What's On the Horizon for Polycystic Kidney Disease (PKD)?

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Announcement: 0:00

Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts .Hosted by cardiologist and top medical researcher, Dr. Michael Koren.

Dr. Michael Koren: 0:11

Hello, I'm Dr. Michael Koren, executive Editor of MedEvidence, and I have the great privilege this morning of speaking with a world expert. I have Dr. Fouad Chebib here, who is a world expert on polycystic kidney disease, and I'm really excited about this discussion, Fouad, to talk about how you got to this point, what motivated you, and then break down polycystic kidney disease for the listeners and viewers of MedEvidence! So welcome to MedEvidence, thank you.

Dr. Fouad Chebib: 0:41

Thank you, Michael, for having me. It's a great pleasure.

Dr. Michael Koren: 0:43

And this is fabulous.

Dr. Michael Koren: 0:45

So just start us off. Tell us about how you got to this point. Tell us a little bit about how you grew up, why you became a doctor and, ultimately, how you got really interested in polycystic kidney disease, or PKD We'll use that term.

Dr. Fouad Chebib: 0:58

Yeah Well, thank you again for having me. I mean, every doctor has their own journey, why they picked medicine, why they picked a certain specialty, and mine might be a little bit unique, but also it's not. You probably have heard a lot of stories you know family history of inspiring our physicians to go into their path, but I grew up in Lebanon, a small country on the Mediterranean Sea.

Dr. Fouad Chebib: 1:25

I always wanted to help people, whether through curing something. Always, as a child, I was very intrigued in curing cancer, curing HIV, curing diseases, and I didn't know. I mean, I knew I want to be a doctor, but I didn't know I'm going to become a nephrologist or a PKD specialist.

Dr. Michael Koren: 1:44

Other physicians in the family?

Dr. Fouad Chebib: 1:45

No other physicians in the family. No other physicians in the family. My father is in the flower business, and then wedding events and what have you.

Dr. Fouad Chebib: 1:52

So I grew up doing these in the summertime

Dr. Michael Koren: 1:55

-so you're paving your own path.

Dr. Fouad Chebib: 1:56

Yes, yes. And then you know, one day I was in high school, my dad came and sat next to me and my sister and said I'm about to go on dialysis. So it was a very sudden event for the whole family. He was not sick before and he started becoming uremic, which means kind of buildup of the kidney toxins. So it kind of shaped our whole world. And then going into that, when he started dialysis, starting going to see him in the dialysis unit and seeing how tough it was, he had to kind of continue his work and persevere despite all these challenges. And then understanding more that it was due to polycystic kidney disease. He was the first in the family. So there's about 5% of our patients who have what we call de novo or new mutation, with no other family members.

Dr. Fouad Chebib: 2:48

So it came kind of really as a shock news and so I decided okay, my dad went through a lot of trouble through this, I want to fix it. And the first thing I kind of at the time there was yahoo. com. So you look, there was no Google back then and Mayo Clinic was kind of the go-to place to kind of figure out PKD. And so I said, you know, I was 17 or 18. So I'm going to become a nephrologist, I'm going to come to Mayo to get the expertise and fix PKD,

Dr. Michael Koren: 3:21

-a nd that's what you did!

Dr. Fouad Chebib: 3:22

and that's what I did.

Dr. Michael Koren: 3:23

I love it.

Dr. Fouad Chebib: 3:24

Yes, it took a little bit, a few turns. So I tried to come to the US for med school, but it was very tough for international students to come in. It still is, I think. So I did my med school back in Lebanon. Then I tried to get right away to Mayo Clinic, but also it was very tough not having that expertise to come first. So I came to Boston. I did research for two years in a molecular biology lab.

Dr. Michael Koren: 3:53

Which institute was that?

Dr. Fouad Chebib: 3:54

So it was at Beth Israel Deaconess, Harvard Medical School.

Dr. Michael Koren: 3:57

That's where I did some of my training.

Dr. Fouad Chebib: 3:59

Yes.

Dr. Fouad Chebib: 4:00

So great place, still miss Boston. I stayed there for my intern medicine training at St Elizabeth's with Tufts University program. Then I got the chance finally to get to Mayo Clinic. So I trained as a nephrologist in Mayo Clinic, Rochester. I stayed on on staff to develop my PKD expertise and then three years ago we moved down to Jacksonville to the Mayo Clinic, Florida campus.

