Episode #6: Prevention and Early Intervention for Kidney Disease with Dr. Katherine Tuttle

Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine podcast at the Foresight Medicine Substack where we are envisioning the future of preventive healthcare as a comprehensive whole body framework for leveraging new technology to maintain health as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties, and today we will be talking about the kidneys.I am very honored to have as my guest, Dr. Katherine Tuttle. Dr. Tuttle is professor of medicine in the Division of Nephrology at the University of Washington and Executive Director of Research at Providence Inland Northwest Health. She is one of today’s most prolific and impactful clinical and translational scientists in the area of kidney disease.She has led foundational research on the pathophysiology of diabetic kidney disease, and her work has been pivotal in establishing the current pillars of therapy for chronic kidney disease more broadly. Her work is broad, and it spans elucidating the mechanisms of those therapies, the clinical trials that have established their benefit, and the interrelationship between kidney disease and cardiovascular and overall health. She’s a leader in many of the major national and international organizations focused on kidney health that shape the practice of nephrology through guidelines and grant making.Listeners should note that we are recording this on Friday, May 22nd 2026, and this conversation is for general informational purposes only and does not constitute individual medical advice.Kathy, welcome. Thank you so much for joining me today.Katherine Tuttle: Well, it’s great to join you.Robert Rogers: So I’m really looking forward to this conversation, and on the Foresight Medicine project, we’re really going organ system by organ system, disease category by disease category, thinking about the future of preventive and proactive health.And for some of the diseases, the tools that we have both from a diagnostic and therapeutic standpoint are really exciting, but they’re almost somewhat aspirational. And I think one of the really cool things, and I think we’re gonna get into this today when it comes to kidney disease, is that of course, the tools in our toolbox are evolving and expanding, and you’re a major participant and leader in those efforts, but they’re actually already quite good in many ways.And so there’s this additional challenge of how can we deploy optimally what we already have. And so I’m really excited to get into both aspects of that. And so I guess I would just like to start out by saying how did you first become particularly interested among your interests in the early identification and prevention of chronic kidney disease?Katherine Tuttle: Well, thanks for that question, Rob because it really goes back a long time. And before I was a nephrologist, I actually did a fellowship in endocrinology and metabolism. And the focus was really on physiology, glucose metabolism, glucose regulation. And there were people who volunteered for these studies. These were the original insulin and glucose clamping studies done some 40 years ago. Mostly people with type 1 diabetes who would spend eight to 10 hours in a room with multiple lines and blood draws. And we had a machine called the Biostator, which was an artificial pancreas. Today, people wear it on their belt, but in those days, it filled an entire room.And when I was doing those experiments, I got to know the study participants really well. We didn’t have helpers then either. I mean, I was drawing the blood, processing the samples, and staying with the patient the entire time while running the Biostator. And I got to know them quite well. We were all about the same age in our late 20s, and it really stunned me one day when one of our study participants, this altruistic volunteer who signed up for these experiments with the hope that it would somehow help people, crashed into dialysis at Barnes Hospital. We didn’t see it coming. We weren’t even looking for kidney disease. We weren’t even thinking about it. We were focused on the physiology of glucose metabolism, really important. I’m still a physiologist. I still do preclinical research. But it occurred to me that we really need to get much more focused on solving problems that matter to patients, and not-- virtually nothing was being done about kidney disease and diabetes in the mid-1980s.We weren’t screening for albuminuria. We had maybe a serum creatinine, but no one knew what to do with it. And I realized that this was an enormous unmet need, and I just decided that something needed to be done about it. I wasn’t sure what I was going to do but I decided I would do something, and then I pivoted to nephrology and went on to train in nephrology. And then I’ve spent most of my career focused on trying to solve problems related to diabetes and the kidney. And thankfully, after decades of work and along with really an army of other people in the field, we now have truly transformative therapies, so I’m glad I’ve been here for the whole journey.Robert Rogers: I just want listeners to appreciate how unique it is to have fully trained in both endocrinology and in nephrology. But it clearly set you up very well because diabetes which we’ll get into is of course one of the major contributors to kidney disease. And so your own training and career trajectory kind of follows along.So I’d like to lay a little bit of foundation and help people understand the scope of the problem that we care about preventing or intervening upon when we talk about kidney disease. And I mentioned to a few friends who were kind enough to listen to this podcast that I was gonna be doing an episode on kidney disease and the first couple of comments that I got were like, “Oh yeah, ending up on dialysis is really terrible.”And that is of course true. When many people think of kidney disease, our minds immediately go to perhaps the most severe or extreme outcome, which is when your kidneys completely fail and you require dialysis or a transplant. And there’s several hundred thousand people in this country, I think about eight hundred thousand, who are currently on dialysis, tens of thousands more who live with a with a transplanted kidney. And so that is of course a problem of significant scope. But in some ways it’s really only the tip of the iceberg. And so maybe you could explain how is it that decrements in kidney function that are