nonsteroidals are not great for people with kidney disease. If you have kidney disease, the nonsteroidals tend to decrease blood flow to the kidney, and it’s usually reversible. The kidney function gets worse for a few days and then gets better, but people who chronically take nonsteroidals can get kidney disease that’s permanent. It can happen, and very high doses of nonsteroidals can cause real significant kidney injury.
So, in people with kidney disease, we try to avoid using those anti-inflammatories for gout. They’re usually treated with steroids or colchicine, and sometimes with other drugs. This is problem number one, which is that our classic treatment for gout is not good for the kidneys, and yet the kidneys are often involved in gout.
It may be as much as a third of people with gout, or 50% have some evidence of kidney disease. It’s really common. About a third to 50% of people with chronic kidney disease have gout. So there’s a real relationship with gout and kidney disease. If you ever get a gout attack, make sure you have your doctor check your kidney function.
Dr. Larry Edwards
Besides nonsteroidals, there are other medications, too, that have a negative impact on the kidneys and on uric acid accumulation. Hydrochlorothiazide and loop diuretics have issues as well.
Dr. Richard Johnson
Yes. There’re drugs that can raise uric acid that are commonly given to people. So if you develop a gout attack, even if you don’t have kidney disease, it’s sometimes because you’re on a medicine that tends to cause uric acid retention. Hydrochlorothiazide is one of the top ones that does that. And so if you do get gout, you should kind of review with your doctor what medicines you’re being prescribed, make sure your kidneys’ function is okay, and so forth.
But anyway, so to answer the first part of your question, yes, we have to be careful with the drugs we’re on and the drugs we take for gout to make sure that the kidneys stay healthy.
But a second issue is whether gout itself could lead to kidney disease even when you’re doing everything right. It’s kind of an interesting thing. It was noted a long time ago that gout and high uric acid could predict the development of kidney disease. So if kidney disease causes gout, kidney disease should come first, and then the gout comes, right? If kidney disease predisposes the gout, you get kidney disease, and that increases your risk for gout.
But there’s a lot of studies, probably a hundred studies, that show that if you have a high uric acid level and normal kidney function, or if you have gout and normal kidney function, that you are at increased risk for developing kidney disease. So this shouldn’t happen if gout is simply secondary to kidney disease. And of course, it could be just spontaneous, but when they look at general populations, if you have a high uric acid level, you have a greater risk than if you have a normal uric acid level.
So this was an area that I was really interested in, and I found that if I raised uric acid in animals, they could get low-grade kidney damage, and we tried to understand how that happened. And when we studied it, we discovered that uric acid is not just a toxic waste product that causes gout, but it actually has biologic properties, too, and some of them are pro-inflammatory and stimulate inflammation and cause blood vessels to become reactive and to constrict more.
We found that if we raised uric acid levels in rats, for example, that their blood pressure went up, and we even went on and did a study in humans in which we showed that high blood pressure in children could be reduced if they took allopurinol to lower their uric acid. Adolescents who develop high blood pressure often have a high uric acid level, and the uric acid correlates with the blood pressure, and if you lower the uric acid, you can improve the blood pressure.
So these studies kind of led to the suggestion that high uric acid might actually have a role in high blood pressure and kidney disease. But the clinical trials, the big, big clinical trials, have been mixed, and some show benefits, and some don’t show benefits. It’s a controversial area. You’ll have experts who will quote, “This trial didn’t show an effect, and this trial did.” And with me as an expert looking at it, I believe that there is a real pathway where uric acid causes these conditions.
But the clinical trials that failed failed because they didn’t quite pick the right people to treat. So some of the trials that lowered uric acid included people with normal uric acid levels. When someone has normal uric acid levels, lowering it further is not gonna do much, and so it could give you a negative result. But anyway, it is a controversial area.
Our work suggests that uric acid is more important than just gout and that it may be linked with other diseases in a way where chronically lowering uric acid might provide benefit. But this remains a controversial topic, and not all studies show this.
Dr. Larry Edwards
Yeah. There’s a number of controversies in the management of gout, and one last one I’d like to discuss with you has to do with what many feel is the reason gout is a significantly undertreated disease: that they aren’t being given enough of the xanthine oxidase inhibitors to get the uric acid down to target. And some of this is because of suggestions back in the mid-’80s that your allopurinol should be dosed according to what your kidney function is and not to go above a certain dose of allopurinol, say, if your glomerular filtration is in the forty-fifty range.
Dr. Richard Johnson
You’re absolutely right that allopurinol, one of its products, is oxypurinol, and that can be retained in kidney disease. And so there was worry that that might actually lead to problems. And yours truly found that with sky-high doses in rats, the allopurinol could form its own crystals.
So this kind of scared me, but what was done in humans with real-life data has been really strong evidence that you can continue to increase allopurinol slowly in patients with chronic kidney disease. And we do go slow, but when you do that, you can titrate up to even higher doses, as high as five, six hundred milligrams a day, which is quite more than the average dose in people with gout, which is around three hundred.
So these studies, which were done by, I think, Nicola Dalbeth, Lisa Stamp, and others, really provide evidence that reassures us that we can use higher doses of allopurinol, and if we just do it slowly.