Dr. Michael Koren: 4:25

Wow, great journey, great journey.

Dr. Fouad Chebib: 4:27

Yes, thank you.

Dr. Michael Koren: 4:28

So that's fabulous and inspiring. So thank you for that. So you're exactly where you thought you would be in high school, which very few people can say. So it says something about you as a person that you set a plan and you go after it and you get it. So that's terrific, and I think that speaks also to why you've been so successful as now a world-known PKD researcher. So let's break down PKD for our audience. I think obviously people have a sense what kidney disease is, but probably not a good sense for disease. So one polycystic kidney disease. Tell us about the incidence of it, the genetics of it and also a little bit about how referral patterns work. So go ahead.

Dr. Fouad Chebib: 5:17

Yeah, so polycystic kidney disease, as the term implies, is polycystic, so multiple cysts. And cysts are fluid-filled sacs, so the kidney is normally the size of a fist. It's kind of the shape of a bean. You have two of those. They filter the blood continuously throughout the day, regulate the electrolytes, the fluids, the blood pressure, lots of hormones produced by the kidney, a lot of great function of the kidney and you never notice that until the kidney function goes down.

Dr. Fouad Chebib: 5:40

Now, with polycystic kidney disease, instead of the size of a fist, our patients are born with hundreds of these cysts on each kidney, so hundreds of these very small fluid filled sacs. And then with time, as they grow in age, in their teenage and early adulthood, these cysts grow and the kidney grows to become almost the size of a football. So big, big size. It takes big volume. It can cause a lot of symptoms also a lot of weight and pain and what have you. Also, these cysts can have many complications which we will talk about. So it's an inherited disease. The majority of the patients would know someone else in the family who had PKD. So they understand kind of that journey where patients, when they're diagnosed, they kind of understand that in the next few years or depending on when they get diagnosed. Kidney failure is in the horizon. So it's very unique, also as a medical disease in general, that you get the diagnosis and then nothing happens until 10, 20, 30 years later. So also it has its own unique burden on the patients

Dr. Michael Koren: 6:45

-now in the genetics.

Dr. Michael Koren: 6:46

Just to interrupt for a second. Is it autosomal, dominant, recessive, or are there different types?

Dr. Fouad Chebib: 6:51

Yes, absolutely so. In genetics world we divide those into different patterns of inheritance. The common polycystic kidney disease that we always refer to as PKD is the ADPKD or autosomal dominant polycystic kidney disease, which means that you only need the change in the DNA in one copy of the genes. So we always inherit one copy from each parent. So if one of the parents has PKD, there's 50% chance that this parent would pass on that copy to the child. So each child would have 50% chance of having autosomal dominant polycystic kidney disease and if they inherit that copy they will definitely get the disease. So it's what we call fully penetrant. There's other types of PKD autosomal recessive which where the parents don't have the disease, they just carry the gene changes and then 25% chance for each child to have that. Typically it's a childhood disease. Unfortunately our young children with ARPKD. They end up being on dialysis early on.

Dr. Michael Koren: 7:53

And has a breakdown between the autosomal dominant version and the autosomal recessive version.

Dr. Fouad Chebib: 7:59

So the ADPKD is the most common inherited kidney disease. We think one in a thousand of our population might have polycystic ADPKD, as compared to ARPKD, which is rarer one in 20,000. So let's say in the US 350 million, so 350,000 patients with ADPKD.

Dr. Michael Koren: 8:20

-so it's still it's a number.

Dr. Fouad Chebib: 8:22

Yes, so it's the most common inherited kidney and even if you compile all the other rare diseases, it might be as common as all the other common diseases that we a lot of people know about, like cystic fibrosis and other things. So one in a thousand. Some other studies may be a little bit less, but that's usually the typical.

Dr. Michael Koren: 8:42

So focusing on the autosomal dominant version, which is the most common version, give us a little sense for how prognosis works.