well short of complete loss, end-stage kidney disease, really are quite important, significant and a health burden?Katherine Tuttle: Oh, thanks for that question, Rob. I think it’s been the great under-recognized public health crisis, frankly. In fact, The Lancet published an updated global burden of disease study on CKD in November of twenty twenty-five, coincident with American Society of Nephrology’s Kidney Week with new estimates of the global burden of disease. They’re now estimating eight hundred million people worldwide, and half of it is attributable to diabetes, so some four hundred million people with diabetes and kidney disease in this world. The other thing, too, is they projected the death rate squarely attributable to kidney disease. In 2013, it was the nineteenth leading cause of death. By 2023, it’s now... It became the ninth leading cause of death. And if we don’t change the trajectory we’re on by 2040, they’re projecting it’ll be the fifth leading cause of death in the world. So it is an enormous public health problem. And I think that is really the issue. It’s the mortality associated with this.So nine out of ten people who develop chronic kidney disease, particularly if they have diabetes, will die on the road to kidney failure. And the people who make it to dialysis or transplant to the end of the line are a ragtag survivor bunch because of the enormous complications that are highly fatal, and these include cardiovascular complications. And yes, there’s a high burden of conventional cardiovascular risk factors, but it’s the kidney disease that really accelerates the risk. So if you have low kidney function and you spill protein in your urine, above and beyond diabetes, the risk of cardiovascular death is increased thirty, three zero, fold. We published those data over 15 years ago.And so I think people have not recognized how fatal this condition is. The next leading cause of death is infections due to impaired immune response associated with CKD. And the reason it matters is not just scary to statistics, and I imagine we’ll get to this but we now have therapies that reduce mortality, and mortality from both cardiovascular disease and infections in people with chronic kidney disease.So you’re right, it is the tip of the iceberg, and people are very sick, and many will die and never make it to dialysis. So we can say if you get to the point you need kidney replacement therapy, congratulations, you made it. Wow. Yeah. But then, life on dialysis is also very burdensome. And even today, let’s just talk about survival as the starting point. The median survival of a person with diabetes who initiates dialysis is two years, worse than most forms of bad cancer which we fear because of the death risk. So what I wanna call out is we need to recognize that this is a killer. It’s rising in prevalence, and it’s rising in importance of causes of death as we’ve done better with other causes of death at least historically reducing cardiovascular risk and risk from infections because we vaccinated people at least historically. Now what we have emerging is this other cause which has been left unaddressed.Robert Rogers: Yeah. And so in your very compelling answer there, you mentioned a couple of things that I really want us to take a deeper dive on. One is how now we have medicines that really do impact the mortality of having kidney disease and diabetic kidney disease. But you also mentioned how the presence of kidney disease is a real risk factor for many other forms of death, particularly cardiovascular morbidity. And so you have been I think, one of the leading people from the field of nephrology who’s helped to really set forth a new paradigm in how we think about kidney and cardiovascular care in the past few years.And the paradigm is called CKM or sometimes CKLM, which stands for cardiovascular, kidney, liver, sometimes it’s thrown in there, and metabolic health. And instead of looking at each of these organs in isolation, it sort of appreciates the interrelationship between them. And maybe you could just tell us a little bit about how that paradigm and that lens is a more helpful contemporary way to think about these problems.Katherine Tuttle: Well, it’s much more realistic. It’s integrative pathophysiology. These organs don’t act in isolation. And yes, I was involved with the initial scientific working group for the American Heart Association that wrote the scientific statement, the presidential advisory. The first American Heart Association, American College of Cardiology guideline is set to publish early in June, and I’m an author on that.And I guess one thing I wanna say about liver, it actually is included in the original CKM construct. It is under the metabolic umbrella. So people sometimes misunderstand that. So the liver was always there- M But it really is one of the metabolic organs. When we think about again, integrative pathophysiology, it’s liver metabolism along with fat and pancreatic metabolism. So I always feel like I have to say that because we never left that out, but it really acknowledges the liver as a metabolic organ that also is very important in terms of integrating these risks. And what we know is that dysfunctional adiposity, diabetes, liver disease creates a systemic inflammatory milieu, also particularly from the standpoint of adiposity, increases the burden of conventional risk factors, again, like diabetes, hypertension, dyslipidemia.And those are factors that cause both heart and kidney disease to be accelerated. And then the really bad actor is that once kidney, the kidneys begin to fail, it’s gasoline on the fire of cardiovascular disease because then the sick kidney produces bad humors that accelerate atherosclerotic disease and particularly heart failure, preserved ejection fraction. But then the heart doesn’t behave very nicely either when it begins to fail or become diseased--even, even with coronary disease, there are systemic factors that then cause further kidney injury, so we end up in this vicious positive feedback cycle of spiraling downhill. And with the new therapies, they really address three main pathways: metabolic, hemodynamic, and fibrosis and inflammation.And so I sort of call that the box at the bottom. These are the final common pathways. Irrespective of the inciting injury, these organs sort of collapse into those pathways. And so now what we recognize is while it’s always important to try to treat the original cause, whatever