And there is another alternative. Febuxostat, for example, is another xanthine oxidase inhibitor that appears not to accumulate to the same degree in kidney failure and is probably equally effective. It did scare people for a while because there was a study in which it didn’t do as well with allopurinol in cardiovascular protection, and there were more cardiovascular events in the febuxostat group in this famous study that was published in The New England Journal. But subsequent studies really show that febuxostat doesn’t really carry increased risk for cardiovascular events, and so I think people are using that more and more in patients with kidney disease to treat gout.
But with allopurinol, you’re absolutely right, Larry. I’ve been convinced, as have others, that we can go to higher doses. I may have actually been one of the people who sent out the warnings. The warning signs preceded me for a long time, of course.
Dr. Larry Edwards
Just a few more things before we end this dialogue. Just talking about the importance of screening patients for kidney disease if they come in with a gout attack, and vice versa, if they come in with kidney disease, looking for uric acid elevations. We don’t do a very good job of this, of looking for the comorbid diseases that are associated with gout, and I guess the comorbid diseases associated with kidney disease.
Dr. Richard Johnson
Yeah. Well, I would say that there’s three things that I would do.
When a person comes to you with gout, when you’re working them up, ask about genetic or family episodes. Is gout a problem in the family? And there are rare diseases where you can get gout and kidney disease, and it’s due to a genetic problem. It’s actually called uromodulin disease, but it’s a form of autosomal dominant tubular interstitial disease in which you present with high uric acid levels, develop gout at an early age, and develop chronic kidney disease. I think that if there’s a strong genetic component, being tested for genetic mutations that might be responsible would be helpful.
So that’s one thing, and there’s also certain things that can lead to chronic kidney disease and gout, in particular, lead poisoning. It’s often associated with kind of anemia that’s out of proportion to kidney disease, and sometimes bone disease and other conditions, but if the person has an exposure to lead, they can be tested for that, and you can be treated for that.
But most people coming in with gout don’t have those, and it’s related to genes and Western diet, and I do recommend reducing foods, and so forth that can raise uric acid. Usually, that’s not enough to control the uric acid, and I believe that you do need to treat the uric acid.
Dr. Larry Edwards
Pharmacologically.
Dr. Richard Johnson
Yeah, pharmacologically in the majority of cases, and I’m more aggressive than even most rheumatologists. I think that even one episode of gout is enough for me to want to try to control that uric acid, and I also look for the comorbidities.
When you look at medications that you can change that might make the uric acid worse, and there are medications that can make uric acid better, like these SGLT2 inhibitors, and also things like Losartan can lower uric acid a little bit. And then you want to look for comorbidities, and one is kidney stones, and there’s a significant association of uric acid kidney stones with gout, and there’s now new data that just taking citrate along with your allopurinol can really help lower uric acid and control gout and reduce the risk of kidney stones.
I just wrote an editorial on this because of a paper that was published in Rheumatology that showed this. Also, you want to look for things like chronic kidney disease. You really need to know it because not only is it a potential result of gout, it can also be a cause of gout, and seeing a kidney doctor or seeing someone who feels comfortable with treating kidney disease is important.
And then there’s all the cardiovascular. If you have a history of heart attacks or things like that, I want to be more aggressive. Now they’re finding that urate crystals can form in blood vessels, too, and there’s these new scanners called the DEXA scan where you can see crystals at areas of atherosclerotic plaques in people with gout, and especially in the coronaries and the aorta. If the crystals are there, they actually correlate with increased cardiovascular risk. So I think that if you have gout, hopefully you’ll just have gout and no kidney problems and everything, and just modify the diet, take a little allopurinol or something, and everything’s fine.
But, you know, we want to kind of expand it out. Do you have a cause that we can figure out and treat, or do you have a specific disease? Can we manage the gout itself? How easily? Change the medicines. And then what are the comorbidities? So those are the three things to look for. It’s a systemic disease. It isn’t just a nuisance.
Dr. Larry Edwards
Yeah, it’s not just the big toe hurting, ha ha.
Dr. Richard Johnson
Yeah, ha ha.
Dr. Larry Edwards
It progresses into a systemic disease, like you say, with a whole different pro-inflammatory milieu, not just around the toe, but in these other organs that are affected in the metabolic syndrome.
Dr. Richard Johnson
Absolutely.
Dr. Larry Edwards
Yeah. So it’s been wonderful having you on today. I so enjoy all of the talks that we’ve had over the decades, and you always offer a new, fresh outlook on gout and uric acid metabolism.
Thank you for being here with us, Rick.
Dr. Richard Johnson
You’re welcome, and you’ve been a leader in the field. I’ve learned a lot from you over the years myself, so thank you, Larry, for everything you bring to the field.
Dr. Larry Edwards
Oh, you’re kind. Thank you.
Ian Ponitz
Thanks both for having this fruitful discussion today that can help those with gout, their caregivers, and medical professionals alike kick gout in the acid. If you have gout or treat gout, you can learn more through the website: gouteducation.org
Stay up to date with our organization by signing up for our monthly newsletter or by following us on X or Facebook @gouteducation.
We’ll be back next month with another episode of Kicking Gout In The Acid. Until then, make sure to like, subscribe, and follow our shows on Apple Podcasts, Spotify, and other major platforms.
Thanks for listening in.