Dr. Fouad Chebib: 8:50

Yeah. So with ADPKD again, a lot of times we don't have these symptoms. So patients usually grow. They don't know that they have ADPKD Very rarely. They have very early onset disease where they start getting a lot of symptoms, where these cysts either burst and they see a lot of blood, so what we call gross hematuria, or they have cyst infection. The typical is patients grow in age, they start having high blood pressure. Then their physician look at their family history and they say, oh yeah, my parent has PKD or got on dialysis. Then they do a kidney ultrasound so they get screened for PKD and they end up having the diagnosis and the typical trajectory is kidney function remains normal for the most part until the 20s and 30s and then later on it starts declining year after year and it depends on the severity.

Dr. Fouad Chebib: 9:48

So in terms of prognosis it's considered a relatively good prognosis in general. If we take the big picture, we've done studies in Mayo Clinic Rochester where we looked at all PKD patients and the general population in Minnesota and the survival was the same between the two groups. So meaning our ADPKD patients If they have healthcare and they take good care of themselves, they should live normal life. However they would be expected. The majority of the patients would be expected to have kidney failure. So that does not happen regularly at the same time for all the patients and even within the same family there can be some variability, so it's a spectrum. We think that patients might reach kidney failure in their 30s up till their 80s, and then there's a small group that they will never reach kidney failure. They might have some chronic kidney disease but not kidney failure.

Dr. Michael Koren: 10:39

If the history runs its natural course, people will eventually get on dialysis somewhere between 30 and 80, with 50s being typical for most people.

Dr. Fouad Chebib: 10:49

Yeah, so half of our patients would reach kidney failure by age 60. That can vary between the cohorts, between the US, europe, other places, but if you reach to 60 and you haven't reached kidney failure, you're better than half of ADPKD patients.

Dr. Michael Koren: 11:05

-and obviously dialysis is something we do to take over the filtering function of the kidneys. How about the other functions of the kidneys? Are they affected by PKD and how do you have to deal with that?

Dr. Fouad Chebib: 11:15

Yeah, so early on. Again, the high blood pressure is controlled by the kidney, but also these proteins are in the blood vessel. So blood pressure can be high even if the kidney function is normal and even if the kidneys are not that enlarged. Then later on that creatinine number, the blood test, starts rising, which tells us that the GFR, the kidney function, is declining. And if the kidney function goes down to the 8% to 10% or milliliter per minute, then we need to replace the kidney function through dialysis and preferably through a preemptive kidney transplant and preferably to delay this as much as we can. And that's kind of the focus of our research. We'll talk a lot about how we can push someone who was supposed to get kidney failure in their 40s like my dad, early 40s how can we give them maybe five more years, maybe 10 more years on their kidneys and have all these milestones in life which is huge not to be on dialysis or needing transplantation.

Dr. Michael Koren: 12:08

Right and other types of complications of kidney disease in general are anemia, for example? Yes, is that relevant for PKD patients?

Dr. Fouad Chebib: 12:18

Yeah, like any other chronic kidney disease patients as their kidney function goes down, these other functions of the kidney, so not only the electrolytes and the potassium being filtered and the water and the blood pressure, but also there's other hormones that regulate the red blood cells. So there's anemia. That kind of occurs at advanced stages of chronic kidney disease and that occurs same as in PKD. So in these situations we need to make sure that you have the iron stores and then they potentially we need to give them injections under the skin to replace the stimulating hormone to kind of stimulate the bone marrow to produce red cells. And the other function is regulating the parathyroid hormone, which also helps us regulate the calcium, phosphorus and the bone health.

Dr. Fouad Chebib: 13:05

And that's also the responsibility of the kidney. So definitely a lot on the shoulders of these small two organs, or, in the case of PKD, these big two organs.

Dr. Michael Koren: 13:14

So you're diagnosed with PKD but you're not symptomatic yet. What do you do to treat it at this stage? We'll get into some of the research elements in a second. But with current technology, what's done?

Dr. Fouad Chebib: 13:26

Yeah, so the current standard of care, which also has been recognized by international guidelines. We got our first guidelines in PKD just this January 2025. So there's a kind of what we call basic optimized management and we define this as making sure that you're the healthiest possible to slow your disease process as much as you can. So that entails keeping your blood pressure under very, very good control, maybe much tighter than the general population. So we give numbers like 110 mmHg, over 75 for those who we would think they would advance faster. We want them to hydrate a lot because vasopressin or the thirst hormone stimulates these kidney cysts to grow. So we want them to hydrate very, very well, meaning kind of 3 to 3.5 liters, so like 100 ounces of fluids throughout the day. We want them to cut the salt in their diet because that's not only helps us with blood pressure control but helps us suppress the vasopressin or the thirst hormone much easier with less water. And then we want them not to gain weight. So body mass index is key to keep it on the normal level. There's a lot of studies showing that if we gain weight, our cysts are gonna grow faster, our kidney function is gonna decline faster.