it is if we don’t treat the final common pathways, we still have progression. So a great example of that is back to diabetes. We’ve done studies of intensive glycemic control, trying to reduce cardiovascular and kidney risk in people with established diabetes. It does very little. And it’s because while acknowledging it’s very important to control blood glucose or everything gets worse, it’s because they’re already on a on a downhill train, and you’ve gotta break the cycle at the bottom. So the new therapies then on top of say, good blood pressure, glycemic control, treatment of lipids, then interrupt those final common metabolic hemodynamic and fibroinflammatory pathways.Robert Rogers: Great, and I really wanna get into those new therapeutic options, and modalities in just a bit. But we’ve already talked about it quite a bit, the relationship between diabetes and the risk of chronic kidney disease. There’s also another major risk factor, epidemiologically that accounts for a lot of chronic kidney disease, which is hypertension, high blood pressure. And so maybe just walk us through for both of those two major risk factors, how much do they elevate one’s risk of kidney disease, and how much does aggressive treatment of those risk factors actually reduce the risk?Katherine Tuttle: Yeah, so if we go back to the dialysis population that we’re working with 75% of people on dialysis either have diabetes or hypertension as the primary at least clinically identified cause. Now that said, 95% of people with diabetes and kidney disease have hypertension, so that’s actually half. And then about a quarter are hypertensive people who don’t have diabetes. We also know from studies of hypertension control, while we can reduce the rate of losing kidney function versus uncontrolled hypertension, it’s still really a modest effect compared to the newer therapies. That said, it’s very important to control blood pressure though, because if we don’t control blood pressure, then we have another accelerating factor.But what we’re saying is we’ve done this for a long... We’ve for a long time, controlled blood pressure and controlled glucose, and still have had only an explosion of kidney disease. So there really... It’s important, but by the time people are diagnosed, there’s already been target organ injury, and it will do little other than mildly mitigate the disease just to control the original risk factors. So I hope I’ve answered your question. It’s foundational. Right. ‘Cause if you leave those uncontrolled, it’s just, it’s, it’s another accelerant. But that’s really only one part of it, and actually once the disease is established, probably lesser, it... I don’t wanna say it’s unimportant, but the in terms of driving the disease, there’s gonna be less benefit from blood pressure or glucose control than the highly effective therapies that target tissue-level mechanisms.Robert Rogers: Okay. Great. So I think we’ve now laid enough foundation to go into those highly effective therapies that target tissue-level mechanisms. So say, say a little bit more about what these new classes of therapies are that have really changed the whole care paradigm over the past decade, and that we’re still learning how to use and deploy further.Katherine Tuttle: Yes, and if I could, I’m gonna also speak about heart failure because it is the closest adjacent condition to CKD. And of all forms of cardiovascular disease, the most likely cause of exiting the planet. So and both of them basically have kind of converged into the very similar, treatments. So the first breakthrough... Well, if we go back historically, and again, since your audience is a general medical audience, I would like to acknowledge the importance of the renin-angiotensin system.Robert Rogers: Sure. Say a little bit about what that is for- Yeah... For our audience. Yeah. Right. And how, and how the original, the kind of foundational medications that have been treating that have been around for 40 or more years in some ways, right?Katherine Tuttle: Right. So these are agents... The renin-angiotensin system is a very important physiologic, hormonal regulating system that controls sodium retention by the kidney, vascular function, cardiac function, and kidney function in fundamental ways. And so with overactivation of the system, this is a major cause of hypertension.So originally, targeting the renin-angiotensin system was viewed as a way to treat hypertension and certainly, agents in these in these classes, either ACE inhibitors or angiotensin receptor blockers do that. But for the first... But there was biology mechanisms that in both the heart and the kidney that there were tissue-level activation pathways for these systems, and that there could be benefit beyond blood pressure control. So 25 years ago, after these drugs were first approved for the treatment of high blood pressure, they were studied for heart failure and for chronic kidney disease and diabetes initially. And these were the first classes of agents that beyond conventional risk factor control, beyond blood pressure control, added additional survival benefit.And again for people who aren’t steeped in the specialty, this means that these people had beyond controlling their blood pressure, they were more likely to stay alive, and their organs were less likely to fail. So for about 20 years that is all we had for these conditions. However, the treatment benefit by today’s standard was modest.So let me go to the kidney side of this. So we had two major trials, RENAL of losartan and IDNT of irbesartan. The relative risk reductions for kidney failure or dying were reduced 15 to 20%. But at the time that was really heralded as a major breakthrough. That was in September of 2001. And between, over the next 20 years, though, we saw nothing but the end-stage kidney disease population double. So I mean, it wasn’t really having a huge population effect, although during that time, electronic health records came forward, and when we actually looked at real-world data, we found that only, like, 25% of people who should be on these therapies for CKD were getting them. So it wasn’t entirely, ineffective therapy. It was also ineffective implementation.Robert Rogers: Right.Katherine Tuttle: But be that as it may that was what we had. But that was the first signal that we could interrupt disease risk at the target organ level beyond just treating blood pressure and diabetes. So enter the SGLT2 inhibitors. So this was the first breakthrough class. The signal came from something called the cardiovascular outcome trials. And the story here is that It was-- these were safety trials that were mandated by the US Food & Drug Administration in 2008 for any new glucose-lowering agent that was put on the market.And the reason was that in 2006, there was a so-called rosiglitazone debacle where rosiglitazone was placed on the market for treatment of type 2 diabetes. But within the first year of being on the market, the agency received, the FDA, when I say the agency, received a number of post-market approval reports of major adverse cardiovascular events. So there had been a long signal that glucose-lowering agents could increase cardiovascular risk, going all the way back to sulfonylureas, but nobody was gonna go back and restudy those old generic drugs.Robert Rogers: Right.Katherine Tuttle: But they knew they had a lever with the new drugs. So they said, then if you-- if we approve a new drug for lowering glucose in type 2 diabetes, the sponsor has to do a post-market approval safety study to stay on the market. There was a lot of pushback, but it really became the gift that keeps on giving because not only were these agents safe, they were highly efficacious for reducing major cardiovascular risk. And the really interesting thing was especially with SGLT2, while there was some benefit on a atherosclerotic disease, the big win was on heart failure, particularly preserved ejection heart failure, which had not benefited from the same therapies that were working for reduced ejection fraction heart failure.And that’s important because the majority of heart failure in this country is preserved ejection fraction. Right. Very much like CKD. The major secondary outcomes were kidney outcomes. And remember, the people put in the study weren’t put in for kidney risk. They were put in for heart risk, and most of them didn’t have kidney disease. Yet, we saw a reduction in new onset of kidney disease marked by albuminuria, slowed kidney function decline, and even prevented kidney failure. Interestingly enough, in 1987, one of my mentors, Dr. Ralph DeFronzo, and I gave a derivative of SGLT2 inhibitors to diabetic rats. And that paper was published in the JCI in 1987. And while the intent wasn’t originally about organ protection, we actually knew at that time that there would be reasons to study kidney function because the drug works in the kidney.Robert Rogers: So just to sort of for our listeners, you talked about how there was this longstanding foundation of medications, initially for hypertension, but then showing benefit in kidney disease and in heart failure, the ACE inhibitors and angiotensin receptor blockers. And then you just took us through this really, beautiful history of the SGLT2 inhibitors, this next, this next class. And I think you’re gonna get into the class that people are hearing so much about these days, the GLP-1s, the incretin therapies, the big weight loss drugs in just a second.But as we, as we sit here today, let me just ask you, which patients do we know should be on the SGLT2 inhibitors in terms of it would benefit their kidney function and their health? And are there patient populations where we don’t yet know whether or not, they would benefit, but that’s being actively investigated, and you think we might have additional answers in the in the coming years?Katherine Tuttle: Yeah. So after those initial chronic vascular trials, we had what we called the CKD trilogy. We did three major kidney outcome trials, and these ran in parallel to the big heart failure trials. I do wanna say this was another historic moment. Every single one was stopped early for overwhelming efficacy. Very unusual! In our field, we had stopped... Plenty of studies for futility or safety, but never for overwhelming efficacy. And for those of you who aren’t in nephrology, I would say if you look around in your field, it is a rare moment when something’s stopped for overwhelming efficacy.The bar is very high for that. So that was how profound the effect was. And long story short is originally the first study was exclusively in type 2 diabetes with more severe kidney disease. The next study, DAPA-CKD, and then EMPA-KIDNEY progressively broadened the entry criteria such that in the last study, more than half the people didn’t even have diabetes, and they didn’t even have to have protein in their urine, which had historically been a criteria for our trials.So bottom line to answer your question, these work across most forms of chronic kidney disease, irrespective of diabetes or protein in the urine. So now we have grade 1A guideline recommendations from our major guideline-forming organization, which is called KDIGO, Kidney Disease Improving Global Outcomes, but also endorsed by the American Diabetes Association, the American Heart Association, or the ACC because we have so much overlap that these drugs are indicated for people with CKD with or without diabetes, and with or without albuminuria.These are fundamental therapies. The relative risk reductions are in the range of thirty to forty percent on top of an ACE or an ARB. And the other really important thing is you can’t just look at relative risk reduction. You have to look at absolute risk because the higher the absolute risk, the greater the clinical benefit. So you’re talking about people who in these trials that were cut short because of benefit, only went about two years, primary outcome, kidney outcome event rates approaching twenty percent, and that going down by thirty or forty percent is an enormous clinical benefit. So then the same thing happened with heart failure, and the really interesting thing in the heart failure trials to me anyway, is that they also included people with CKD, and the heart failure patients who benefited most for cardiovascular survival were the people with CKD. So they benefit broadly, back to our call to recognize the mortality risk, is in this high-risk population, especially if they have diabetes, we reduce risk of death, particularly heart failure death, and among the living, markedly preserve kidney function and reduce the risk of kidney failure.Robert Rogers: Great. And now the latest class in the last five years are the GLP-1 agonist drugs like semaglutide, Wegovy, Ozempic, the GLP-1/GIP combined, tirzepatide, Mounjaro. People are very interested in this class of medications. They have lots of benefits. People think of them primarily as