Dr. Fouad Chebib: 14:47

And then we look at all the other things that come with chronic kidney disease. So that's for all the patients. Now there's about two-thirds of the patients. We think they're gonna reach kidney failure by age 60. And that's defined by guidelines and by us that these patients are at risk of rapid progression, which means, again, they're at risk of needing dialysis or transplantation by age 60. We're now trying to push to treat more patients who reach even by 65, because we think you need to push even longer for these patients. So in these situations there's an FDA approved treatment that has been approved since 2018. It's called Tolvaptan or Jynarque. It blocks the effect of vasopressin, that thirst hormone. So this medication goes and blocks that receptor and then studies years over years have shown that it slows the disease progression.

Dr. Michael Koren: 15:45

Yeah, and just an aside, we did some of that work here in Northeast Florida. Quite a bit of it actually. Yeah, absolutely.

Dr. Fouad Chebib: 15:51

It was very interesting because it was the first trials in PKD and it paved the way hopefully now for many, many new other treatments. Now this treatment that's approved, not all the patients are eligible for it in terms of risk and benefit. It does come with risks, especially with the liver enzymes. We have to check those on a monthly basis for the first year and a half and then every three months. Then also the patients are gonna, because we're blocking the effect of the thirst. Then the kidney thinks it needs to make a lot of urine. So our patients are gonna make five to six liters of urine and then our patients have to keep drinking the fluid, the same amount of fluids or even more. So that comes with kind of what we call on target effect. But for patients, they feel it as a side effect that they're very thirsty, they're drinking tons of fluids, they're going to the bathroom a lot.

Dr. Fouad Chebib: 16:40

However, a lot of patients tolerate that, adapt to that and they see a lot of benefit. But not all the patients are able to tolerate it. So now we need definitely more treatments and more advances to slow it as much as we can.

Dr. Michael Koren: 16:54

So many questions, so that was an amazing summary, but it triggers a number of questions in my mind. So you mentioned about potentially diagnosing people at a younger age and obviously, because it's a genetic illness, you could screen offspring of people. Is there any advantage to that? Is it important to know that a five-year-old has the disease, and how do you change their course and their trajectory?

Dr. Fouad Chebib: 17:18

Yeah, at the moment we don't recommend to screen kids less than 18, because even if we know there's not anything different that we can do, in a sense that there's no big clinical trials that can go they can go to, at least not yet, and then there's no FDA approved treatment for patients who are not adults. So for younger patients we say to the family establish a healthy lifestyle in your house. So make sure you, you know you, you encourage them and develop this habit of drinking fluids, avoiding non-steroidal anti-inflammatories unless it's really necessary. Make sure they don't gain weight, they don't smoke, so all these things are important to become a habit and natural habit for them. And then also we advise them to tell their pediatrician that there's a family history of PKD. So then their blood pressure is checked very carefully and if there is high blood pressure, which could be the case, then just treat it as such and then wait until they're an adult age, then discuss when it's the right time to be screened and get diagnosed.

Dr. Fouad Chebib: 18:17

But definitely for our patients who are 18 and above or individuals at risk. So anyone who has family history of ADPKD and there are 18 or above they should start talking about. Okay, should I go get screened?" Talk to my doctor, get the kidney ultrasound and the only caveat to getting screened early is there might be a risk of not getting a life insurance. So they need to kind of consider that and then either get a life insurance before going and getting screened. But the earlier the diagnosis, the earlier we start treatment, the earlier they're proactive about their health, the more benefit they're gonna have. But it's definitely there's no kind of one answer for everybody, because some of our younger folks they need to go through college and they need to pass through some milestones in life before they get this big diagnosis, so it's very different for each of them.

Dr. Michael Koren: 19:09

It's a heavy burden psychologically.

Dr. Michael Koren: 19:11

Yeah understood.