medicines that aid in weight loss and control of blood sugar for diabetes, but their benefits really redound ar beyond that.So how are those being, used now in the context of kidney disease and kidney disease prevention?Katherine Tuttle: So GLP-1s really work very differently. Our lab did a lot of the pre-clinical work, again, because we were interested in the effect of metabolic processes to exacerbate target organ injury. But here, these are mostly non-hemodynamic drugs. And at the level of the kidney and blood vessels, they are anti-inflammatory and anti-fibrotic. And so when those drugs were approved for the treatment of type 2 diabetes, they too had to conduct cardiovascular outcome trials for safety. And the second gift that kept on giving.But the really great thing was first off on the heart disease side, while there’s overlap in benefit, the SGLT2s mainly are heart failure drugs, although a slight benefit on atherosclerosis, and it’s the opposite with GLP-1s, primarily anti-atherosclerotic, but with some heart failure benefit. But again, secondary kidney outcomes lined up just as we would have predicted based on the models, less protein in the urine, and preserved kidney function.So we went from the CVOTs to one, and only one, dedicated kidney trial, which was the FLOW trial. And this is number four, stopped early for overwhelming efficacy. And some of us had been involved in the SGLT2 inhibitor trials and knew we would only get one shot at goal with the GLP-1, so the bar was set even higher to stop this trial, called FLOW, earlier than for the SGLT2 trials. And I’ll never forget the day. On October 13th, 2023, we received a message from the Data Safety Monitoring Board, which is our independent review committee who advises us on safety, and they recommended that we stop the trial. And the reason was it would no longer be ethical to keep people on placebo when this drug was on the market So again, four trials stopped for overwhelming efficacy.Again, this is historic. Never happened in our field, and probably very few fields within a five-year period of time. And FLOW was set up very rigorously. It tested semaglutide, and I wanna be clear that this was not a weight loss study. We used the one milligram once weekly subcutaneous injectable dose. We started the trial in 2019, and it ended in 2024. The median follow-up for people in the study was 3.4 years, and they lost very little weight, 4.5%. They came in at a mean weight of 90 kilos, and they went down to 85. This was not a weight loss study, yet we had profound benefits. We reduced the primary. On top of standard of care, ACE or ARBs, and some SGLT2 inhibitor use. So it, SGLT2s were increasing. It was 16% at the beginning of the trial, 33% at the end. But in spite of using SGLT2s and ACEs and ARBs, we had profound benefits, 24% reduction on top of those therapies- Right... For the primary kidney outcome.We had as much or more benefit on cardiovascular outcomes in the cardiovascular trials. And most importantly, 20% reduction in all-cause mortality. So yes, there was a 20% reduction in CV death, but it did not account for all the mortality benefit. And we think this is because these agents also reduce the risk of infection which we monitored very closely because the trial was largely conducted during the pandemic.Robert Rogers: Well, that’s great, ‘cause you’ve given a really... You’ve given a just a beautiful overview of how each of these therapies have developed, how they’ve shown their extraordinary benefit, how that benefit is manifest in several ways, it both through a direct improvement in or a reduction in the amount of kidney mortality and kidney failure, but also these much broader benefits.And so I wanted to sort of sort of ask you— I learned, about a concept from something you wrote, this idea of kidney disease going into remission. Now, we don’t usually talk about the word remission in the context of kidney disease, right? People might think of it in cancer. But I think what you’re trying to get at is this that there is a natural decline that happens in kidney function with aging.It’s probably accelerated by many parts of our modern lifestyle, but there just is an intrinsic aging of the kidney. And so we do expect the amount of what we measure called the glomerular filtration rate to go down as people age, but the rate at which it goes down is of course, quite modifiable. And so you sort of wrote about how now that we have all of these emerging therapies, we could actually hope to get somebody who has kidney disease, whose kidney is aging faster than normal, they’re losing that GFR faster than normal that the slope of that decline could actually converge back to normal, and that would essentially in some sense, be remission. And so what I wanted to ask you was you talked about these three very powerful classes of therapies, and if we start to layer them, how many people can... That currently have kidney disease can we get to remission or pretty close?Katherine Tuttle: So yeah, really important question. And so first, we have to go back to the data to answer your question. But because these agents work by different mechanisms, the combination appears to be additive. Now, the studies of combination therapy are just beginning. We’re doing that. But we can look at for example, in FLOW, all those SGLT2 inhibitor users who were in the GLP-1 study, and we see that they still get additional benefit from GLP-1.So everything points in that direction. So my research group and others have done modeling analyses to project what the expected benefit could be. And as you’ve said, we see that if we optimally use these agents in people with CKD. We could get to the point that the rate of kidney function decline is no different than people without kidney disease, which really is remission of the disease. And with the GLP-1s, and I wanna be clear that this is still in the research realm, but the direction things are going is also not just slowing decline. We actually see signals that kidney function can improve. Restoration of function. I hate to use. BeyondRobert Rogers: Remission. Beyond remission,Katherine Tuttle: Yeah. Regeneration. Regenerativeness.Katherine Tuttle: So with FLOW, we also did a mechanistic companion study called REMODEL which we have presented at two international conferences, American Society of Nephrology Kidney Week 2025, World Congress of Nephrology 2026 in Yokohama, and hopefully the paper will be out soon. But what’s been presented at the meetings I can tell you. So we see something called filtration fraction go up on the physiology on the functional imaging. That’s the proportion of blood that gets filtered into the urine. That is the basis of glomerular filtration rate. The fraction filtered increases. That means increased glomerular filtration rate. And we saw that in the remodel study where we had much more precise measurements than we would have in a big clinical trial in FLOW. So it’s early days, but there is a signal not only based on function, but structurally there can be repair of the glomerular filtration barrier.Robert Rogers: That’s really exciting, and I think we’ve spent most of our time today talking about the therapies, the tools that are really just getting more and more exciting in terms of their power for treatment. But of course, more powerful treatments, one of the things is it does is it really extends the logic of the benefit of early identification and early intervention and prevention if you have better tools with which to intervene. And so I wanted to just have you briefly explain at this point in time, what does screening for chronic kidney disease really entail? What are the what are the components of screening for it, and who do we think should be screened?Katherine Tuttle: Yep. Actually, those are big questions. Well, what I think is well established, and again, guideline recommended by the kidney people, KDIGO, the diabetes people, ADA, and the heart people, AHA/ACC, are all people with diabetes, all people with hypertension, all people with cardiovascular disease, and anybody with a family history of kidney disease. Now that’s probably about 70% of the United States’ population. Right. The other question is should we do population-wide screening? This is just my opinion. Unfortunately, the US Preventative Health Services Task Force did not recommend that. That is their decision. But there’s probably still a lot of kidney disease out there that goes undiagnosed because it’s so common, and they don’t necessarily have those criteria.They don’t know their family history for example. And because kidney disease was so undiagnosed until recently, how would if anybody in your family died of kidney disease unless they were on dialysis? So there are some of us who think that there should be population-wide screening. I happen to be in that camp. There have actually been cost effectiveness analyses done, out of Stanford, for example. Economic analysis showing that if you did population level screening, even the cost of an SGLT2 inhibitor, the return on investment would still be in favor of screening, even, even taking that into account.Robert Rogers: And I’ll just say, I’ll just say for our for our listeners, when we talk about screening for kidney disease, it’s, it’s really not all that cumbersome. We’re generally talking about two very, inexpensive and accessible laboratory tests. A blood test that measures how well your kidney is filtering at any given moment in time, and then, a test of the urine to see if you’re spilling protein into the urine. Really, those two are quite powerful. And we call that measuring your estimated GFR and testing for albuminuria. And I guess, just, just a couple questions on the screening front, though. Is there any recommended interval with which you think it makes sense to screen? If somebody has normal kidney function and no protein in their urine when they’re 40, is that a lifetime warranty? Probably not, right? So how frequently would it make sense to even check these things?Katherine Tuttle: Well, we know most is diabetes. So all people with type one, type two diabetes annually. And type 1, five years after diagnosis ‘cause it usually starts early in life and takes a while to accrue. We would say the same for the other high-risk groups, hypertension and cardiovascular disease.But the other really important thing is once it’s detected, you need to be rechecking more often, just like you do lipids or blood pressure, ‘cause you’re gonna intervene, and then you wanna get to some goals. And actually, the goal that we titrate to is albuminuria, and we want to get albuminuria as low as possible. So after it’s diagnosed, we’ll be rechecking every three to six months until they’re on a stable regimen. And then with established kidney disease, we still recommend every three to six months ‘cause it can take off and get away from you pretty quick, and we need to get therapies on board because to quote one of my colleagues, “Time is nephrons.” So with regard to general population screening, we don’t know ‘cause it hasn’t been recommended.So that remains an unanswered question. But people should at least be screened once in my opinion. Yeah. And then, it’s a subject of research, again to continue to evaluate for example, the cost effectiveness and what frequency of testing would remain cost effective. If you’re not in a high-risk group, it might not be every year. It might be every five or every 10 years, but we don’t know that.Robert Rogers: So those are the sorts of things that are gonna have to be better established with population research. But just a couple more questions now along the vein of balancing the great benefits, both in individual and public health with early detection and early intervention of kidney disease with this risk of over-medicalization and creating, patient, anxiety.And I guess I have kind of just a broad, almost philosophical question about this. We have used the three-letter abbreviation probably 15 times on this discussion already, CKD, chronic kidney disease. And just that labeling, kidney disease, can sound alarming, especially to somebody who has no symptoms of kidney disease, as most people don’t until it’s quite until it’s quite progressed. And I’m just wondering if we’re gonna be entering this world where we think it makes sense for a broad swath of the population to find out about their kidney disease risk through screening where there’s a lot of benefit to using these therapies probably at an earlier point to prevent deterioration in kidney function and also to promote overall health and reductions in mortality. Is that terminology, you think, the most helpful framing? Do we need to help, help explain the issue to patients in perhaps a less alarming way?Katherine Tuttle: Well, a couple things, too. I wanna go back to again where we started- Which was my patient who crashed into dialysis and didn’t think there was anything