Dr. Michael Koren: 19:13

So you mentioned the vasopressin antagonists and we'll call them Vaptans to make it easy. I know there was a number of them that are being studied. Are there others on the market now other than Tolvaptan?

Dr. Fouad Chebib: 19:25

So Tolvaptan just or Jynarque just, became generic. So there's other genetic forms. There's early studies on other types of Vaptans. There was one that was about to go into larger clinical trials but they stopped doing that. The main kind of benefit of these other Vaptans is trying to see if they don't affect the liver and so there's less need to do all these monitoring, so less burden on the patients. But all the Vaptans will have the same effect of drinking a lot of fluids because that's how they work. So there's potentially other formulations, maybe longer acting, maybe there's other types of Vap tans. For example there's a study on snake venom that can cause, that, can kind of simulate-

Dr. Michael Koren: 20:10

-through a vasopressin mechanism?

Dr. Fouad Chebib: 20:12

Yeah, it's like a peptide that kind of blocks the vasopressin.

Dr. Fouad Chebib: 20:15

But they're still very early in.

Dr. Michael Koren: 20:17

And are there any other classes of drugs that are specifically approved for treating polycystic kidney disease?

Dr. Fouad Chebib: 20:23

So other than blood pressure control, which we favor, the first line is ACE inhibitors or ARB. Those are kind of the first class types of blood pressure medications. The only FDA approved treatment is tolvaptine, and the others are still in clinical trial.

Dr. Michael Koren: 20:39

So the classes of blood pressure medicines that you mentioned ultimately block a hormone called angiotensin II and that has specific effects on the cysts, or just general good for reducing proteinuria and things like that.

Dr. Fouad Chebib: 20:52

Yeah, so with PKD we expect very little bit of proteinuria, so less than one gram, but the main effect is. So there has been a lot of hypothesis, a lot of studies, that blocking the pathway of the angiotensin pathway could slow the disease progression and that led to a very large study within the US called HALT PKD, H-A-L-T, P-K-D and trying to look at giving two types, so the ACE inhibitors and the ARV together, and also targeting much lower blood pressure target. So one arm was 110 over 75 or less, actually between 95 to 110, and then the other was the 120 130 and the study was called negative but the p-value was 0.05. Okay, and what was significant is that in the group that was treated much aggressively on the blood pressure target of 110 over 75, the kidney volumes or the cysts grew a little bit less faster, so 6% versus 5%. It was significant statistically and that's where the recommendation now from PKD goes for patients who are younger and at risk of rapid progression, let's target 110 over 75.

Dr. Michael Koren: 22:04

Got it. So just for the lay audience out there. We got a little technical there with p-values and things, but it was a borderline study. But the gestalt is that there's probably some value to go lower and use the class of drug that blocks the angiotensin pathway.

Dr. Fouad Chebib: 22:20

Right, yeah, so as long as they tolerate it, we think there is some benefit, although it's not substantial and we could improve it in trials. It's still a good idea to keep the blood pressure lower for these patients, as long as they tolerate it.

Dr. Michael Koren: 22:33

Got it. You mentioned a little bit of dietary things. Any other words of wisdom for people in terms of how strict they need to be with their diet if they have PKD problems?

Dr. Fouad Chebib: 22:44

Yeah, there's a lot of interest from our patients and from the scientific community on interventions on diet. Now it's very interesting for PKD we think it's a metabolic type of disease, so there's issues with the mitochondria, the powerhouse of the cell, where in PKD that's affected, and so we think that if we do some interventions on the diet we can reprogram how the kidney cells are using the energy in a little bit more efficient way, because right now with PKD I think it's not as efficient. So there's a lot of studies on ketogenic diet, on giving some either medical food or other compounds to kind of reprogram the mitochondria. So all these are still in clinical trials. There's a lot of studies under what we call preclinical, so animal models who have PKD.

Dr. Fouad Chebib: 23:40

They were given these interventions, either restricting calories or do ketogenic diet or do some beta-hydroxybutyrate, which is kind of the ketogenic form that is given as a supplement. So all these were positive in animal models. There's not a lot of big trials in humans. So we came up actually with what we call the PKD diet and we said there's a lot of evidence that if you're overweight your disease is gonna progress faster. So let's bring down that weight. And the most efficient way, or the safest way that is now for other weight loss, is to do caloric restriction. And even if you cut down by 10 to 20% of your calories and keep your body mass index close to that 20 to 25 range, then you're probably gonna gain a lot of benefit years. The other restrictions become. We don't like to restrict protein unless the kidney function is low, so that's something that we-.

Dr. Michael Koren: 24:38

Yeah, that's a little bit of a trade off, because in kidney disease. We often talk about restricting protein, but it sounds like that may not be the right thing, by and large, for your patients.

Dr. Fouad Chebib: 24:46

Yes. So if the kidney function is above 30 milliliter per minute or for patients they think it's 30, or they know about it as 30% then we could go... we don't have to restrict too much. So 0.8 gram per kilogram of protein up to 1.3 gram per kilogram per day If their kidney function is less than 30, then we start doing some more restrictions. If they're on dialysis, it's completely opposite. We want them to be on because they get malnourished and they lose a lot of the energy and the protein. We want them to be on heavy protein.

Dr. Michael Koren: 25:16

Right, so complicated.

Dr. Fouad Chebib: 25:18

Yeah, so in each stage it's different. So the best thing is, if they start seeing a lot of these restrictions, is to talk to a PKD dietician or a renal nephrology dietician and they can guide them through these other restrictions. And as the kidney function goes low, we restrict potassium, phosphorus, other things, but sodium. Water weight is kind of key early on in life.

Dr. Michael Koren: 25:41

Right. So we're both research people and we like to look at the future. We perceive that part of our role as physicians is not only to do what's known today, but to figure out what to do for tomorrow. So give us a little insight into what people are thinking about in terms of what we're going to do tomorrow for people that have PKD.

Dr. Fouad Chebib: 26:02

Yes. So it's very, very exciting in PKD in 2025, 2026, because all the scientific advances that happened over the 10 to 20 years, mostly over the last five to 10 years, has now culminated into things that we could start testing in humans, not only kind of talk about it in the papers and in animal models, right. So all this kind of work now it's almost at the same time coming together. There's also interest from industry or pharmaceutical company where they did a lot of the research and development. They took all the other academic scientific work and moved it on to potential new treatments, and so definitely there's a big unmet need. There's a big gap in taking care of our patients because, yes, we talk about how we keep them healthy, but we haven't talked about how to completely prevent kidney failure. So completely preventing kidney failure, that's my lifetime goal. Dream is when patients come to me I'm like, okay, we're gonna do this, this and this and you don't have to worry about dialysis, transplant. We're not there yet. I keep promising my patients and our community.

Dr. Fouad Chebib: 27:15

Five to eight years maybe is kind of my goal, and by that we talk about gene therapy, about cures, and that's gonna happen. We have a lot of initiatives. At Mayo Clinic Florida, for example, we have now an organ perfusion studies unit that I co-direct and we're working on gene therapy.

Dr. Michael Koren: 27:32

Organ perfusion, explain that a little bit.

Dr. Fouad Chebib: 27:42

So usually when we take a kidney out, from a deceased donor goes in a what we call cold perfusion. So there's just kind of a pump that keeps the fluid or liquid kind of going through the kidney, but it's on a cold temperature and the fluid is very primitive, was created 30 years ago and so that leads to these kidneys to kind of not be as happy and then it goes into the recipient, the patient who needs that organ transplant, and usually that kidney doesn't work well right away. It takes some time, so there's some injury or kind of issues that happen with the tubules of these kidneys. So what we're trying to create is to perfuse the kidneys or livers and keep them metabolically and physiologically active. So we want to keep these kidneys that we take out, that were not good enough to go and get transplanted in a patient, put them in our perfusion system.

Dr. Fouad Chebib: 28:32

That's warm perfusion with new liquid new fluids and a system that keeps that kidney making even urine for almost three days and by doing that it becomes a platform to test gene therapy or other rejuvenating, anti-aging kind of processes. Doing the same for the liver for two weeks for the liver.

Dr. Michael Koren: 28:54

So there's thoughts that we can eventually fix the gene that's responsible for the problem.