wrong with her except diabetes. And that’s really the problem. And it doesn’t bother us to screen for cancer, which is asymptomatic, right? Because people know that diagnosis is serious, and they need treatment to stay alive and function. It’s, it’s this it should be the same level of urgency. And I don’t think this is over-medicalization. I think it’s health maintenance. Because the most common question that nephrologists get asked is “Why didn’t anybody tell me?”And these therapies can prevent, what’s gonna, what’s about to become the fifth leading cause of death in the world. I mean, this is right up there with the top leading causes. It doesn’t bother us to screen for heart disease or cancer. I think we should be screening for this and I don’t think it’s over-medicalization. Because whether people know it or not or feel it, many people are hurdling toward the abyss without even knowing it. And I’m on the other end trying to catch them and them saying, “How come nobody told me?” So I’m not saying that everyone needs four drugs. There are probably some people who will do fine just on a good old-fashioned ACE inhibitor. But I guess it’s a matter of what you value and what you choose. But if you have diabetes and you’re not getting tested for kidney disease, I mean, you’re really playing, you’re really playing roulette with your life.Robert Rogers: Yeah. I think something you said at the outset is actually an interesting turn of phrase, health maintenance. It’s part of health maintenance. And perhaps, discussing this as a sort of a very common problem that many people encounter for which there are specific risk factors and for which you can be proactive about maintaining is… Perhaps can be less alarming to people than labeling, labeling them as having chronic kidney disease. Although certainly you don’t want to as you’re saying, underplay it and have people not recognize the degree of risk that they carry, especially if they have diabetes or other high risk factors.Katherine Tuttle: Yeah. And in fact, some people in our field have called that renalism, right? Like avoiding it-Robert Rogers: I haven’t heard that term before. That’s an interesting term.Katherine Tuttle: Yeah. Avoiding it because you don’t wanna know about it. And so I think there’s that part of it, too. I don’t think... People have high blood pressure or heart disease, and they manage it, and I think we can do the same with kidney disease. And then back to what I’ve told you, I mean, our therapies are now showing evidence that kidney function can be preserved. And in fact, I’ve also written about prevention of kidney disease. But it will require some form of intervention. You can’t just think it away. And I would say in the area, area of kidney disease, maybe even more we can do to maintain kidney health than maintain health in some of these other areas.Robert Rogers: Yes. That is that is certainly, an exciting, prospect that it... That finding out, these things is much more actionable with the kidney than in many other areas.A few kind of quicker rapid-fire questions to help us close up here. We’ve spent the vast majority of our time with good reason because epidemiologically it accounts for the biggest proportion of kidney disease, about kidney disease that’s really driven by metabolic disease risk factors, diabetes and hypertension.But there are a couple of other forms. And on Foresight Medicine, we’ve had episodes and we talk a lot about genomics, as a general purpose technology that is going to really expand what individualized, personalized preventive care can look like across a variety of diseases. A healthy person today could walk into a genomic screening clinic or get a commercial test and find out their risk of several single gene, monogenic kidney disorders. And I don’t really in the interest of time and complexity, want us to start going through individual kidney genetic disorders. Would just be curious on your thoughts if there are any that you think you would advise a patient, a healthy person who’s kinda doing this screening to learn their risk for where it would actually be actionable and where the utility of finding out about that increased risk would outweigh any sort of anxiety.Katherine Tuttle: Yeah, genetic testing is becoming important. There are two really, major forms of kidney disease. They’re rare diseases, but two that have become, actionable based on genetics, and one is polycystic kidney disease, and the other is APOL1 kidney disease. I think that one is particularly, exciting because it is a genetic variant that is found in people of recent African ancestry and helps, not completely, but partially explain the excess risk of kidney disease and kidney failure in the African American population.And it now, is becoming actionable. There are actually clinical trials going on targeting APOL1 that look very promising. Polycystic kidney disease is another monogenic form, although there are several different types. But similarly, we’re having some major advances for example, using microRNA technologies to restore kidney health and reduce cyst formation. So I think if you have a family history of polycystic kidney disease, the... You definitely should be screened. And with regard to the genetic testing and interventions that’s really in clinical research studies, so I’d encourage people to consider participating in a trial. And same for APOL1, but there it would go beyond just family history, but somebody of African ancestry.Or sometimes on a kidney biopsy, we see a certain diagnosis that we call FSGS, focal segmental glomerulosclerosis. And irrespective of your racial identity, if you have that we recommend APOL1 testing because can’t tell what... By what people look like. There are people who might not identify as African American who have African ancestry. And that too is becoming, targetable, but still in clinical trials. But genomics is very important in kidney disease. We’re also identifying some disorders where there are polygenic risk scores that may become actionable as well. So you’re right, we talked about big chronic diseases. But the really exciting thing is even in our rare diseases, like IgA nephropathy is one, 70 clinical trials going on.We don’t recommend genetic testing in everyone at this point. But for certain, ancestries, family history, or kidney biopsy features, we will do genetic testing if we think it could potentially be actionable or affect prognosis that might influence, the