Dr. Fouad Chebib: 28:59

Yes, so, as you know, with gene therapy now it became also extremely advanced over the past 10 years. You know you can go in and just kind of edit one change in the DNA and there is a lot of therapies that are now well, there's FDA approved therapies for gene therapy. The kidney is quite challenging, so one is, the kidney protects itself. So it's very hard, very challenging to get these vectors, whether it's a virus or something non-viral vectors, to go and deliver these tools to fix the kidney, the cells.

Dr. Fouad Chebib: 29:35

So the first thing is how can we get it to the kidney? And then how can we get it to the right place in the kidney, and then what is within the package, what should go into the kidney? So these three things if we kind of overcome and I think technology is helping us how to deliver directly to the kidney, there's kind of almost like a bypass on the kidney. Uh, you know, while the kidney is still in the body we can perfuse it for two hours not affecting the other organs interesting and deliver this. There's a lot of advance on the vectors, on how to deliver and then understanding the genetics. Now there's also more advances on what should go in and get fixed. Like what is that tool? So hopefully, with lining everything together, that's kind of my dream is to start doing these procedures where patients come in early, even at younger age, at 12, 15, will go in, fix one kidney, come back in a month, fix the other kidney.

Dr. Michael Koren: 30:30

Cool.

Dr. Fouad Chebib: 30:31

This is the dream right so hopefully we'll do a podcast in five to eight years and we'll be talking about that.

Dr. Michael Koren: 30:36

Sounds great.

Dr. Fouad Chebib: 30:37

But that's still fish in the sea.

Dr. Michael Koren: 30:39

-but you created a model to start studying some of these things,

Dr. Michael Koren: 30:42

It sounds like so, a scientific model.

Dr. Fouad Chebib: 30:44

-a big investment from our institution.

Dr. Michael Koren: 30:47

And between now and then there may be some approaches. I know one of them has to do with growth factors. Just briefly mention that or any others that look particularly promising in sort of the short to intermediate term.

Dr. Fouad Chebib: 30:59

Yes, absolutely.

Dr. Fouad Chebib: 31:00

So before we reach the stars we still have some relatively low hanging fruits. So in any disease we wanna slow it down if we cannot completely prevent it. So we don't want the perfect to be the enemy of very good. So the very good that's now in the next three to five years it's going into clinical trials and there's a lot of science and great science actually behind it. So there's multiple things that are now ongoing.

Dr. Fouad Chebib: 31:27

So you know, think about these kidney cysts. So in addition to that, vasopressin or the thirst is stimulating the fluid secretion. Also, these cells are kind of proliferating or they're kind of doubling up with time. So then you can create this structure right. It's almost like a benign, mass, benign tumor. It's growing, it's filling fluids but also it's growing in size. So if we can find something that's tolerated, that's almost like stops the proliferation or the growth of these kidney, it would be perfect, right?

Dr. Fouad Chebib: 32:00

So with studies actually done at Mayo Clinic, Florida with Dr. Eduardo Chini, he found out he was working, he's actually a scientist, a physician, and a scientist works on anti-aging processes and he found through the anti-aging process that there's a growth factor that if you target it you stop PKD from growing. So if you create, for example, an antibody that prevents the cleavage or the, so let's kind of step back. So you have kind of a growth factor, you have a receptor. That receptor, if it gets stimulated, the kidney is being stimulated, so it's Insulin Growth Factor Receptor. Now for that to be stimulated it kind of comes as like a key and like a two pieces, and if those two pieces are still together then you cannot stimulate the growth factor. So naturally there's something that comes and breaks them apart and then it stimulates the growth factor.

Announcement: 33:03

That's the natural physiology.

Dr. Fouad Chebib: 33:03

So how can you fix it for PKD? Is you prevent this from kind of opening up and then there's no more growth factor free to be stimulated, and so that's science started, actually.

Dr. Michael Koren: 33:17

Interesting, very cool and, just as a little tease, this type of approach to treating PKD may be coming to a clinical trial center near you in the near future.

Dr. Fouad Chebib: 33:29

Absolutely

Dr. Michael Koren: 33:30

And we'll leave it at that until we're ready to talk more about that. Absolutely, yeah.

Dr. Fouad Chebib: 33:34

What I tell my patients is actually. It's extremely exciting that we have a lot of options. Again, some patients don't tolerate Tolvaptine. They cannot be on Tolvaptine because they have work. They cannot be in bathroom breaks every so often, so that gives them a lot of options and there's a lot of studies behind this and we hope that it's safe.

Dr. Fouad Chebib: 33:56

We think it's safe.

Dr. Michael Koren: 33:58

Any other approaches other than the growth factor approach that people should know about?

Dr. Fouad Chebib: 34:02

Yeah. So there's other kind of approaches as well. So there's what we call anti-microRNA. So with PKD, again one copy is not working, one copy of the gene, so that DNA is defected. So the protein that's supposed to be made out of that copy is what we call less functional. So there is less of this polycystin, one protein or polycystin two.

Dr. Fouad Chebib: 34:30

So these are the proteins that if you have less of, then the kidney starts making the kidney cyst. So there's an approach where you know just also stepping back. So DNA goes to messenger RNA, then goes to protein. So typically in a natural way the cells are making these messenger RNA and then they're degrading them or they go away. You make more and so forth. There's a process where it comes and particularly for the PKD1 and polycystin1, it stops that messenger RNA from being degraded. So you keep kind of the machinery and the factory. You overwork almost your other parents.

Dr. Michael Koren: 35:09

Gotcha.

Dr. Fouad Chebib: 35:09

And then you make more of these.

Dr. Michael Koren: 35:11

So it's sort of the opposite of small interfering RNA. This would be small, accelerating RNA yeah anti-microRNA.

Dr. Fouad Chebib: 35:18

Yeah, so exactly, yes, exactly. So you're kind of making more of that protein Interesting. That's the concept. It went through the first phase of phase 1B Interesting and it's going into phase 3.

Dr. Fouad Chebib: 35:30

So that's one option.

Dr. Fouad Chebib: 35:33

And then there's another set of treatments. That's also very exciting, but it will only right now, for the first part, it's gonna be only for 10% of patients with specific area where they have the PKD1 mutation. So PKD1 is one of the largest genes in our body and it's a big protein. But if some of these mutations or these changes in the DNA, the protein, what happens is it gets misfolded and stuck in the endoplasmic reticulum. So almost like you make it in the factory but you cannot get it up and get it to your home, uh, to your location. So if that's stuck there, there's some uh medications that called are called correctors. So it kind of tried to unfold it and then sent and patched it up just to go there. So there's, those are going to come into trials also. End of this year.

Dr. Fouad Chebib: 36:28

It's gonna be an oral medication and it's only a small portion of patients. So again, a lot of excitement. Not all these options are for all the patients. So what's exciting to me in clinic is when I see our patients, I give them the option of the standard of care first. This is what we need to do. If you're eligible for tolvap, then let's try it. If you don't feel this is the right thing, we definitely need to go to clinical trial, and that's how we advance, not only for our patients but, also for their kids.

Dr. Fouad Chebib: 37:01

And that's the unique thing about PKD they're always motivated because not only for them they want to fix this for their kids.

Dr. Michael Koren: 37:07

Sure, and you follow a lot of PKD patients.

Dr. Fouad Chebib: 37:11

We do. We have one of the largest clinics in the country and it's very exciting. So we have a kind of process where our patients come in. We have myself, our co-director, Dr. Mao, and then two of our nurse practitioners and we follow quite a large number.

Dr. Michael Koren: 37:28

Wow,

Dr. Michael Koren: 37:29

Very nice. Well, this has been a fascinating discussion. Thank you so much for sharing all your knowledge. It's been amazing. I've learned a tremendous amount and it looks like we're on the precipice of a lot of really exciting things in this space and I'm looking forward to being part of these advances hopefully in the very, very near future, but a lot of different ways that we may be able to impact the lives of people that have this interesting, slowly, progressive but inevitable disease and change that pathway.

Dr. Fouad Chebib: 38:00

Absolutely. This is very exciting times. Thank you for having me and for shedding the light about PKD and for all of our listeners. If you know anyone with PKD, make sure they know there's a lot of advances, so don't stay at home. There's a lot of things you can do about your disease.

Dr. Michael Koren: 38:14

And we'll have some information about how to get in touch with you, specifically because you're a great clinician as well as a great researcher, and how to get in touch with us in terms of research opportunities Absolutely researcher and how to get in touch with us in terms of research opportunities, absolutely so. Thank you again for being part of MedEvidence. Thank you for having me.

Announcement: 38:27

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