way people think about themselves or their lives.Robert Rogers: Yeah, and just to very briefly touch on maybe that last major category of kidney diseases, and you sort of alluded to it in your answer beyond, genetically mediated ones are diseases where the immune system attacks the kidney. And there are many, many, many of these and again, don’t wanna get into too much detail on any one of them. But just to make the larger point that we recently had an episode of the show where we talked about the early, early identification and interception of the autoimmune disease rheumatoid arthritis. And this idea that the antibodies in rheumatoid arthritis can actually become apparent as many as five years before people have any joint symptoms. And if you can identify them at a certain stage, there’s a lot of research, I don’t, hasn’t, hasn’t quite, hasn’t quite panned out to a to a clear to a clear, defined clinical pathway of what to do. But there’s a lot of research that we could maybe nip the autoimmune disease in the bud and prevent the downstream damage.And just wanted to gauge your sense here, we’re farther away probably from being able to do that for any individual immune-mediated kidney disease. But what I was gonna ask you is one, if you could just briefly comment on that. But secondly, the general tools of screening for kidney disease by measuring the eGFR and protein in the urine, those are actually quite good and will start to pick up problems at a pretty early stage. And if you can’t explain them by the usual things, are a good reason to start a more detailed, immunologic workup. So I was just curious your thoughts on those points.Katherine Tuttle: No, I’m glad you asked that because it’s really important when possible to identify cause as well. So even in people with diabetes for example, they can get other... It’s common and other diseases are common. So a good example would be type 1 diabetes is an autoimmune disease. So a young woman with type 1 diabetes and a high urine albumin who if she also has blood in her urine might have lupus, might have lupus nephritis, right? So we didn’t get into details about diagnosis, but maybe this is a good chance to say that in the context of doing the urine albumin screening or the uACR test as well as eGFR, there should be a conventional urinalysis done as well.Because you won’t know for example, that people have hematuria or other abnormalities in the urine if you don’t look. And so while we recommend UACR screening, our guidelines actually say there should be an investigation into cause. So if the urine sediment is bland and they have typical features of diabetes, you don’t need to do anything else. But what you wanna pick up is that person who might just happen to have hypertension, diabetes and have an autoimmune disease as well. And that’s where I think the urinalysis is really important because in many of those diseases, it’ll either be hematuria or heavier albuminuria that is not explained by the metabolic condition.And that... Again, that’s a larger conversation. And then I also wanna promote the importance of imaging and kidney biopsy in those individuals. So to diagnose polycystic kidney disease, that’s gonna be an imaging test, usually an ultrasound. And then with regard to the immunologic diseases, it’s biopsy.And we find a lot of unexpected findings at the tissue level that we’re not gonna get any other way. And so many of us have moved to becoming much more tissue-based, more like oncology, that part of our routine workup for kidney disease, if it’s not typical for CKM, it does include a biopsy.And I do think to be honest with you, when we do more-- when there’s more awareness on CKM and albuminuria screening, I think we’re gonna pick up more of these rare diseases that are out in the population that we just didn’t see until it was too late before. So I do wanna encourage people to have their eyes open that other kidney diseases may occur. They’re not that rare, even though we call them rare. They’re not that rare in the world of kidney diseases, and we don’t wanna miss lupus, IgA nephropathy, and other forms of immunologic diseases that have now become treatable. And like you said for rheumatoid arthritis, if we identify these immune diseases early, then there’s a lot more we can do about it.But I will walk back to what we where we started, is we’re gonna treat the inciting factor. So let’s say it’s lupus, or IgA nephropathy. We have highly effective therapies now for the immune side, but they’re still gonna need the kidney protective therapies because by the time they’ve taken a hit in that organ, they’re in the box at the bottom again. And those are the progression factors. And even the guidelines now for immunologic kidney diseases say treat the immune disease plus ACE inhibitor/ARB and SGLT2.Robert Rogers: Great way to tie, tie our whole discussion together. Very last question for today. What is one big open question in the field of kidney disease prevention that is currently being studied that you think will have a much better answer to in say, five years or sooner?Katherine Tuttle: I think we need implementation science, frankly. So you said on prevention, so what is the best approach to screening? Do we need to do population screening or stay focused on high-risk groups? And then on the prevention side, getting to precision approaches, can we phenotype people better so that we don’t necessarily need to use all drugs on all patients?I’d like to see us eventually look more like clinical oncology, right? So for example in breast cancer, there’s, biomarkers, there’s tissue, there’s imaging, and then depending on those features, you might end up in a low-risk category with a lumpectomy and have a nice life or at the other extreme, have a bone marrow transplant and be in a clinical trial at about 15 or 20 variations in between.So I think real prevention will be at the time of identification, getting a proper diagnosis, and then being stratified into the right pathway, which might be diet and exercise for some people. Maybe you’re so low risk that you don’t need to take any drugs. Other people might need the full-court press and some new thing, and other people might need various combinations of our pillars.Robert Rogers: Dr. Katherine Tuttle, a great leader in the field of kidney disease treatment and prevention. Thank you so much for joining us today.Katherine Tuttle: Thank you. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe